Skip to main content

Main menu

  • Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Info for
    • Authors
    • Reviewers
  • About Us
    • About the Ochsner Journal
    • Editorial Board
  • More
    • Alerts
    • Feedback
  • Other Publications
    • Ochsner Journal Blog

User menu

  • My alerts
  • Log in

Search

  • Advanced search
Ochsner Journal
  • Other Publications
    • Ochsner Journal Blog
  • My alerts
  • Log in
Ochsner Journal

Advanced Search

  • Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Info for
    • Authors
    • Reviewers
  • About Us
    • About the Ochsner Journal
    • Editorial Board
  • More
    • Alerts
    • Feedback
Review ArticleReviews and Contemporary Updates

Cardio-Oncology: A Focused Review of Anthracycline-, Human Epidermal Growth Factor Receptor 2 Inhibitor–, and Radiation-Induced Cardiotoxicity and Management

Jean Domercant, Nichole Polin and Eiman Jahangir
Ochsner Journal September 2016, 16 (3) 250-256;
Jean Domercant
1Department of Internal Medicine, Leonard J. Chabert Medical Center, Houma, LA
MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nichole Polin
2Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA
3The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
MD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eiman Jahangir
2Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA
MD, MPH, FACC
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • References
  • Info & Metrics
  • PDF
Loading

Abstract

Background: Cardio-oncology is a collaborative approach between cardiologists and oncologists in the treatment of patients with cancer and heart disease. Radiation and chemotherapy have played a major role in the decreased cancer-related mortality achieved in the past 2 decades. However, anthracycline-, tyrosine kinase-, and radiation-based therapies are each associated with independent cardiovascular (CV) risks, and these risks are cumulative when these therapies are used in combination.

Methods: We analyzed several published articles, studies, and guidelines to provide a focused review of cardiotoxicity associated with anthracyclines, human epidermal growth factor receptor 2 inhibitors, and radiation therapy and its management.

Results: The focus on CV risk among individuals being treated with cardiotoxic agents is important because once the cancer is cured, CV disease becomes the number 1 cause of death among cancer survivors. Cardio-oncology focuses on assessing CV risk prior to starting therapy, optimizing modifiable risk factors, and providing surveillance and treatment for any early signs of cardiotoxicity in patients undergoing radiation and chemotherapy. A collaborative approach between oncologists and cardiologists is integral to the optimal care of patients with cancer. Although radiation and chemotherapy treatments have evolved with the aim of targeting cancer cells while having minimal effect on the heart, the increased risk of cardiomyopathy in patients receiving these treatments remains significant.

Conclusion: Proper screening and treatment of cardiotoxicity are essential for patients with cancer. As cardiac diseases and cancer remain the first and second causes of mortality in developed nations, respectively, cardio-oncology is the answer to this group of individuals who are especially vulnerable to both causes of mortality.

Keywords
  • Anthracyclines
  • cardiotoxicity
  • heart failure
  • radiation
  • trastuzumab

INTRODUCTION

Cardio-oncology is an integrative medical approach that involves close interaction between cardiologists and oncologists with the goal of mitigating cardiac risk and providing optimal care to patients who will be receiving cardiotoxic agents. This collaborative approach aims to address 3 general emerging factors that affect cancer survivors. First, virtually all antineoplastic drugs and radiation therapies are potentially cardiotoxic.1 Second, patients with preexisting cardiac abnormalities are especially susceptible to chemotherapy and radiation-induced cardiotoxicity. Third, even when antineoplastic therapy is not the main culprit of cardiomyopathy (CMY), the decreased cancer-related mortality achieved in the past 25 years has inadvertently increased the prevalence of cardiovascular (CV) diseases among cancer survivors.

Chemotherapy-induced cardiotoxicity is often categorized in 5 major groups: (1) cardiac systolic and diastolic dysfunction, (2) arrhythmias, (3) pericardial disease, (4) repolarization abnormalities (QT prolongation), and (5) ischemia.1 Radiation therapy is associated with coronary artery disease, as well as fibrotic changes to cardiac valves, the myocardium, and the pericardium.1 As is the case for neoplastic cells, rapidly dividing normal cells are targeted by antineoplastic treatments. Abdominal discomfort, for instance, is a recognized side effect of chemotherapy linked to the speed of cell turnover in the gastrointestinal tract. Unlike the gastrointestinal system, however, some CV cells have limited regenerative capabilities. Consequently, the CV system is susceptible to long-term damage from antineoplastic agents.2

To address the relatively new problem of cardiotoxicity in patients with cancer, several institutions have created cardio-oncology departments focused on managing the cardiac risk factors and diseases among cancer patients and survivors. As of 2015, there were at least 49 cardio-oncology departments in the United States, with our clinic at Ochsner Medical Center being the first in Louisiana. This combined approach allows for additional screening of CV disease prior to initiating radiation or chemotherapy, prompt evaluation and treatment once cardiotoxicity is observed, and adequate monitoring for late symptoms. The International CardiOncology Society and the online journal Cardio-Oncology have been formed to increase awareness and information regarding cardio-oncology.

