Skip to main content

Advertisement

SpringerLink
Log in

The Double Edged Sword of Bleeding and Clotting from VEGF Inhibition in Renal Cancer Patients

  • Palliative Medicine (A Jatoi, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Vascular endothelial growth factor (VEGF) inhibitors have significantly improved outcomes in patients with advanced renal cell carcinoma (RCC). Multiple VEGF inhibiting orally administered tyrosine kinase inhibitors (TKIs) have been approved including sunitinib, sorafenib, pazopanib and most recently, axitinib. One VEGF inhibiting monoclonal antibody, bevacizumab, is approved in combination with interferon. However, these agents, besides the known progression-free survival benefits, are associated with a small but real risk of potentially life threatening and contrasting toxicities of thrombosis (both venous and arterial) and bleeding. Appropriate patient selection for VEGF inhibitors and prevention as well as prompt intervention to manage thrombosis and bleeding are necessary to forestall serious morbidities and mortality.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

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

  1. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.

    Article  PubMed  CAS  Google Scholar 

  2. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–8.

    Article  PubMed  CAS  Google Scholar 

  3. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26:5422–8.

    Article  PubMed  CAS  Google Scholar 

  4. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28:2144–50.

    Google Scholar 

  5. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.

    Article  PubMed  CAS  Google Scholar 

  6. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312–8.

    Article  PubMed  CAS  Google Scholar 

  7. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280–9.

    Article  PubMed  CAS  Google Scholar 

  8. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81.

    Article  PubMed  CAS  Google Scholar 

  9. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133–41.

    Article  PubMed  CAS  Google Scholar 

  10. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256–65.

    Article  PubMed  CAS  Google Scholar 

  11. Rini BI EB, Tomczak P, Kaprin A, Hutson TE, Szczylik C, et al. Axitinib versus sorafenib as second-line therapy for metastatic renal cell carcinoma (mRCC): Results of phase III AXIS trial. J Clin Oncol. 2011;29 (suppl; abstr 4503).

  12. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293:715–22.

    Article  PubMed  CAS  Google Scholar 

  13. Rickles FR, Patierno S, Fernandez PM. Tissue factor, thrombin, and cancer. Chest. 2003;124:58S–68S.

    Article  PubMed  CAS  Google Scholar 

  14. Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ. Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol. 2009;27:4865–73.

    Article  PubMed  CAS  Google Scholar 

  15. Stone JR, Collins T. The role of hydrogen peroxide in endothelial proliferative responses. Endothelium. 2002;9:231–8.

    Article  PubMed  CAS  Google Scholar 

  16. Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res. 2001;49:568–81.

    Article  PubMed  CAS  Google Scholar 

  17. Gonzalez-Pacheco FR, Deudero JJ, Castellanos MC, Castilla MA, Alvarez-Arroyo MV, Yague S, et al. Mechanisms of endothelial response to oxidative aggression: protective role of autologous VEGF and induction of VEGFR2 by H2O2. Am J Physiol Heart Circ Physiol. 2006;291:H1395–401.

    Article  PubMed  CAS  Google Scholar 

  18. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788–95.

    Article  PubMed  CAS  Google Scholar 

  19. Hesser BA, Liang XH, Camenisch G, Yang S, Lewin DA, Scheller R, et al. Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood. 2004;104:149–58.

    Article  PubMed  CAS  Google Scholar 

  20. Kuenen BC, Levi M, Meijers JC, Kakkar AK, van Hinsbergh VW, Kostense PJ, et al. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol. 2002;22:1500–5.

    Article  PubMed  CAS  Google Scholar 

  21. Meyer T, Robles-Carrillo L, Robson T, Langer F, Desai H, Davila M, et al. Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost. 2009;7:171–81.

    Article  PubMed  CAS  Google Scholar 

  22. Huang WC, Levey AS, Serio AM, Snyder M, Vickers AJ, Raj GV, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol. 2006;7:735–40.

    Article  PubMed  Google Scholar 

  23. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–91.

    Article  PubMed  CAS  Google Scholar 

  24. •• Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232–9. This is an important individual patient level meta-analysis of 1745 patients that demonstrated an increased risk of ATEs but not VTEs with bevacizumab compared to controls with advanced solid tumors.

    Article  PubMed  Google Scholar 

  25. Streiff MB. Diagnosis and initial treatment of venous thromboembolism in patients with cancer. J Clin Oncol. 2009;27:4889–94.

