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  • Review Article
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Vascular complications of selected cancer therapies

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 797–805 (2008)Cite this article

Abstract

Over the past decade, therapies for several previously untreatable types of cancer have emerged or have improved; thus, more focus has been given to long-term complications of cancer therapy. The most commonly known cardiac toxicities of cancer therapy are cardiac dysfunction or congestive heart failure. Vascular complications—such as ischemia, myocardial infarction, venous or arterial thrombosis, and newly developed or worsened hypertension—are also relatively common following cancer treatment, particularly in patients with advanced-stage cancer. Experimental studies have suggested a number of potential mechanisms that might account for vascular complications of cancer therapies, which include dysfunction or damage of endothelial cells, increased platelet aggregation, and modulation of nitric oxide levels. This Review describes the vascular complications of treatment with 5-fluorouracil, bevacizumab, and several new tyrosine kinase inhibitors, with special emphasis on thrombotic complications and hypertension.

Key Points

  • Vascular complications of chemotherapy include ischemia, hypertension, and arterial and venous thrombosis, as well as proteinuria

  • Complications associated with 5-fluorouracil include arterial spasm and increased thrombogenesis, and are probably due to toxic effects of the agent on endothelial cells

  • Bevacizumab, a monoclonal antibody to human vascular endothelial growth factor that has antiangiogenic properties, is associated with a high incidence of vascular toxicities, including hypertension, proteinuria and vascular thrombosis

  • The newly developed antiangiogenesis agents sunitinib and sorafenib are associated with a high incidence of hypertension (up to one quarter of patients)

  • Cisplatin has been linked with coronary ischemia and with cardiovascular complications such as hypertension, left ventricular hypertrophy, and myocardial ischemia and infarction, which, as shown in one study of metastatic testicular cancer, can occur many years after cancer remission

  • Thalidomide is associated with increased rates of deep venous thrombosis, particularly when used in combination therapy

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Figure 1: Chemical structures of some common chemotherapeutic agents.

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References

  1. Hewitt ME et al. (2006) From Cancer Patient To Cancer Survivor: Lost In Transition. Washington, DC: The National Academies Press

    Google Scholar 

  2. Death rates by age, sex, race, and underlying cause: United States, 1981–2004 (NMR04a). [http://205.207.175.93/aging/TableViewer/tableView.aspx?ReportId=424]

  3. Yeh ET et al. (2004) Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 109: 3122–3131

    Article  Google Scholar 

  4. Yeh ET (2006) Cardiotoxicity induced by chemotherapy and antibody therapy. Annu Rev Med 57: 485–498

    Article  CAS  Google Scholar 

  5. van den Belt-Dusebout AW et al. (2006) Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24: 467–475

    Article  Google Scholar 

  6. Giordano SH et al. (2005) Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97: 419–424

    Article  Google Scholar 

  7. Gradishar WJ and Vokes EE (1990) 5-Fluorouracil cardiotoxicity: a critical review. Ann Oncol 1: 409–414

    Article  CAS  Google Scholar 

  8. Ranieri G et al. (2006) Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem 13: 1845–1857

    Article  CAS  Google Scholar 

  9. Grem J (1990) Fluorinated pyrimidines. I. Cancer Chemotherapy, Principles and Practice, 197–200 (Eds Chabner BA and Collins JM) Philadelphia, PA: JB Lippincott

    Google Scholar 

  10. Kikuchi KS et al. (1982) Clinical survey on cardiotoxicity of tegafur (FT-207)—compilation of a nationwide survey [Japanese]. Gan To Kagaku Ryoho 9: 1482–1488

    CAS  PubMed  Google Scholar 

  11. Frickhofen N et al. (2002) Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol 13: 797–801

    Article  CAS  Google Scholar 

  12. Labianca R et al. (1982) Cardiac toxicity of 5-fluorouracil: a study on 1,083 patients. Tumori 68: 505–510

    Article  CAS  Google Scholar 

  13. Gradishar WJ (1990) Catastrophic vascular events in patients receiving 5-fluorouracil based chemotherapy [abstract #1128]. Proc Am Assoc Can Res 31: 190

    Google Scholar 

  14. Hansen RM et al. (1996) Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst 88: 668–674

    Article  CAS  Google Scholar 

  15. Lokich JJ et al. (1989) A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 7: 425–432

    Article  CAS  Google Scholar 

  16. Poplin EA et al. (2005) Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer. J Clin Oncol 23: 1819–1825

    Article  CAS  Google Scholar 

  17. Doll DC et al. (1986) Vascular toxicity associated with antineoplastic agents. J Clin Oncol 4: 1405–1417

    Article  CAS  Google Scholar 

  18. Tham J and Albertsson M (2004) Upper extremity deep venous thrombosis in patients with 5-fluorouracil-containing adjuvant chemotherapy—three case reports and a review. Acta Oncol 43: 108–112