We discuss anthracycline, human epidermal growth factor receptor 2 (HER2) inhibitor, and radiation therapy cardiotoxicity and its management to provide a basic understanding for other institutions planning to form a cardio-oncology clinic.

ANTHRACYCLINES

Anthracyclines are antibiotics that promote DNA damage. This group, which includes doxorubicin, is found in the soil of Streptomyces bacteria. Anthracyclines were introduced in the 1960s and remain a major component of many chemotherapy regimens, including those for lymphomas, breast cancer, and small cell lung cancer. Anthracycline-induced CMY can occur at any time during treatment. Acutely, most patients present with arrhythmias, whereas congestive heart failure appears to be the most common chronic presentation.3 While acute cardiotoxicity has been a known reversible side effect for decades, chronic cardiotoxicity of anthracyclines is a relatively new challenge. Moreover, acute symptoms are relatively rare compared to chronic complications. For example, in a trial that included 1,697 individuals, only 3.2% of trial participants developed acute symptoms that included atrial fibrillation, acute heart failure, myocarditis, and myocardial infarction,3 whereas, in the now-famous study by Lipshultz et al published in 2013, two-thirds of asymptomatic patients with a history of childhood chemotherapy were found to have progressive CMY.2 Therefore, while monitoring in the peritreatment period is important, chronic monitoring, particularly of childhood cancer survivors during adulthood, is important.

The strongest risk factor for anthracycline-induced CMY is the cumulative dose (Table 1). The risk of doxorubicin-induced CMY increases significantly with doses >550 mg/m2.4 Weaker risk factors, such as age, hypertension, diabetes, previous heart disease, concurrent treatment with other chemotherapy agents, hematopoietic cell transplantation, host susceptibility, and previous radiation therapy, are, however, clinically relevant.5,6 For example, the probability of developing heart failure at a cumulative dose of 550 mg/m2 was 0.07% in one study, while in patients >64 years, a 29% increased risk of congestive heart failure occurred with any doxorubicin dose.4,7 Finally, hypertension has been reported as the only synergistic risk factor with doxorubicin for the development of congestive heart failure.7

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table 1.

Risk of Cardiotoxicity Associated With Chemotherapy

The mechanism of injury of doxorubicin has long been thought to be secondary to formation of doxorubicin-iron complexes that catalyze the generation of free radicals. Free radicals, in return, interfere with mitochondrial function inside the myocardium, resulting in decreased contractility of the heart.8 Additionally, the oxidative stress causes lipid peroxidation, vacuolation, and myocyte death.9,10 Doubt about this hypothesis has, however, been raised by at least 2 studies that failed to prevent doxorubicin-induced cardiotoxicity with the use of reactive oxygen species scavengers.11,12

An alternative hypothesis suggests the involvement of the enzyme topoisomerase-II.13,14 Topoisomerase-II-alpha (α) is a known marker of rapid cellular proliferation that is overexpressed in tumor cells,15 while topoisomerase-II-beta (β) is prevalent among all cells.16 The mechanism of action of doxorubicin has been described as the binding of the drug to DNA and topoisomerase-II (doxorubicin has affinity to both the α and β types) to form a cleavage complex that promotes cell death.17 Adult mammalian cardiomyocytes only express topoisomerase-II-β.18 As previously stated, however, doxorubicin interacts with both types of topoisomerase-II. In the case of topoisomerase-II-β, the resulting topoisomerase-doxorubicin-DNA complex breaks DNA strands and thereby causes cardiac cell death in a fashion similar to tumor cell death. This alternative hypothesis has been supported by animal studies that show the deletion of the gene that encodes topoisomerase-II-β is protective against doxorubicin-induced DNA damage and, consequently, prevents progressive heart failure.15 Interestingly, dexrazoxane, a drug that chelates iron and prevents hydroxyl radical formation in the presence of anthracyclines, has been shown to be cardioprotective, thus lending support to the classic mechanism of action.19 However, some studies suggest dexrazoxane may be involved in topoisomerase-II-α–dependent cell death while depleting topoisomerase-II-β.17,20 Therefore, an alternative explanation of the cardioprotective effect of dexrazoxane is the prevention of doxorubicin binding to topoisomerase-II-β.16

TRASTUZUMAB

Trastuzumab (Herceptin) is a monoclonal antibody that targets the HER2. HER2 normally helps in growth, proliferation, repair, and control of abnormal cells.21 HER2s are found in up to 30% of breast cancers and are associated with an increased risk of brain metastases, a decreased response to hormonal therapy, an increased risk of recurrence, and death.21-23 Treatment with trastuzumab for 1 year after standard chemotherapy has been shown to improve outcomes in patients with HER2-positive breast cancer.24