    Article  PubMed  Google Scholar 

  26. •• Schutz FA, Je Y, Azzi GR, Nguyen PL, Choueiri TK. Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes. Ann Oncol. 2011;22:1404–12. This is a large trial-level meta-analysis of 13,026 patients that demonstrated an increased risk of ATEs with bevacizumab compared to control patients with advanced solid tumors.

  27. •• Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol. 2010;49:287–97. This is another large trial-level meta-analysis of 12,617 patients that demonstrated an increased risk of ATEs with bevacizumab compared to control patients with advanced solid tumors, and also demonstrated that the risk of high-grade cardiac ischemia was significantly higher, while the risk of ischemic stroke was not significantly different from controls.

  28. •• Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28:2280–5. This is a large trial-level meta-analysis of 10,255 patients that demonstrated an increased risk of ATEs with sunitinib and sorafenib compared to control patients with advanced solid tumors.

    Article  PubMed  CAS  Google Scholar 

  29. •• Hurwitz HI, Saltz LB, Van Cutsem E, Cassidy J, Wiedemann J, Sirzen F, et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol. 2011;29:1757–64. This is an important individual patient level meta-analysis of 6055 patients with advanced solid tumors that demonstrated no increase in risk of VTEs with bevacizumab compared to control patients.

  30. •• Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277–85. This is a large trial-level meta-analysis of 7956 patients with advanced solid tumors that demonstrated an increase in risk of VTEs with bevacizumab compared to control patients.

    Article  PubMed  CAS  Google Scholar 

  31. Chu D, Wu S. Risk of venous thromboembolism with bevacizumab in cancer patients: reply. JAMA. 2009;301:1435–6.

    Article  CAS  Google Scholar 

  32. Stadler WM, Cao D, Vogelzang NJ, Ryan CW, Hoving K, Wright R, et al. A randomized Phase II trial of the antiangiogenic agent SU5416 in hormone-refractory prostate cancer. Clin Cancer Res. 2004;10:3365–70.

    Article  PubMed  CAS  Google Scholar 

  33. Zangari M, Anaissie E, Stopeck A, Morimoto A, Tan N, Lancet J, et al. Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma. Clin Cancer Res. 2004;10:88–95.

    Article  PubMed  CAS  Google Scholar 

  34. Heymach JV, Desai J, Manola J, Davis DW, McConkey DJ, Harmon D, et al. Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas. Clin Cancer Res. 2004;10:5732–40.

    Article  PubMed  CAS  Google Scholar 

  35. • Schutz FA RJ, Je Y, Bellmunt J, Choueiri TK. Risk of venous thromboembolic events with sunitinib and sorafenib: A systematic review and meta-analysis of clinical trials. Genitourinary Cancer Symposium 2010, San Francisco, abstract 348. This is a trial-level meta-analysis of 2167 patients with advanced solid tumors presented at a major conference that demonstrated no increase in risk of VTEs with sunitinib and sorafenib compared to control patients.

  36. •• Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology. 2010;79:27–38. This is a large trial-level meta-analysis of 12,617 patients that demonstrated an increased risk of bleeding with bevacizumab compared to control patients with advanced solid tumors.

  37. •• Hang XF, Xu WS, Wang JX, Wang L, Xin HG, Zhang RQ, et al. Risk of high-grade bleeding in patients with cancer treated with bevacizumab: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2011;67:613–23. This is another large trial-level meta-analysis of 14,277 patients with advanced solid tumors that demonstrated an increased risk of high-grade bleeding with bevacizumab compared to control patients, which appeared dose dependent.

  38. •• Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 2009;10:967–74. This is a large trial-level meta-analysis of 6779 patients that demonstrated an increased risk of bleeding with sunitinib and sorafenib compared to control patients with advanced solid tumors.

    Article  PubMed  CAS  Google Scholar 

  39. Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28:2817–23.

    Google Scholar 

  40. •• Schutz FA, Je Y, Richards CJ, Choueiri TK. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol. This is a large trial-level meta-analysis of 4679 patients that demonstrated an increased risk of fatal adverse events with VEGF receptor TKIs compared to control patients with advanced solid tumors, which were most commonly attributable to bleeding events.

  41. •• Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA. 2011;305:487–94. This is a large trial-level meta-analysis of 10,217 patients that demonstrated an increased risk of fatal adverse events with bevacizumab compared to control patients with advanced solid tumors, which were most commonly attributable to bleeding events.

  42. •• Carden CP, Larkin JM, Rosenthal MA. What is the risk of intracranial bleeding during anti-VEGF therapy? Neuro Oncol. 2008;10:624–30. This retrospective study examined 121 patients with advanced solid tumors and brain metastasis and demonstrated no intracranial hemorrhage with bevacizumab or VEGF receptor TKIs.

