UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects

Authors
Toni K Choueiri, MD
Guru Sonpavde, MD
Section Editors
Michael B Atkins, MD
Richard M Goldberg, MD
Richard A Larson, MD
Deputy Editors
Diane MF Savarese, MD
Jennifer S Tirnauer, MD

INTRODUCTION

The use of angiogenesis inhibitors in cancer therapy is expanding. Following the recognition of the role of angiogenesis in promoting tumor growth [1], multiple trials have shown that angiogenesis inhibitors yield incremental improvements in outcomes for a variety of advanced solid tumors.

Several classes of agents are available:

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) that inhibits binding of the normal VEGF ligand to its receptor. In the United States, the approval of bevacizumab for metastatic colorectal cancer (mCRC) by the US Food and Drug Administration (FDA) ushered in the modern era of antiangiogenic therapy. The European Medicines Agency (EMA) granted approval for bevacizumab in mCRC in January 2006. Subsequently, bevacizumab has been approved by the FDA for treatment of metastatic non-squamous non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), ovarian cancer, cervical cancer, and glioblastoma multiforme (GBM). In the European Union, bevacizumab is approved for breast cancer, NSCLC, ovarian cancer, and renal cell cancer but not for GBM or cervical cancer.

(See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Bevacizumab'.)

(See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation", section on 'Toxicity'.)

                                                          