Asymptomatic decreased left ventricular ejection fraction (EF) is the most common trastuzumab-associated cardiotoxicity. In contrast to anthracycline-induced cardiotoxicity, trastuzumab cardiotoxicity is not dose dependent, is often reversible, and does not show typical anthracycline-induced myocyte cell death on biopsy.25-27 Concurrent or previous use of anthracyclines and age >50 years have been reported as the main risk factors in multiple studies (Table 1).28-32 Risk factors such as radiation, diabetes, valvular heart disease, or coronary artery disease do not appear to be associated with an increased risk of trastuzumab-induced cardiotoxicity.31,33-35 Trastuzumab binds to the extracellular domain of HER2 and inhibits the activation of intracellular tyrosine kinase.36 Several mechanisms of action have been proposed for trastuzumab. For instance, several studies report that trastuzumab cleaves the extracellular domain in targeted cells and promotes cell death via antibody- and complement-dependent pathways.37-39 Trastuzumab's mechanism of injury is not clear, but several studies suggest involvement of HER2. One hypothesis is that myocytes depend on HER2 activation to induce a repair mechanism when responding to stress.40 Consequently, the blockage of this repair mechanism in the presence of anthracyclines leads to cardiotoxicity.23 This hypothesis may explain the increased risk of cardiotoxicity associated with the concurrent use of trastuzumab and anthracyclines. Other studies suggest a direct cardiac effect from HER2 downregulation, a hypothesis that is supported by elevated HER2 levels in patients with chronic heart failure.23,41

RADIATION

The impact of radiation therapy can be appreciated from the mortality rate of patients with breast cancer. Mortality has decreased yearly for the past 30 years, and as of 2012, there were an estimated 3 million breast cancer survivors in the United States.42,43 Breast cancer management has evolved from radical surgeries, diffuse chest radiation, and high-dose chemotherapy to targeted therapies and smaller surgeries. Radiation therapy is now a major component of the treatment of breast cancer in patients undergoing breast conservation surgery or patients with a high risk of recurrence after mastectomy.42,44 Early radiation therapy techniques involved the whole chest and were associated with cardiac complications. The newer approach to radiation therapy aims to target the breast with the least amount of exposure to the heart.42

However, a 2013 population-based case-control study of patients who underwent radiation therapy using the localized radiation approach found an increase in subsequent ischemic heart disease.45 The risk of ischemic heart disease was present even at a minimum dose of radiation. The risk appeared to increase after 5 years and continued for at least 2 decades after radiation therapy. Finally, this study found an even greater absolute risk in patients with preexisting cardiac risk factors or ischemic heart disease. Therefore, novel chemotherapy approaches do not completely remove the risk of cardiac complications.

The most common mechanism of injury is thought to be secondary to direct blood vessel damage resulting from DNA damage by reactive oxygen species.46 Histologically, radiation therapy is associated with diffuse interstitial fibrosis and narrowing of the arterial lumen and capillaries.47 The injury to the capillaries results in decreased vascular access and subsequent myocyte death. Pericardial fibrosis, on the other hand, is thought to be due to replacement of cardiac outer adipose tissue with dense collagen and fibrin.46

TREATMENT AND PREVENTION

The management of chemotherapy- or radiation-induced cardiotoxicity has a 4-pronged approach: (1) pretreatment assessment, (2) risk reduction, (3) surveillance and early treatment of cardiotoxicity during therapy, and (4) posttreatment surveillance. Although no clear guidelines are available, noninvasive cardiac evaluation prior to anthracycline treatment has been endorsed by the American Heart Association/American College of Cardiology.48 The American Society of Clinical Oncology, in addition to providing recommendations for cardioprotective therapies, has set guidelines for treatment alteration based on cardiac function.49 Multiple noninvasive imaging modalities exist today to assess left ventricular function, although 2-dimensional (2-D) echocardiography remains the most widely used tool for cardiac assessment because of its cost, availability, and lack of radiation. Left ventricular EF is a common parameter used to screen patients at risk of cardiotoxicity. For instance, an EF <30% on 2-D echocardiography is generally used as a contraindication for anthracycline-based chemotherapy.50

The 2 major chemotherapy/radiation CMY preventive measures are treatment modification and cardiac risk reduction. For instance, to decrease the risk of cardiotoxicity, anthracycline lifetime cumulative dose is often limited to <550 mg/m2 (Table 2). Moreover, an infusion delivered during a period of 6 hours or more is favored over bolus therapy, based on data from multiple studies.51-54 Additional approaches to reduce the cardiotoxicity of anthracyclines include encapsulation and the use of cardioprotective agents such as dexrazoxane. Despite concerns that dexrazoxane may blunt the effect of chemotherapy, a Cochrane metaanalysis review found it to be cardioprotective without having an effect on mortality from interference with chemotherapies.54 Finally, agents such as doxorubicin have been modified to reduce cardiotoxicity. Epirubicin and mitoxantrone are 2 analogs of doxorubicin that are associated with less cardiotoxicity compared to doxorubicin.55-58

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table 2.

