Skip to main content

Changing Hearts and Minds: Improving Outcomes in Cancer Treatment-Related Cardiotoxicity

Abstract

Purpose of Review

Cardiovascular effects from cancer treatment remains a leading cause of treatment-associated morbidity and mortality among cancer survivors. The National Cancer Institute and National Heart, Lung, and Blood Institute convened a Workshop in June 2018 entitled “Changing Hearts and Minds: Improving Outcomes in Cancer Treatment-Related Cardiotoxicity” to highlight progress, ongoing work, and update scientific priorities since the 2013 Workshop. Here we will describe these advances and provide an overview of the research priorities identified.

Recent Findings

Since 2013, the National Institutes of Health has increased its support of cancer treatment-related cardiotoxicity research through the funding of grants and coordination of internal and external working groups. Workshop participants identified knowledge gaps and recommended over 20 new promising opportunities in basic and clinical cardiotoxicity research.

Summary

Significant progress on mechanisms, detection, management, and prevention of cardiotoxicity has been made over the past 5 years, yet some critical gaps remain.

This is a preview of subscription content, access via your institution.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel R, DeSantis C, Virgo K, et al. Current treatment and survivorship statistics. CA Cancer J Clin. 2012;62(4):220–41. https://doi.org/10.1158/1055-9965.

    Article  PubMed  Google Scholar 

  2. Mertens AC, Yasui Y, Neglia JP, Potter JD, Nesbit ME Jr, Ruccione K, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the childhood Cancer survivor study. J Clin Oncol. 2001;19(13):3163–72. https://doi.org/10.1200/JCO.2001.19.13.3163.

    Article  CAS  PubMed  Google Scholar 

  3. Armstrong GT, Chen Y, Yasui Y, Leisenring W, Gibson TM, Mertens AC, et al. Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med. 2016;374:833–42. https://doi.org/10.1056/NEJMoa1510795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Abdel-Qadir H, Austin PC, Lee DS, Amir E, Tu JV, Thavendiranathan P, et al. A population-based study of cardiovascular mortality following early-stage breast cancer. JAMA Cardiol. 2017;2:88–93. https://doi.org/10.1001/jamacardio.2016.3841.

    Article  PubMed  Google Scholar 

  5. Meacham LR, Chow EJ, Ness KK, Kamdar KY, Chen Y, Yasui Y, et al. Cardiovascular risk factors in adult survivors of pediatric cancer—a report from the childhood cancer survivor study. Cancer Epidemiol Biomark Prev. 2010;19(1):170–81. https://doi.org/10.1158/1055-9965.

    Article  Google Scholar 

  6. Armenian SH, Armstrong GT, Aune G, et al. Cardiovascular Disease in Survivors of Childhood Cancer: Insights into Epidemiology, Pathophysiology, and Prevention. JCO. 2018;36(21):2135–44. https://doi.org/10.1200/JCO.2017.76.3920.

    Article  CAS  Google Scholar 

  7. Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med. 375(15):1457–67. https://doi.org/10.1056/NEJMra1100265.

  8. Shelburne N, Adhikari B, Brell J, Davis M, Desvigne-Nickens P, Freedman A, et al. Cancer treatment-related cardiotoxicity: Current state of knowledge and future research priorities. JNCI. 2014;106(9). https://doi.org/10.1093/jnci/dju232.

  9. NIH, 2015a. https://grants.nih.gov/grants/guide/pa-files/PA-18-003.html. Accessed 03 Dec 2018.

  10. NIH, 2015b. https://grants.nih.gov/grants/guide/pa-files/PA-18-013.html. Accessed 03 Dec 2018.

  11. NCI, 2018a. https://epi.grants.cancer.gov/events/cardiotoxicity/improving-outcomes.html. Accessed 03 Dec 2018.

  12. • Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(8):893–911. https://doi.org/10.1200/JCO.2016.70.5400. This review provides evidence based clinical practice guidelines for cardiotoxicity prevention and management in adult patients with cancer. Guidelines were developed by an expert panel and highlights existing evidence and knowledge gaps.

    Article  PubMed  Google Scholar 

  13. • Armenian SH, Hudson MM, Mulder RL, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015;16(3):e123–36. https://doi.org/10.1016/S1470-2045(14)70409-7. This review provides evidence based clinical practice guidelines for identifying pediatric cancer survivors at risk for treatment related cardiomyopathy, including surveillance and management modalities. Guidelines were developed by an international expert panel and highlights existing evidence and knowledge gaps.

    Article  PubMed  PubMed Central  Google Scholar 

  14. DuBois VFS, Casarotto E, Danhof M, Della PO. Pharmacokinetic-pharmacodynamic modelling of drug-induced QTc interval prolongation in man: prediction from in vitro human ether-à-go-go-related gene binding and functional inhibition assays and conscious dog studies. Br J Pharmacol. 2016;173:2819–32.