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Mon Oct 03 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285:1182.
  2. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet 2016; 388:518.
  3. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 2011; 305:487.
  4. 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 2012; 30:871.
  5. Sivendran S, Liu Z, Portas LJ Jr, et al. Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Cancer Treat Rev 2012; 38:919.
  6. Sandler AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res 2004; 10:4258s.
  7. Gressett SM, Shah SR. Intricacies of bevacizumab-induced toxicities and their management. Ann Pharmacother 2009; 43:490.
  8. Costero O, Picazo ML, Zamora P, et al. Inhibition of tyrosine kinases by sunitinib associated with focal segmental glomerulosclerosis lesion in addition to thrombotic microangiopathy. Nephrol Dial Transplant 2010; 25:1001.
  9. Izzedine H, Massard C, Spano JP, et al. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. Eur J Cancer 2010; 46:439.
  10. Tomita Y, Uemura H, Fujimoto H, et al. Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: a phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma. Eur J Cancer 2011; 47:2592.
  11. Wu S, Kim C, Baer L, Zhu X. Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol 2010; 21:1381.
  12. Shah SR, Gressett Ussery SM, Dowell JE, et al. Shorter bevacizumab infusions do not increase the incidence of proteinuria and hypertension. Ann Oncol 2013; 24:960.
  13. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012; 30:3499.
  14. Zhang ZF, Wang T, Liu LH, Guo HQ. Risks of proteinuria associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a systematic review and meta-analysis. PLoS One 2014; 9:e90135.
  15. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381:303.
  16. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 2007; 49:186.
  17. Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 2009; 48:9.
  18. Shord SS, Bressler LR, Tierney LA, et al. Understanding and managing the possible adverse effects associated with bevacizumab. Am J Health Syst Pharm 2009; 66:999.
  19. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008; 358:1129.
  20. Johnson DH, Fehrenbacher L, Novotny WF, 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.
  21. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111:649.
  22. Bollée G, Patey N, Cazajous G, et al. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant 2009; 24:682.
  23. George BA, Zhou XJ, Toto R. Nephrotic syndrome after bevacizumab: case report and literature review. Am J Kidney Dis 2007; 49:e23.
  24. Eremina V, Quaggin SE. The role of VEGF-A in glomerular development and function. Curr Opin Nephrol Hypertens 2004; 13:9.
  25. Ostendorf T, Kunter U, Eitner F, et al. VEGF(165) mediates glomerular endothelial repair. J Clin Invest 1999; 104:913.
  26. Yeh J, Frieze D, Martins R, Carr L. Clinical utility of routine proteinuria evaluation in treatment decisions of patients receiving bevacizumab for metastatic solid tumors. Ann Pharmacother 2010; 44:1010.
  27. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009; 27:4462.
  28. Patel TV, Morgan JA, Demetri GD, et al. A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst 2008; 100:282.
  29. Halimi JM, Azizi M, Bobrie G, et al. [Vascular and renal effects of anti-angiogenic therapy]. Nephrol Ther 2008; 4:602.
  30. Robinson BG, Paz-Ares L, Krebs A, et al. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2010; 95:2664.
  31. Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010; 28:767.
  32. Tam BY, Wei K, Rudge JS, et al. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med 2006; 12:793.
  33. Alexandrescu DT, McClure R, Farzanmehr H, Dasanu CA. Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib. J Clin Oncol 2008; 26:4047.
  34. Harshman LC, Kuo CJ, Wong BY, et al. Increased hemoglobin associated with VEGF inhibitors in advanced renal cell carcinoma. Cancer Invest 2009; 27:851.
  35. van der Veldt AA, Boven E, Vroling L, et al. Sunitinib-induced hemoglobin changes are related to the dosing schedule. J Clin Oncol 2009; 27:1339.
  36. Alexandre I, Billemont B, Meric JB, et al. Axitinib induces paradoxical erythropoietin synthesis in metastatic renal cell carcinoma. J Clin Oncol 2009; 27:472.
  37. Harshman LC KC, Srinivas S. Bevacizumab-associated erythrocytosis in metastatic renal cell carcinoma. J Clin Oncol 26: 2008 (May 20 suppl; abstr 16096).
  38. Hang XF, Xu WS, Wang JX, 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.
  39. 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.
  40. 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.
  41. Kozloff M, Yood MU, Berlin J, et al. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 2009; 14:862.
  42. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383:31.
  43. Qi WX, Tang LN, Sun YJ, et al. Incidence and risk of hemorrhagic events with vascular endothelial growth factor receptor tyrosine-kinase inhibitors: an up-to-date meta-analysis of 27 randomized controlled trials. Ann Oncol 2013; 24:2943.
  44. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001; 19:843.
  45. Besse B, Lasserre SF, Compton P, et al. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res 2010; 16:269.
  46. Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol 2009; 27:5255.
  47. Crinò L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol 2010; 11:733.
  48. Carden CP, Larkin JM, Rosenthal MA. What is the risk of intracranial bleeding during anti-VEGF therapy? Neuro Oncol 2008; 10:624.
  49. Kreisl TN, Kim L, Moore K, 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.
  50. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27:4733.