Prevention of Anthracycline-Induced Cardiomyopathy

CV risk reduction includes treatment of modifiable risk factors such as hypertension and diabetes. Although data are lacking and no clear guidelines are available, patients with nonmodifiable risk factors such as advanced age are sometimes treated with β-blockers and/or angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) prophylactically. This practice is supported by multiple small trials that show some possible benefits of these drugs. Enalapril has been shown to possibly prevent late cardiotoxicity in patients with elevated troponin after treatment with high-dose chemotherapy.59 The PRADA (PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy) trial results suggest that prophylactic ACEIs/ARBs may be beneficial, whereas no statistically significant results were observed with β-blockers.60 This study is significant for being a randomized controlled trial, but its power was limited by a small sample size (n=120), and the long-term benefit of therapy was limited by its short follow-up time (about 3 years). Furthermore, the findings for β-blockers in the PRADA study differ from several previous trials that showed possible benefits.61-63 The OVERCOME (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) trial findings further suggest that combined enalapril and carvedilol may have additive protective effect against chemotherapy-induced CMY.63 Thus, although β-blockers and ACEIs/ARBs are main components of guideline-directed medical therapy for heart failure, their role in chemotherapy-induced heart failure is less clear because of small study populations.

Once signs of cardiotoxicity are observed, the risks and benefits of proceeding with the current treatment strategy vs using an alternate therapy are reevaluated. This risk-benefit evaluation highlights the importance of cardiac surveillance during treatment. For example, discontinuation of anthracycline is recommended once EF reaches ≤30% or decreases by at least 10%.50 Routine posttreatment surveillance with echocardiography for children who received anthracycline therapy is recommended.64 The role and timing of surveillance in asymptomatic adults after treatment are, however, less clear. A study that included 201 patients reported that the amount of recovery in left ventricular EF was associated with early initiation of treatment after chemotherapy. Complete recovery was only achieved when therapy (enalapril and carvedilol) was initiated 6 months after chemotherapy.65 This trial supports early evaluation and treatment of chemotherapy-induced CMY. Left ventricular EF is often assessed at the completion of chemotherapy in asymptomatic patients with normal EF. The benefits of posttreatment surveillance are perhaps warranted in symptomatic patients or patients with elevated cardiac risks; however, apart from small trials such as the aforementioned,65 significant data and guidelines are lacking.

While the treatment of heart failure is common among clinical cardiologists, the treatment of cancer survivors with cardiac complications is a recent and growing phenomenon. While the arsenal of therapies provided to the cardio-oncologist includes commonly prescribed medications such β-blockers and ACEIs/ARBs, the understanding of the various side effects of chemotherapeutic agents and the significance of altering treatment regimens requires expertise in cardio-oncology. By building a collaborative clinic among cardiologists and oncologists, individuals undergoing cancer treatment can be assured they are being provided pretreatment CV risk assessment, appropriate monitoring for symptomatic and asymptomatic cardiotoxicity with CV treatment initiation if needed, and appropriate follow-up once the cancer has been cured. At the Ochsner Medical Center, we have seen more than 300 individuals during the last 3 years and have received positive feedback from both patients and oncologists regarding this collaborative approach. Patients appreciate the connection with a cardiologist prior to any problems developing, providing reassurance in an already stressful situation.

CONCLUSION

A collaborative approach between oncologists and cardiologists is integral to the optimal care of patients with cancer. Chemotherapy and radiation have played a major role in the survival of patients with cancer but are associated with CMY. Although radiation and chemotherapy treatments have evolved with the aim of targeting cancer cells while having minimal effect on the heart, the increased risk of CMY remains significant. Therefore, proper screening and treatment of cardiotoxicity remain essential for these patients. As cardiac diseases and cancer remain the first and second causes of mortality in developed nations, cardio-oncology is the answer to this group of individuals who are especially vulnerable to both causes of mortality.

This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care, Medical Knowledge, and Practice-Based Learning and Improvement.

ACKNOWLEDGMENTS

The authors have no financial or proprietary interest in the subject matter of this article.