    Article  CAS  Google Scholar 

  15. Burridge PW, Li YF, Matsa E, Wu H, et al. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat Med. 2016;22(5):547–56. https://doi.org/10.1038/nm.4087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Biermann M, Kamp TJ. Cardiotoxicity in a dish: new insights for personalized therapy. Nat Med. 2016;22:459–60. https://doi.org/10.1038/nm.4095.

    Article  CAS  PubMed  Google Scholar 

  17. Sun N, Yazawa M, Liu J, Han L, et al. Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. Sci Transl Med. 2012;4(130):130ra47. https://doi.org/10.1126/scitranslmed.3003552.

    Article  PubMed  PubMed Central  Google Scholar 

  18. • Sharma A, Burridge PW, WL MK, et al. Sci Transl Med. 2017;9(377). https://doi.org/10.1126/scitranslmed.aaf2584. This study utilized induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients treated with tyrosine kinase inhibitors (TKI) to generate a cardiac safety index based on cardiomyocyte viability, contractility, electrophysiology, calcium handling and signaling. The cardiac safety index and HiPSC-CMs can play an important role in assessing novel TKI cardiotoxicity during toxicology testing.

  19. Wang F, Iskra B, Kleinerman E, et al. Aerobic exercise during early murine doxorubicin exposure mitigates cardiac toxicity. J Pediatr Hematol Oncol. 2018;40:208–15. https://doi.org/10.1097/MPH.0000000000001112.

    Article  CAS  PubMed  Google Scholar 

  20. Lipshultz SE, Adams MJ, Colan SD, Constine LS, Herman EH, Hsu DT, 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;128:1927–95. https://doi.org/10.1161/CIR.0b013e3182a88099.

    Article  PubMed  Google Scholar 

  21. Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W, Armstrong GT, et al. Cause-specific late mortality amont 5-year survivors of childhood cancer: the childhood Cancer survivor study. J Natl Cancer Inst. 2008;100:1368–79. https://doi.org/10.1093/jci/djn310.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA. 2010;304:172–9. https://doi.org/10.1001/jama.2010.923.

    Article  CAS  PubMed  Google Scholar 

  23. Ledwidge M, Gallagher J, Conlon C, Tallon E, O’Connell E, Dawkins I, et al. Natriuretic peptide-based screening and collaborative Care for Heart Failure: the STOP-HF randomized trial. JAMA. 2013;310:66–74. https://doi.org/10.1001/jama.2013.7588.

    Article  CAS  PubMed  Google Scholar 

  24. Murtagh G, Lyons T, O’Connell E, Ballot J, Geraghty L, Fennelly D, et al. Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up. Breast Cancer Res Treat. 2016;156:501–6. https://doi.org/10.1007/s10549-016-3781-4.

    Article  CAS  PubMed  Google Scholar 

  25. Amingkeng F, Ross CJD, Rassekh SR, Hwang S, et al. Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity. Br J Clin Pharmacol. 2016;82(3):683–95. https://doi.org/10.1111/bcp.13008.

    Article  CAS  Google Scholar 

  26. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749–55. https://doi.org/10.1056/NEJMoa1609214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. •• Moslehi JJ, Salem J, Sosman JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933. https://doi.org/10.1016/S0140-6736(18)30533-6. This is the first analysis to describe the clinical features of myocarditis in patients with cancer receiving immune check point inhibitors. The analysis of the World Health Organization’s database of individual case safety reports identified early onset and increasing incidence of myocarditis, immune related adverse events and fatalities.

    Article  PubMed  Google Scholar 

  28. •• Khouri MG, Ky B, Dunn G, et al. Echocardiography Core Laboratory Reproducibility of Cardiac Safety Assessments in Cardio-Oncology. J Am Soc Echocardiogr. 2017;31(3):361–71. https://doi.org/10.1016/j.echo.2017.11.018. This is the first study to evaluate reproducibility between echocardiography core labs when conducting multi-site cardio-oncology studies. While high reproducibility within core labs was demonstrated, notable differences between labs existed. Improved echocardiogram reproducibility was seen with the institution of standard operating procedures and the application of measurement conventions across core labs, similar to processes when comparing blood assays between laboratories.

    Article  Google Scholar 

  29. FDA, 2018. https://www.fda.gov/downloads/drugs/guidances/ucm268555.pdf. Accessed 27 Dec 2018.

  30. University of Pennsylvania, 2018. https://rt19.pmacs.upenn.edu/crcu_html/radcomp/website/index.html. Accessed 27 Dec 2018.

  31. van Dalen EC, Caron HN, Dickenson HO, Kremer LCM. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Syst Rev. 2011. https://doi.org/10.1002/14651858.CD003917.pub4.