    Article  Google Scholar 

  19. Blom JW et al. (2006) High risk of venous thrombosis in patients with pancreatic cancer: a cohort study of 202 patients. Eur J Cancer 42: 410–414

    Article  CAS  Google Scholar 

  20. Yoshikawa R et al. (2005) Venous thromboembolism in colorectal cancer patients with central venous catheters for 5-FU infusion-based pharmacokinetic modulating chemotherapy. Oncol Rep 13: 627–632

    CAS  PubMed  Google Scholar 

  21. Papamichael D et al. (1998) 5-Fluorouracil-induced Raynaud's phenomenon. Eur J Cancer 34: 1983

    Article  CAS  Google Scholar 

  22. Rezkalla S et al. (1989) Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study. J Clin Oncol 7: 509–514

    Article  CAS  Google Scholar 

  23. Alter P et al. (2006) Cardiotoxicity of 5-fluorouracil. Cardiovasc Hematol Agents Med Chem 4: 1–5

    Article  CAS  Google Scholar 

  24. Mosseri M et al. (1990) 5-FU induced vasoconstriction in isolated rabbit aortic rings [abstract #2632]. Proc Am Assoc Can Res 30: 443

    Google Scholar 

  25. Hayward R et al. (2004) Training enhances vascular relaxation after chemotherapy-induced vasoconstriction. Med Sci Sports Exerc 36: 428–434

    Article  CAS  Google Scholar 

  26. Baerlocher GM et al. (1997) The anti-neoplastic drug 5-fluorouracil produces echinocytosis and affects blood rheology. Br J Haematol 99: 426–432

    Article  CAS  Google Scholar 

  27. Drevs J et al. (2004) Antiangiogenic potency of various chemotherapeutic drugs for metronomic chemotherapy. Anticancer Res 24: 1759–1763

    CAS  PubMed  Google Scholar 

  28. Cwikiel M et al. (1996) The influence of 5-fluorouracil and methotrexate on vascular endothelium: an experimental study using endothelial cells in the culture. Ann Oncol 7: 731–737

    Article  CAS  Google Scholar 

  29. Basaki Y et al. (2001) γ-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor. Angiogenesis 4: 163–173

    Article  CAS  Google Scholar 

  30. Ray S et al. (2007) In vitro evaluation of protective effects of ascorbic acid and water extract of Spirulina plantesis (blue green algae) on 5-fluorouracil-induced lipid peroxidation. Acta Pol Pharm 64: 335–344

    CAS  PubMed  Google Scholar 

  31. Miller K et al. (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357: 2666–2676

    Article  CAS  Google Scholar 

  32. Fernando NH and Hurwitz HI (2004) Targeted therapy of colorectal cancer: clinical experience with bevacizumab. Oncologist 9 (Suppl 1): S11–S18

    Article  Google Scholar 

  33. Gordon MS and Cunningham D (2005) Managing patients treated with bevacizumab combination therapy. Oncology 69 (Suppl 3): S25–S33

    Article  Google Scholar 

  34. Zhu X et al. (2007) Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 49: 186–193

    Article  CAS  Google Scholar 

  35. van Heeckeren WJ et al. (2007) Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker. J Clin Oncol 25: 2993–2995

    Article  CAS  Google Scholar 

  36. Kabbinavar F et al. (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21: 60–65

    Article  CAS  Google Scholar 

  37. Sandler AB et al. (2004) Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res 10: 4258s–4262s

    Article  CAS  Google Scholar 

  38. Herbst RS and Sandler AB (2004) Non-small cell lung cancer and antiangiogenic therapy: what can be expected of bevacizumab. Oncologist 9 (Suppl 1): S19–S26

    Article  Google Scholar 

  39. Ratner M (2004) Genentech discloses safety concerns over Avastin. Nat Biotechnol 22: 1198

    Article  CAS  Google Scholar 

  40. Roncalli J et al. (2006) Bevacizumab in metastatic colorectal cancer: a left intracardiac thrombotic event. Ann Oncol 17: 1177–1178

    Article  CAS  Google Scholar 

  41. Yoon S et al. (2006) Chemotherapy with bevacizumab, irinotecan, 5-fluorouracil and leucovorin (IFL) associated with a large, embolizing thrombus in the thoracic aorta. Ann Oncol 17: 1851–1852