  • © Academic Division of Ochsner Clinic Foundation

REFERENCES

  1. ↵
    1. Hong RA,
    2. Iimura T,
    3. Sumida KN,
    4. Eager RM.
    Cardio-oncology/onco-cardiology. Clin Cardiol. 2010 12; 33 12: 733- 737. doi: 10.1002/clc.20823. pmid:21184556
    OpenUrlCrossRefPubMed
  2. ↵
    1. Lipshultz SE,
    2. Adams MJ,
    3. Colan SD,
    4. et al.
    Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation. 2013 10 22; 128 17: 1927- 1995. doi: 10.1161/CIR.0b013e3182a88099. pmid:24081971
    OpenUrlFREE Full Text
  3. ↵
    1. Wojnowski L,
    2. Kulle B,
    3. Schirmer M,
    4. et al.
    NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation. 2005 12 13; 112 24: 3754- 3762. doi: 10.1161/CIRCULATIONAHA.105.576850. pmid:16330681
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Von Hoff DD,
    2. Layard MW,
    3. Basa P,
    4. et al.
    Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979 11; 91 5: 710- 717. pmid:496103
    OpenUrlCrossRefPubMed
  5. ↵
    1. Wang X,
    2. Liu W,
    3. Sun CL,
    4. et al.
    Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group. J Clin Oncol. 2014 3 1; 32 7: 647- 653. doi:10.1200/JCO.2013.50.3557. pmid:24470002
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Serrano C,
    2. Cortés J,
    3. De Mattos-Arruda L,
    4. et al.
    Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Ann Oncol. 2012 4; 23 4: 897- 902. doi:10.1093/annonc/mdr348. pmid:21828361
    OpenUrlCrossRefPubMed
  7. ↵
    1. Hershman DL,
    2. McBride RB,
    3. Eisenberger A,
    4. Tsai WY,
    5. Grann VR,
    6. Jacobson JS.
    Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 7 1; 26 19: 3159- 3165. doi: 10.1200/JCO.2007.14.1242. pmid:18591554
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Longhi A,
    2. Ferrari S,
    3. Bacci G,
    4. Specchia S.
    Long-term follow-up of patients with doxorubicin-induced cardiac toxicity after chemotherapy for osteosarcoma. Anticancer Drugs. 2007 7; 18 6: 737- 744. doi: 10.1097/CAD.0b013e32803d36fe. pmid:17762406
    OpenUrlCrossRefPubMed
  9. ↵
    1. Singal PK,
    2. Deally CMR,
    3. Weinberg LE.
    Subcellular effects of adriamycin in the heart: a concise review. J Mol Cell Cardiol. 1987 8; 19 8: 817- 828. doi: 10.1016/S0022-2828(87)80392-9. pmid:3320376
    OpenUrlCrossRefPubMed
  10. ↵
    1. Singal PK,
    2. Iliskovic N,
    3. Li T,
    4. Kumar D.
    Adriamycin cardiomyopathy: pathophysiology and prevention. FASEB J. 1997 10; 11 12: 931- 936. pmid:9337145
    OpenUrlPubMed
  11. ↵
    1. Singal PK,
    2. Iliskovic N.
    Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998 9 24; 339 13: 900- 905. doi: 10.1056/NEJM199809243391307. pmid:9744975
    OpenUrlCrossRefPubMed
  12. ↵
    1. Martin E,
    2. Thougaard AV,
    3. Grauslund M,
    4. et al.
    Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy. Toxicology. 2009 1 8; 255 1-2: 72- 79. doi: 10.1016/j.tox.2008.10.011. pmid:19010377
    OpenUrlCrossRefPubMed
  13. ↵
    1. Tewey KM,
    2. Rowe TC,
    3. Yang L,
    4. Halligan BD,
    5. Liu LF.
    Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984 10 26; 226 4673: 466- 468. pmid:6093249
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Zhang S,
    2. Liu X,
    3. Bawa-Khalfe T,
    4. et al.
    Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012 11; 18 11: 1639- 1642. doi: 10.1038/nm.2919. pmid:23104132
    OpenUrlCrossRefPubMed
  15. ↵
    1. Lyu YL,
    2. Lin CP,
    3. Azarova AM,
    4. Cai L,
    5. Wang JC,
    6. Liu LF.
    Role of topoisomerase IIbeta in the expression of developmentally regulated genes. Mol Cell Biol. 2006 11; 26 21: 7929- 7941. doi: 10.1128/mcb.00617-06. pmid:16923961
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Sawyer DB.
    Anthracyclines and heart failure. N Engl J Med. 2013 3 21; 368 12: 1154- 1156. doi: 10.1056/NEJMcibr1214975. pmid:23514294
    OpenUrlCrossRefPubMed
  17. ↵
    1. Lyu YL,
    2. Kerrigan JE,
    3. Lin CP,
    4. et al.
    Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007 9 15; 67 18: 8839- 8846. doi: 10.1158/0008-5472.can-07-1649. pmid:17875725
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Capranico G,
    2. Tinelli S,
    3. Austin CA,
    4. Fisher ML,
    5. Zunino F.
    Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development. Biochim Biophys Acta. 1992 8 17; 1132 1: 43- 48. pmid:1380833
    OpenUrlCrossRefPubMed
  19. ↵
    1. Lipshultz SE.
    Dexrazoxane for protection against cardiotoxic effects of anthracyclines in children. J Clin Oncol. 1996 2 14; 14 2: 328- 331. pmid:8636739
    OpenUrlFREE Full Text
  20. ↵
    1. Deng S,
    2. Yan T,
    3. Nikolova T,
    4. et al.
    The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells. Br J Pharmacol. 2015 5; 172 9: 2246- 2257. doi: 10.1111/bph.13046. pmid:25521189
    OpenUrlCrossRefPubMed
  21. ↵
    1. Dempsey KS.
    Chemotherapy-induced cardiotoxicity in women. Heart Fail Clin. 2011 7; 7 3: 427- 435. doi: 10.1016/j.hfc.2011.04.004. pmid:21749894