  32. Schuchter LM, Hensley ML, Meropol NJ, Winer EP. Update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society for Clinical Oncology. J Clin Oncol. 2002;20:2895–903. https://doi.org/10.1200/JCO.2002.04.178.

    Article  PubMed  Google Scholar 

  33. Menna P, Salvatorelli E. Primary prevention strategies for anthracycline cardiotoxicity: a brief overview. Chemotherapy. 2017;62:159–68. https://doi.org/10.1159/000464276.

    Article  CAS  PubMed  Google Scholar 

  34. Kheieri B, Abdalla A, Osman M, et al. Meta-analysis of carvedilol for the prevention of anthracycline-induced cardiotoxicity. Am J Cariol. 2018;S0002-9149(18):31738–7. https://doi.org/10.1016/j.amjcard.2018.08.039.

    Article  CAS  Google Scholar 

  35. Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol. 2012;60:2384–90. https://doi.org/10.1016/j.jacc.2012.07.067.

    Article  CAS  PubMed  Google Scholar 

  36. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifer NCT01988571. Preventing Anthracycline Cardiovascular Toxicity With Statins 2018 Aug 31 (PREVENT); [cited 2018 Nov 12]; Available from https://clinicaltrials.gov/ct2/show/NCT01988571. Accessed 03 Dec 2018.

  37. Pituskin E, Mackey JR, Koshman S, Jassal D, Pitz M, Haykowsky MJ, et al. Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol. 2017;35(8):870–7. https://doi.org/10.1200/JCO.2016.68.7830.

    Article  CAS  PubMed  Google Scholar 

  38. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukemia: long-term follow-up of a prospective, randomized, multicentre trial. Lancet Oncol. 2010;11(10):950–61. https://doi.org/10.1016/S1470-2045(10)70204-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Asselin BL, Devidas M, Chen L, Franco VI, Pullen J, Borowitz MJ, et al. Cardioprotection and safety of dexrazoxane in patients treated for newly diagnosed T-cell acute lymphoblastic leukemia or advanced-stage lymphoblastic non-Hodgkin lymphoma: a report of the Children’s oncology group randomized trial pediatric oncology group 9404. J Clin Oncol. 2016;34(8):854–62. https://doi.org/10.1200/JCO.2015.60.8851.

    Article  CAS  PubMed  Google Scholar 

  40. Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, et al. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial. J Am Coll Cardiol. 2018;71(20):2281–90. https://doi.org/10.1016/j.jacc.2018.02.049.

    Article  CAS  PubMed  Google Scholar 

  41. Guglin ME. Lisinopril or carvedilol for prevention of trastuzumab induced cardiotoxicity- lisinopril or carvedilol for cardiotoxicity. 2018. Presented at the American College of Cardiology Annual Scientific Session, Orlando, FL, March 11, 2018.

  42. Lakoski SG, Eves ND, Douglas PS, Jones LW. Exercise rehabilitation in patients with cancer. Nat Rev Clin Oncol. 2012;9:288–96. https://doi.org/10.1038/nrclinonc.2012.27.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Scott JM, Nilesen TS, Gupta D, Jones LW. Exercise therapy and cardiovascular toxicity in cancer. Circulation. 2018;137:1176–91. https://doi.org/10.1161/CIRCULATIONAHA.117.024671.

    Article  PubMed  Google Scholar 

  44. Miller TP, Li Y, Kavcic M, et al. Accuracy of adverse event ascertainment in clinical trials for pediatric acute myeloid leukemia. Alexandria: ASCO; 2015.

    Google Scholar 

  45. Sivendran S, Latif A, McBride RS, et al. Adverse events reporting in cancer clinical trial publication. J Clin Oncol. 2014;32(2):83–39. https://doi.org/10.1200/JCO.2013.52.2219.

    Article  PubMed  Google Scholar 

  46. NCI, 2018b. https://healthcaredelivery.cancer.gov/pro-ctcae.

Download references

Acknowledgements

The authors thank the workshop speakers and attendees and Sarah Fagan for her logistics and support work.

Funding

This work was supported by the National Cancer Institute and National Heart, Lung, and Blood Institute and contract no. HHSN261201400011.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nonniekaye Shelburne.

Ethics declarations

Conflict of Interest

Nonniekaye Shelburne, Naoko I. Simonds, Bishow Adhikari, Michael Alley, Patrice Desvigne-Nickens, Eileen Dimond, Kelly Filipski, Lisa Gallicchio, and Lori Minasian declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Cardio-oncology

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shelburne, N., Simonds, N.I., Adhikari, B. et al. Changing Hearts and Minds: Improving Outcomes in Cancer Treatment-Related Cardiotoxicity. Curr Oncol Rep 21, 9 (2019). https://doi.org/10.1007/s11912-019-0751-0

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-019-0751-0

Keywords