    Article  CAS  Google Scholar 

  42. Shah MA et al. (2005) Thromboembolic events in gastric cancer: high incidence in patients receiving irinotecan- and bevacizumab-based therapy. J Clin Oncol 23: 2574–2576

    Article  Google Scholar 

  43. Seiwert TY et al. (2008) Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol 26: 1732–1741

    Article  CAS  Google Scholar 

  44. Lee S et al. (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130: 691–703

    Article  CAS  Google Scholar 

  45. Verheul HM and Pinedo HM (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7: 475–485

    Article  CAS  Google Scholar 

  46. Kamba T and McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96: 1788–1795

    Article  CAS  Google Scholar 

  47. Fischer C et al. (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131: 463–475

    Article  CAS  Google Scholar 

  48. Roncone D et al. (2007) Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma. Nat Clin Pract Nephrol 3: 287–293

    Article  Google Scholar 

  49. Frangie C et al. (2007) Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol 8: 177–178

    Article  Google Scholar 

  50. Force T et al. (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7: 332–344

    Article  CAS  Google Scholar 

  51. Motzer RJ et al. (2006) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295: 2516–2524

    Article  CAS  Google Scholar 

  52. Demetri GD et al. (2005) Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of SU11248 in patients (pts) following failure of imatinib for metastatic GIST [abstract #4000]. J Clin Oncol 23 (Suppl): S308

    Google Scholar 

  53. Chu TF et al. (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370: 2011–2019

    Article  CAS  Google Scholar 

  54. Kane RC et al. (2006) Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 12: 7271–7278

    Article  CAS  Google Scholar 

  55. Patel TV et al. (2008) A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst 100: 282–284

    Article  CAS  Google Scholar 

  56. Wu S et al. (2008) Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 9: 117–123

    Article  CAS  Google Scholar 

  57. Berliner S et al. (1990) Acute coronary events following cisplatin-based chemotherapy. Cancer Invest 8: 583–586

    Article  CAS  Google Scholar 

  58. Meinardi MT et al. (2000) Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18: 1725–1732

    Article  CAS  Google Scholar 

  59. Berger CC et al. (1995) Secondary Raynaud's phenomenon and other late vascular complications following chemotherapy for testicular cancer. Eur J Cancer 31A: 2229–2238

    Article  CAS  Google Scholar 

  60. Doll DC et al. (1986) Acute vascular ischemic events after cisplatin-based combination chemotherapy for germ-cell tumors of the testis. Ann Intern Med 105: 48–51

    Article  CAS  Google Scholar 

  61. Rajkumar SV et al. (2003) Thalidomide as initial therapy for early-stage myeloma. Leukemia 17: 775–779

    Article  CAS  Google Scholar 

  62. Noel JK et al. (2008) Systematic review to establish the safety profiles for direct and indirect inhibitors of p38 Mitogen-activated protein kinases for treatment of cancer: a systematic review of the literature. Med Oncol [10.1007/s12032-008-9039-1]

  63. Palumbo A et al. (2008) Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 22: 414–423

    Article  CAS  Google Scholar 

  64. Palumbo A et al. (2006) Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367: 825–831

    Article  CAS  Google Scholar 

  65. Facon T et al. (2007) Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 370: 1209–1218

    Article  CAS  Google Scholar 

  66. Baz R et al. (2005) The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 80: 1568–1574

    Article  CAS  Google Scholar 

  67. Goz M et al. (2008) Arterial thrombosis and thalidomide. J Thromb Thrombolysis 25: 224–226

    Article  Google Scholar 

  68. Fanelli M et al. (2003) Thalidomide: a new anticancer drug. Expert Opin Investig Drugs 12: 1211–1225

    Article  CAS  Google Scholar 

  69. Dimopoulos M et al. (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357: 2123–2132

    Article  CAS  Google Scholar 

  70. Richardson PG et al. (2006) Lenalidomide in multiple myeloma. Expert Rev Anticancer Ther 6: 1165–1173

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. IN Daher is Assistant Professor and ETH Yeh is Professor and Chair at the Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,

    Iyad N Daher & Edward TH Yeh

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  1. Iyad N Daher
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  2. Edward TH Yeh
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Correspondence to Edward TH Yeh.

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Daher, I., Yeh, E. Vascular complications of selected cancer therapies. Nat Rev Cardiol 5, 797–805 (2008). https://doi.org/10.1038/ncpcardio1375

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