    OpenUrlCrossRefPubMed
    1. Hortobagyi GN.
    Trastuzumab in the treatment of breast cancer. N Engl J Med. 2005 10 20; 353 16: 1734- 1736. doi: 10.1056/NEJMe058196. pmid:16236745
    OpenUrlCrossRefPubMed
  22. ↵
    1. Bartsch R,
    2. Wenzel C,
    3. Steger GG.
    Trastuzumab in the management of early and advanced stage breast cancer. Biologics. 2007 3; 1 1: 19- 31. pmid:19707345
    OpenUrlPubMed
  23. ↵
    1. Gianni L,
    2. Dafni U,
    3. Gelber RD,
    4. et al.
    Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 3; 12 3: 236- 244. doi: 10.1016/S1470-2045(11)70033-X. pmid:21354370
    OpenUrlCrossRefPubMed
  24. ↵
    1. Keefe DL.
    Trastuzumab-associated cardiotoxicity. Cancer. 2002 10 1; 95 7: 1592- 1600. doi: 10.1002/cncr.10854. pmid:12237930
    OpenUrlCrossRefPubMed
    1. Perez EA,
    2. Rodeheffer R.
    Clinical cardiac tolerability of trastuzumab. J Clin Oncol. 2004 1 15; 22 2: 322- 329. doi: 10.1200/JCO.2004.01.120. pmid:14722042
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Fiuza M.
    Cardiotoxicity associated with trastuzumab treatment of HER2+ breast cancer. Adv Ther. 2009 7; 26 Suppl 1: S9- S17. doi: 10.1007/s12325-009-0048-z. pmid:19669637
    OpenUrlCrossRefPubMed
  26. ↵
    1. Slamon DJ,
    2. Leyland-Jones B,
    3. Shak S,
    4. et al.
    Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 3 15; 344 11: 783- 792. doi: 10.1056/NEJM200103153441101. pmid:11248153
    OpenUrlCrossRefPubMed
    1. Russell SD,
    2. Blackwell KL,
    3. Lawrence J,
    4. et al.
    Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol. 2010 7 20; 28 21: 3416- 3421. doi: 10.1200/JCO.2009.23.6950. pmid:20530275
    OpenUrlAbstract/FREE Full Text
    1. Bowles EJ,
    2. Wellman R,
    3. Feigelson HS,
    4. et al.
    Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012 9 5; 104 17: 1293- 1305. doi: 10.1093/jnci/djs317. pmid:22949432
    OpenUrlCrossRefPubMed
  27. ↵
    1. Ewer SM,
    2. Ewer MS.
    Cardiotoxicity profile of trastuzumab. Drug Saf. 2008; 31 6: 459- 467. pmid:18484781
    OpenUrlCrossRefPubMed
  28. ↵
    1. Suter TM,
    2. Procter M,
    3. van Veldhuisen DJ,
    4. et al.
    Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol. 2007 9 1; 25 25: 3859- 3865. doi: 10.1200/JCO.2006.09.1611. pmid:17646669
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Halyard MY,
    2. Pisansky TM,
    3. Dueck AC,
    4. et al.
    Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. J Clin Oncol. 2009 6 1; 27 16: 2638- 2644. doi: 10.1200/JCO.2008.17.9549. pmid:19349549
    OpenUrlAbstract/FREE Full Text
    1. Perez EA,
    2. Suman VJ,
    3. Davidson NE,
    4. 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 3 10; 26 8: 1231- 1238. doi: 10.1200/JCO.2007.13.5467. pmid:18250349
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Romond EH,
    2. Jeong JH,
    3. Rastogi P,
    4. et al.
    Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012 11 1; 30 31: 3792- 3799. doi: 10.1200/JCO.2011.40.0010. pmid:22987084
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Albanell J,
    2. Bellmunt J,
    3. Molina R,
    4. et al.
    Node-negative breast cancers with p53(-)/HER2-neu(-) status may identify women with very good prognosis. Anticancer Res. 1996 Mar-Apr; 16 2: 1027- 1032. pmid:8687094
    OpenUrlPubMed
  32. ↵
    1. Molina MA,
    2. Codony-Servat J,
    3. Albanell J,
    4. Rojo F,
    5. Arribas J,
    6. Baselga J.
    Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001 6 15; 61 12: 4744- 4749. pmid:11406546
    OpenUrlAbstract/FREE Full Text
    1. Cooley S,
    2. Burns LJ,
    3. Repka T,
    4. Miller JS.
    Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu. Exp Hematol. 1999 10; 27 10: 1533- 1541. pmid:10517495
    OpenUrlCrossRefPubMed
  33. ↵
    1. Gennari R,
    2. Menard S,
    3. Fagnoni F,
    4. et al.
    Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004 9 1; 10 17: 5650- 5655. doi: 10.1158/1078-0432.ccr-04-0225. pmid:15355889
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Clynes RA,
    2. Towers TL,
    3. Presta LG,
    4. Ravetch JV.
    Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000 4; 6 4: 443- 446. doi: 10.1038/74704. pmid:10742152
    OpenUrlCrossRefPubMed
  35. ↵
    1. Chien KR.
    Herceptin and the heart—a molecular modifier of cardiac failure. N Engl J Med. 2006 2 23; 354 8: 789- 790. doi: 10.1056/NEJMp058315. pmid:16495390
    OpenUrlCrossRefPubMed
  36. ↵
    1. Moslehi J.
    The cardiovascular perils of cancer survivorship. N Engl J Med. 2013 3 14; 368 11: 1055- 1056. doi: 10.1056/NEJMe1215300. pmid:23484833
    OpenUrlCrossRefPubMed
  37. ↵
    1. Siegel R,
    2. DeSantis C,
    3. Virgo K,
    4. et al.
    Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012 Jul-Aug; 62 4: 220- 241. doi: 10.3322/caac.21149. pmid:22700443
    OpenUrlCrossRefPubMed
  38. ↵
    1. Buchholz TA.
