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Cardiac dysfunction induced by novel targeted anticancer therapy: An emerging issue

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Abstract

Increasing use of targeted anticancer agents that inhibit tyrosine kinase signaling (monoclonal antibodies or tyrosine kinase inhibitors) has dramatically improved the survival of patients with malignancies. However, cardiotoxicity, including heart failure, left ventricular dysfunction, hypertension, myocardial infarction, and thromboembolism, has occurred. Importantly, these cardiotoxicities are at least partially reversible and responsive to medical management. Early recognition of cardiovascular side effects is vital to allow long-term, continuous therapy with these life-prolonging agents. This article reviews potential cardiovascular side effects of frequently used inhibitors of tyrosine kinase activity (eg, trastuzumab, sunitinib) and discusses the diagnosis and management of cardiotoxicity associated with targeted therapy.

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References and Recommended Reading

  1. Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005, 353:172–187.

    Article  PubMed  CAS  Google Scholar 

  2. Folkman J: Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007, 6:273–286.

    Article  PubMed  CAS  Google Scholar 

  3. Chen MH, Kerkela R, Force T: Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation 2008, 118:84–95.

    Article  PubMed  Google Scholar 

  4. Faivre S, Demetri G, Sargent W, Raymond E: Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007, 6:734–745.

    Article  PubMed  CAS  Google Scholar 

  5. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005, 353:1659–1672.

    Article  PubMed  CAS  Google Scholar 

  6. Slamon DJ, Leyland-Jones B, Shak S, et al.: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001, 344:783–792.

    Article  PubMed  CAS  Google Scholar 

  7. Slamon DJ, Romond EH, Perez EA; CME Consultants, Inc.: Advances in adjuvant therapy for breast cancer. Clin Adv Hematol Oncol 2006, 4(3 Suppl 7):suppl 1, 4–9; discussion suppl 10; quiz 2 p following suppl 10.

    Google Scholar 

  8. Druker BJ, Guilhot F, O’Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006, 355:2408–2417.

    Article  PubMed  CAS  Google Scholar 

  9. Deremer DL, Ustun C, Natarajan K: Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clin Ther 2008, 30:1956–1975.

    Article  PubMed  CAS  Google Scholar 

  10. Chu TF, Rupnick MA, Kerkela R, et al.: Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007, 370:2011–2019.

    Article  PubMed  CAS  Google Scholar 

  11. Veronese ML, Mosenkis A, Flaherty KT, et al.: Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006, 24:1363–1369.

    Article  PubMed  CAS  Google Scholar 

  12. Scappaticci FA, Skillings JR, Holden SN, et al.: Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007, 99:1232–1239.

    Article  PubMed  Google Scholar 

  13. Motzer RJ, Hutson TE, Tomczak P, et al.: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115–124.

    Article  PubMed  CAS  Google Scholar 

  14. Rini BI: Quantifying hypertension in patients with cancer treated with sorafenib. Lancet Oncol 2008, 9:86–87.

    Article  PubMed  Google Scholar 

  15. Khakoo AY, Yeh ET: Therapy insight: management of cardiovascular disease in patients with cancer and cardiac complications of cancer therapy. Nat Clin Pract Oncol 2008, 5:655–667.

    Article  PubMed  CAS  Google Scholar 

  16. Yeh ET, Tong AT, Lenihan DJ, et al.: Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 2004, 109:3122–3131.

    Article  PubMed  Google Scholar 

  17. Joensuu H: Sunitinib for imatinib-resistant GIST. Lancet 2006, 368:1303–1304.

    Article  PubMed  Google Scholar 

  18. Perez EA: Cardiac toxicity of ErbB2-targeted therapies: what do we know? Clin Breast Cancer 2008, (8 Suppl 3):S114–S120.

    Article  Google Scholar 

  19. Sengupta PP, Northfelt DW, Gentile F, et al.: Trastuzumabinduced cardiotoxicity: heart failure at the crossroads. Mayo Clin Proc 2008, 83:197–203.

    Article  PubMed  CAS  Google Scholar 

  20. Mann DL: Targeted cancer therapeutics: the heartbreak of success. Nat Med 2006, 12:881–882.

    Article  PubMed  CAS  Google Scholar 

  21. Maitland ML: Cardiovascular toxicity of new agents. Clin Adv Hematol Oncol 2008, 6:657–659.

    PubMed  Google Scholar 

  22. Kerkela R, Grazette L, Yacobi R, et al.: Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006, 12:908–916.

    Article  PubMed  Google Scholar 

  23. Desai J, Yassa L, Marqusee E, et al.: Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006, 145:660–664.

    PubMed  Google Scholar 

  24. Sica DA: Angiogenesis inhibitors and hypertension: an emerging issue. J Clin Oncol 2006, 24:1329–1331.

    Article  PubMed  Google Scholar 

  25. Force T, Krause DS, Van Etten RA: Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007, 7:332–344.

    Article  PubMed  CAS  Google Scholar 

  26. Escudier B, Eisen T, Stadler WM, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125–134.

    Article  PubMed  CAS  Google Scholar 

  27. Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335–2342.