  51. Norden AD, Bartolomeo J, Tanaka S, et al. Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol 2012; 106:121.
  52. Harshman LC, Yu RJ, Allen GI, et al. Surgical outcomes and complications associated with presurgical tyrosine kinase inhibition for advanced renal cell carcinoma (RCC). Urol Oncol 2013; 31:379.
  53. Sandler A, Hirsh V, Reck M, et al. An evidence-based review of the incidence of CNS bleeding with anti-VEGF therapy in non-small cell lung cancer patients with brain metastases. Lung Cancer 2012; 78:1.
  54. Pouessel D, Culine S. High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor. Eur Urol 2008; 53:376.
  55. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542.
  56. Crabb SJ, Patsios D, Sauerbrei E, et al. Tumor cavitation: impact on objective response evaluation in trials of angiogenesis inhibitors in non-small-cell lung cancer. J Clin Oncol 2009; 27:404.
  57. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009; 27:1227.
  58. Marom EM, Martinez CH, Truong MT, et al. Tumor cavitation during therapy with antiangiogenesis agents in patients with lung cancer. J Thorac Oncol 2008; 3:351.
  59. Sandler AB, Schiller JH, Gray R, et al. Retrospective evaluation of the clinical and radiographic risk factors associated with severe pulmonary hemorrhage in first-line advanced, unresectable non-small-cell lung cancer treated with Carboplatin and Paclitaxel plus bevacizumab. J Clin Oncol 2009; 27:1405.
  60. Socinski MA, Novello S, Brahmer JR, et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol 2008; 26:650.
  61. Blumenschein GR Jr, Gatzemeier U, Fossella F, et al. Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. J Clin Oncol 2009; 27:4274.
  62. Reck M, Barlesi F, Crinò L, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts. Ann Oncol 2012; 23:1111.
  63. Valipour A, Kreuzer A, Koller H, et al. Bronchoscopy-guided topical hemostatic tamponade therapy for the management of life-threatening hemoptysis. Chest 2005; 127:2113.
  64. Kvale PA, Selecky PA, Prakash UB, American College of Chest Physicians. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132:368S.
  65. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005; 91:173.
  66. Cortés J, Caralt M, Delaloge S, et al. Safety of bevacizumab in metastatic breast cancer patients undergoing surgery. Eur J Cancer 2012; 48:475.
  67. Chamberlain MC. Bevacizumab plus irinotecan in recurrent glioblastoma. J Clin Oncol 2008; 26:1012.
  68. Clark AJ, Butowski NA, Chang SM, et al. Impact of bevacizumab chemotherapy on craniotomy wound healing. J Neurosurg 2011; 114:1609.
  69. Erinjeri JP, Fong AJ, Kemeny NE, et al. Timing of administration of bevacizumab chemotherapy affects wound healing after chest wall port placement. Cancer 2011; 117:1296.
  70. Zawacki WJ, Walker TG, DeVasher E, et al. Wound dehiscence or failure to heal following venous access port placement in patients receiving bevacizumab therapy. J Vasc Interv Radiol 2009; 20:624.
  71. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 2010; 28:43.
  72. Gore E, Currey A, Choong N. Tracheoesophageal fistula associated with bevacizumab 21 months after completion of radiation therapy. J Thorac Oncol 2009; 4:1590.
  73. Goodgame B, Veeramachaneni N, Patterson A, Govindan R. Tracheo-esophageal fistula with bevacizumab after mediastinal radiation. J Thorac Oncol 2008; 3:1080.
  74. US Food and Drug Administration (FDA)-approved prescribing information for ramucirumab available online at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477lbl.pdf (Accessed on April 25, 2014).
  75. Feyerabend S, Schilling D, Wicke C, Stenzl A. Toxic dermatolysis, tissue necrosis and impaired wound healing due to sunitinib treatment leading to forefoot amputation. Urol Int 2009; 82:246.
  76. Chapin BF, Delacroix SE Jr, Culp SH, et al. Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma. Eur Urol 2011; 60:964.
  77. Jonasch E, Wood CG, Matin SF, et al. Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27:4076.
  78. Powles T, Kayani I, Blank C, et al. The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer. Ann Oncol 2011; 22:1041.
  79. Eisen T, Sternberg CN, Robert C, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst 2012; 104:93.
  80. Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol 2007; 105:3.
  81. Mir O, Mouthon L, Alexandre J, et al. Bevacizumab-induced cardiovascular events: a consequence of cholesterol emboli syndrome? J Natl Cancer Inst 2007; 99:85.
  82. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007; 7:475.
  83. Ganapathi AM, Westmoreland T, Tyler D, Mantyh CR. Bevacizumab-associated fistula formation in postoperative colorectal cancer patients. J Am Coll Surg 2012; 214:582.
  84. Kabbinavar FF, Flynn PJ, Kozloff M, et al. Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: results from a large treatment observational cohort study. Eur J Cancer 2012; 48:1126.
  85. Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol 2009; 10:559.
  86. Schellhaas E, Loddenkemper C, Schmittel A, et al. Bowel perforation in non-small cell lung cancer after bevacizumab therapy. Invest New Drugs 2009; 27:184.
  87. 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.
  88. Bège T, Lelong B, Viret F, et al. Bevacizumab-related surgical site complication despite primary tumor resection in colorectal cancer patients. Ann Surg Oncol 2009; 16:856.
  89. Ley EJ, Vukasin P, Kaiser AM, et al. Delayed rectovaginal fistula: a potential complication of bevacizumab (avastin). Dis Colon Rectum 2007; 50:930.
  90. Liu SV, Gollard R, Iqbal S. Case report of perforation of an ileal neobladder after treatment of rectal cancer with bevacizumab and comment on mechanisms of intestinal perforation associated with bevacizumab. J Clin Pharm Ther 2012; 37:607.