    Radiation therapy for early-stage breast cancer after breast-conserving surgery. N Engl J Med. 2009 1 1; 360: 63- 70. doi: 10.1056/NEJMct0803525. pmid:19118305
    OpenUrlCrossRefPubMed
  39. ↵
    1. Darby SC,
    2. Ewertz M,
    3. McGale P,
    4. et al.
    Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013 3 14; 368 11: 987- 998. doi: 10.1056/NEJMoa1209825. pmid:23484825
    OpenUrlCrossRefPubMed
  40. ↵
    1. Marks LB,
    2. Constine LS,
    3. Adams MJ.
    Cardiotoxicity of radiation therapy for malignancy . UpToDate. Updated May 20, 2015. http://www.uptodate.com/contents/cardiotoxicity-of- radiation-therapy-for-malignancy?source=search_result& search=radiation+cardiotoxicity&selectedTitle=1∼150. Published 2015. Accessed January 1, 2016.
  41. ↵
    1. Cuzick J,
    2. Stewart H,
    3. Rutqvist L,
    4. et al.
    Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994 3; 12 3: 447- 453. pmid:8120544
    OpenUrlAbstract
  42. ↵
    1. Cheitlin MD,
    2. Armstrong WF,
    3. Aurigemma GP,
    4. et al.
    ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation. 2003 9 2; 108 9: 1146- 1162. doi: 10.1161/01.CIR.0000073597.57414.A9. pmid:12952829
    OpenUrlFREE Full Text
  43. ↵
    1. Hensley ML,
    2. Hagerty KL,
    3. Kewalramani T,
    4. et al.
    American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009 1 1; 27 1: 127- 145. doi: 10.1200/JCO.2008.17.2627. pmid:19018081
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Schwartz RG,
    2. McKenzie WB,
    3. Alexander J,
    4. et al.
    Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med. 1987 6; 82 6: 1109- 1118. pmid:3605130
    OpenUrlCrossRefPubMed
  45. ↵
    1. Smith LA,
    2. Cornelius VR,
    3. Plummer CJ,
    4. et al.
    Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010 6 29; 10: 337 doi: 10.1186/1471-2407-10-337. pmid:20587042
    OpenUrlCrossRefPubMed
    1. Casper ES,
    2. Gaynor JJ,
    3. Hajdu SI,
    4. et al.
    A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer. 1991 9 15; 68 6: 1221- 1229. pmid:1873773
    OpenUrlCrossRefPubMed
    1. Shapira J,
    2. Gotfried M,
    3. Lishner M,
    4. Ravid M.
    Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. Cancer. 1990 2 15; 65 4: 870- 873. pmid:2297656
    OpenUrlCrossRefPubMed
  46. ↵
    1. van Dalen EC,
    2. van der Pal HJ,
    3. Caron HN,
    4. Kremer LC.
    Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev. 2006 Oct 7;(4):CD005008. doi: 10.1002/14651858.CD005008.pub3.
  47. ↵
    1. Ryberg M,
    2. Nielsen D,
    3. Skovsgaard T,
    4. Hansen J,
    5. Jensen BV,
    6. Dombernowsky P.
    Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol. 1998 11; 16 11: 3502- 3508. pmid:9817267
    OpenUrlAbstract
    1. Neidhart JA,
    2. Gochnour D,
    3. Roach R,
    4. Hoth D,
    5. Young D.
    A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol. 1986 5; 4 5: 672- 677. pmid:3517241
    OpenUrlAbstract/FREE Full Text
    1. Henderson IC,
    2. Allegra JC,
    3. Woodcock T,
    4. et al.
    Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol. 1989 5; 7 5: 560- 571. pmid:2468745
    OpenUrlAbstract
  48. ↵
    1. Bennett JM,
    2. Muss HB,
    3. Doroshow JH,
    4. et al.
    A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol. 1988 10; 6 10: 1611- 1620. pmid:3049953
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Cardinale D,
    2. Colombo A,
    3. Sandri MT,
    4. et al.
    Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006 12 5; 114 23: 2474- 2481. doi: 10.1161/CIRCULATIONAHA.106.635144. pmid:17101852
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Bavry A.
    Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy—PRADA. American College of Cardiology. http://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2015/11/11/12/14/PRADA. Accessed February 4, 2016.
  51. ↵
    1. Kalay N,
    2. Basar E,
    3. Ozdogru I,
    4. et al.
    Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006 12 5; 48 11: 2258- 2262. doi: 10.1016/j.jacc.2006.07.052. pmid:17161256
    OpenUrlFREE Full Text
    1. Kaya MG,
    2. Ozkan M,
    3. Gunebakmaz O,
    4. et al.
    Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol. 2013 9 1; 167 5: 2306- 2310. doi: 10.1016/j.ijcard.2012.06.023. pmid:22727976
    OpenUrlCrossRefPubMed
  52. ↵
    1. Bosch X,
    2. Rovira M,
    3. Sitges M,
    4. 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 6 11; 61 23: 2355- 2362. doi: 10.1016/j.jacc.2013.02.072. pmid:23583763
    OpenUrlFREE Full Text
  53. ↵
    Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers . Version 3.0. Arcadia, CA: Children's Oncology Group; www.survivorshipguidelines.org. Accessed January 4, 2016.
  54. ↵
    1. Cardinale D,
    2. Colombo A,
    3. Lamantia G,
    4. et al.
    Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010 1 19; 55 3: 213- 220. doi: 10.1016/j.jacc.2009.03.095. pmid:20117401
    OpenUrlFREE Full Text
PreviousNext
Back to top