    Article  PubMed  Google Scholar 

  43. •• Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res. 2010;16:269–78. This large retrospective trial-level analysis of patients with advanced solid tumors and brain metastasis demonstrated no significant increase in intracranial hemorrhage with bevacizumab.

  44. De Braganca KC, Janjigian YY, Azzoli CG, Kris MG, Pietanza MC, Nolan CP, et al. Efficacy and safety of bevacizumab in active brain metastases from non-small cell lung cancer. J Neurooncol. 2010;100:443–7.

    Google Scholar 

  45. • Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol. 2009;27:5255–61. This is a prospective trial that demonstrated that none of 115 patients with NSCLC and brain metastasis receiving bevacizumab with either platinum-based doublet chemotherapy or oral erlotinib followed by single-agent bevacizumab until disease progression, developed grade ≥2 intracranial hemorrhage.

    Article  PubMed  CAS  Google Scholar 

  46. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740–5.

    Article  PubMed  CAS  Google Scholar 

  47. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–40.

    Article  PubMed  CAS  Google Scholar 

  48. Norden AD, Bartolomeo J, Tanaka S, Drappatz J, Ciampa AS, Doherty LM, et al. Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol. 2012;106:121–5.

    Google Scholar 

  49. Richards CJ, Je Y, Schutz FA, Heng DY, Dallabrida SM, Moslehi JJ, et al. Incidence and risk of congestive heart failure in patients with renal and nonrenal cell carcinoma treated with sunitinib. J Clin Oncol. 2011;29:3450–6.

    Google Scholar 

  50. Di Lorenzo G, Autorino R, Bruni G, Carteni G, Ricevuto E, Tudini M, et al. Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol. 2009;20:1535–42.

    Article  PubMed  Google Scholar 

  51. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:234S–64S.

    Article  PubMed  CAS  Google Scholar 

  52. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA. 2004;292:1867–74.

    Article  PubMed  CAS  Google Scholar 

  53. Khorana AA, Streiff MB, Farge D, Mandala M, Debourdeau P, Cajfinger F, et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. J Clin Oncol. 2009;27:4919–26.

    Article  PubMed  CAS  Google Scholar 

  54. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29–37.

    Google Scholar 

  55. Becattini C, Agnelli G, Poggio R, et al. Aspirin after oral anticoagulants for prevention of recurrence in patients with unprovoked venous thromboembolism. The Warfasa STUDY. Abstract #543; Annual Meeting of the American Society of Hematology; Dec 10–13, 2011; San Diego, California.

  56. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146–53.

    Article  PubMed  CAS  Google Scholar 

  57. Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123–9.

    Article  PubMed  CAS  Google Scholar 

  58. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S–94S.

    Google Scholar 

  59. Leighl NB, Bennouna J, Yi J, Moore N, Hambleton J, Hurwitz H. Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study. Br J Cancer. 2011;104:413–8.

    Google Scholar 

  60. Cooper H, Hedges L. The handbook of research synthesis. New York: Russell Sage; 1994.

    Google Scholar 

Download references

Disclosure

G. Sonpavde: research support from Novartis, Celgene, Teva, BMS, and Pfizer, and speaking honoraria from Novartis and GSK; T. K. Choueiri: research support from Pfizer, and advisory board for Pfizer, GSK, Novartis, Aveo, and Bayer/Onyx; F. Schutz: none; J. Bellmunt: advisory board for Pfizer, GSK, Novartis, Aveo, and Bayer/Onyx.

Author information

Authors and Affiliations

  1. Texas Oncology, Houston, TX, USA

    Guru Sonpavde

  2. Veterans Affairs Medical Center and the Baylor College of Medicine, Houston, TX, USA

    Guru Sonpavde

  3. Medical Oncology, University Hospital Del Mar–IMIM, UPF University, Paseig Maritim 25-29, Barcelona, Spain

    Joaquim Bellmunt

  4. Sao Jose Hospital, Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil

    Fabio Schutz

  5. Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Toni K. Choueiri

Authors
  1. Guru Sonpavde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joaquim Bellmunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fabio Schutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toni K. Choueiri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joaquim Bellmunt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sonpavde, G., Bellmunt, J., Schutz, F. et al. The Double Edged Sword of Bleeding and Clotting from VEGF Inhibition in Renal Cancer Patients. Curr Oncol Rep 14, 295–306 (2012). https://doi.org/10.1007/s11912-012-0237-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-012-0237-9

Keywords

Search

Navigation