    Article  PubMed  CAS  Google Scholar 

  28. Sherman SI, Wirth LJ, Droz JP, et al.: Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 2008, 359:31–42.

    Article  PubMed  CAS  Google Scholar 

  29. Wu S, Chen JJ, Kudelka A, et al.: Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 2008, 9:117–123.

    Article  PubMed  CAS  Google Scholar 

  30. Rixe O, Bukowski RM, Michaelson MD, et al.: Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007, 8:975–984.

    Article  PubMed  Google Scholar 

  31. Telli ML, Witteles RM, Fisher GA, Srinivas S: Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 2008, 19:1613–1618.

    Article  PubMed  CAS  Google Scholar 

  32. Schmidinger M, Zielinski CC, Vogl UM, et al.: Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008, 26:5204–5212.

    Article  PubMed  Google Scholar 

  33. Suter TM, Procter M, van Veldhuisen DJ, et al.: Trastuzumabassociated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 2007, 25:3859–3865.

    Article  PubMed  CAS  Google Scholar 

  34. Bird BR, Swain SM: Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res 2008, 14:14–24.

    Article  PubMed  CAS  Google Scholar 

  35. Ewer MS, Vooletich MT, Durand JB, et al.: Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005, 23:7820–7826.

    Article  PubMed  CAS  Google Scholar 

  36. Perez EA, Koehler M, Byrne J, et al.: Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc 2008, 83:679–686.

    Article  PubMed  Google Scholar 

  37. Khakoo AY, Kassiotis CM, Tannir N, et al.: Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer 2008, 112:2500–2508.

    Article  PubMed  CAS  Google Scholar 

  38. Hasinoff BB, Patel D, O’Hara KA: Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib. Mol Pharmacol 2008, 74:1722–1728.

    Article  PubMed  CAS  Google Scholar 

  39. Kerkela R, Woulfe KC, Durand JB, et al.: Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin Transl Sci 2009, 2:15–25.

    Article  Google Scholar 

  40. Lenihan DJ: Tyrosine kinase inhibitors: can promising new therapy associated with cardiac toxicity strengthen the concept of teamwork? J Clin Oncol 2008, 26:5154–5155.

    Article  PubMed  Google Scholar 

  41. National Cancer Institute: Cancer Therapy Evaluation Program: Common terminology criteria for adverse events, version 3.0 (CTCAE). Bethesda, MD: August 9, 2006. Available at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed February 2009.

  42. Cardinale D, Sandri MT, Martinoni A, et al.: Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 2000, 36:517–522.

    Article  PubMed  CAS  Google Scholar 

  43. Chen MH, Rupnick MA, Chu TF, et al.: Cardiotoxicity associated with sunitinib—authors’ reply. Lancet 2008, 371:1245.

    Article  Google Scholar 

  44. Lenihan DJ, Esteva FJ: Multidisciplinary strategy for managing cardiovascular risks when treating patients with early breast cancer. Oncologist 2008, 13:1224–1234.

    Article  PubMed  CAS  Google Scholar 

  45. Telli ML, Hunt SA, Carlson RW, Guardino AE: Trastuzumabrelated cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 2007, 25:3525–3533.

    Article  PubMed  CAS  Google Scholar 

  46. Hunt SA, Abraham WT, Chin MH, et al.: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005, 112:e154–e235.

    Article  PubMed  Google Scholar 

  47. Heart Failure Society Of America: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail 2006, 12:e1–e2.

    Article  PubMed  CAS  Google Scholar 

  48. Lindenfeld J: Pharmacotherapy of acute and chronic heart failure: part 1 and 2. Curr Cardiol Rep 2008, 10:165–167.

    Article  PubMed  Google Scholar 

  49. Seidman A, Hudis C, Pierri MK, et al.: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002, 20:1215–1221.

    Article  PubMed  CAS  Google Scholar 

  50. Chien KR: Herceptin and the heart—a molecular modifier of cardiac failure. N Engl J Med 2006, 354:789–790.

    Article  PubMed  CAS  Google Scholar 

  51. Jones LW, Haykowsky MJ, Swartz JJ, et al.: Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 2007, 50:1435–1441.

    Article  PubMed  Google Scholar 

  52. Azizi M, Chedid A, Oudard S: Home blood-pressure monitoring in patients receiving sunitinib. N Engl J Med 2008, 358:95–97.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA, 02115, USA

    Ming Hui Chen

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  1. Ming Hui Chen
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Correspondence to Ming Hui Chen.

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Chen, M.H. Cardiac dysfunction induced by novel targeted anticancer therapy: An emerging issue. Curr Cardiol Rep 11, 167–174 (2009). https://doi.org/10.1007/s11886-009-0025-9

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  • DOI: https://doi.org/10.1007/s11886-009-0025-9

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