In this issue

Ochsner Journal
Vol. 16, Issue 3
Sep 2016
  • Table of Contents
  • Index by author
Print
Download PDF
Email Article

Thank you for your interest in spreading the word on Ochsner Journal.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Cardio-Oncology: A Focused Review of Anthracycline-, Human Epidermal Growth Factor Receptor 2 Inhibitor–, and Radiation-Induced Cardiotoxicity and Management
(Your Name) has sent you a message from Ochsner Journal
(Your Name) thought you would like to see the Ochsner Journal web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Cardio-Oncology: A Focused Review of Anthracycline-, Human Epidermal Growth Factor Receptor 2 Inhibitor–, and Radiation-Induced Cardiotoxicity and Management
Jean Domercant, Nichole Polin, Eiman Jahangir
Ochsner Journal Sep 2016, 16 (3) 250-256;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Cardio-Oncology: A Focused Review of Anthracycline-, Human Epidermal Growth Factor Receptor 2 Inhibitor–, and Radiation-Induced Cardiotoxicity and Management
Jean Domercant, Nichole Polin, Eiman Jahangir
Ochsner Journal Sep 2016, 16 (3) 250-256;
del.icio.us logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • INTRODUCTION
    • ANTHRACYCLINES
    • TRASTUZUMAB
    • RADIATION
    • TREATMENT AND PREVENTION
    • CONCLUSION
    • ACKNOWLEDGMENTS
    • REFERENCES
  • Figures & Data
  • References
  • Info & Metrics
  • PDF

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • Beta-Blocker Usage in Patients With Heart Failure With Reduced Ejection Fraction During Acute Decompensated Heart Failure Hospitalizations
  • Impact of Coffee Consumption on Cardiovascular Health
  • COVID-19 Physician Burnout: Louisiana's Workforce Vulnerability and Strategies for Mitigation
Show more REVIEWS AND CONTEMPORARY UPDATES

Similar Articles

Keywords

  • Anthracyclines
  • cardiotoxicity
  • heart failure
  • radiation
  • trastuzumab

Ochsner Journal Blog

Current Post

Be Careful Where You Publish

Our Content

  • Home
  • Current Issue
  • Ahead of Print
  • Archive
  • Featured Contributors
  • Ochsner Journal Blog
  • Archive at PubMed Central

Information & Forms

  • Instructions for Authors
  • Instructions for Reviewers
  • Submission Checklist
  • FAQ
  • License for Publishing-Author Attestation
  • Patient Consent Form
  • Submit a Manuscript

Services & Contacts

  • Permissions
  • Sign up for our electronic table of contents
  • Feedback Form
  • Contact Us

About Us

  • Editorial Board
  • About the Ochsner Journal
  • Ochsner Health
  • University of Queensland-Ochsner Clinical School
  • Alliance of Independent Academic Medical Centers

© 2025 Ochsner Clinic Foundation

Powered by HighWire