  91. Tol J, Cats A, Mol L, et al. Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation. Invest New Drugs 2008; 26:393.
  92. Tarnawski AS. Cellular and molecular mechanisms of gastrointestinal ulcer healing. Dig Dis Sci 2005; 50 Suppl 1:S24.
  93. Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2009; 75:156.
  94. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 2007; 25:5180.
  95. Richardson DL, Backes FJ, Hurt JD, et al. Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab? Gynecol Oncol 2010; 118:47.
  96. Aghajanian C. The role of bevacizumab in ovarian cancer--an evolving story. Gynecol Oncol 2006; 102:131.
  97. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008; 26:76.
  98. Nimeiri HS, Oza AM, Morgan RJ, et al. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol 2008; 110:49.
  99. Simpkins F, Belinson JL, Rose PG. Avoiding bevacizumab related gastrointestinal toxicity for recurrent ovarian cancer by careful patient screening. Gynecol Oncol 2007; 107:118.
  100. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365:2473.
  101. Burger RA, Brady MF, Bookman MA, et al. Risk factors for GI adverse events in a phase III randomized trial of bevacizumab in first-line therapy of advanced ovarian cancer: A Gynecologic Oncology Group Study. J Clin Oncol 2014; 32:1210.
  102. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365:2484.
  103. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30:2039.
  104. Walraven M, Witteveen PO, Lolkema MP, et al. Antiangiogenic tyrosine kinase inhibition related gastrointestinal perforations: a case report and literature review. Angiogenesis 2011; 14:135.
  105. Flaig TW, Kim FJ, La Rosa FG, et al. Colonic pneumatosis and intestinal perforations with sunitinib treatment for renal cell carcinoma. Invest New Drugs 2009; 27:83.
  106. Hur H, Park AR, Jee SB, et al. Perforation of the colon by invading recurrent gastrointestinal stromal tumors during sunitinib treatment. World J Gastroenterol 2008; 14:6096.
  107. Peters NA, Richel DJ, Verhoeff JJ, Stalpers LJ. Bowel perforation after radiotherapy in a patient receiving sorafenib. J Clin Oncol 2008; 26:2405.
  108. Park SG, Chung CH, Park CY. Colon perforation during sorafenib therapy for advanced hepatocelluar carcinoma. A case report. Tumori 2011; 97:794.
  109. Kindler H, Campbell NP, Wroblewski K, et al. Final results of a University of Chicago phase II consortium trial of sorafenib (SOR) in patients (pts) with imatinib (IM)- and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST) (abstract). Data presented at the 2011 ASCO GI Cancers Symposium, January 20-22, San Francisco, CA. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=103&abstractID=70751 (Accessed on March 03, 2011).
  110. Qi WX, Sun YJ, Tang LN, et al. Risk of gastrointestinal perforation in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis. Crit Rev Oncol Hematol 2014; 89:394.
  111. Diaz JP, Tew WP, Zivanovic O, et al. Incidence and management of bevacizumab-associated gastrointestinal perforations in patients with recurrent ovarian carcinoma. Gynecol Oncol 2010; 116:335.
  112. Shinagare AB, Howard SA, Krajewski KM, et al. Pneumatosis intestinalis and bowel perforation associated with molecular targeted therapy: an emerging problem and the role of radiologists in its management. AJR Am J Roentgenol 2012; 199:1259.
  113. Badgwell BD, Camp ER, Feig B, et al. Management of bevacizumab-associated bowel perforation: a case series and review of the literature. Ann Oncol 2008; 19:577.
  114. Ghatalia P, Je Y, Nguyen PL, et al. Fatigue with vascular endothelial growth factor receptor tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors in patients with renal cell carcinoma (RCC) and other malignancies: A meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2015; 95:251.
  115. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931.
  116. Motzer RJ ND, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial. J Clin Oncol 2012; 30s (suppl; abstr 4501).
  117. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372:621.
  118. Estilo CL, Fornier M, Farooki A, et al. Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol 2008; 26:4037.
  119. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol 2012; 113:e1.
  120. Nicolatou-Galitis O, Migkou M, Psyrri A, et al. Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications. Oral Surg Oral Med Oral Pathol Oral Radiol 2012; 113:234.
  121. Pakosch D, Papadimas D, Munding J, et al. Osteonecrosis of the mandible due to anti-angiogenic agent, bevacizumab. Oral Maxillofac Surg 2013; 17:303.
  122. Bevacizumab, sunitinib: osteonecrosis of the jaw. Prescrire Int 2011; 20:155.
  123. Van Poznak C. Osteonecrosis of the jaw and bevacizumab therapy. Breast Cancer Res Treat 2010; 122:189.
  124. Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol 2008; 19:2091.
  125. Koch FP, Walter C, Hansen T, et al. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 2011; 15:63.
  126. Antonuzzo L, Lunghi A, Giommoni E, et al. Regorafenib Also Can Cause Osteonecrosis of the Jaw. J Natl Cancer Inst 2016; 108.
  127. Guarneri V, Miles D, Robert N, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 2010; 122:181.
  128. Sclafani F, Giuseppe G, Mezynksi J, et al. Reversible posterior leukoencephalopathy syndrome and bevacizumab in breast cancer. J Clin Oncol 2012; 30:e257.
  129. Lou E, Turner S, Sumrall A, et al. Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma. J Clin Oncol 2011; 29:e739.
  130. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006; 354:980.
  131. Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006; 354:980.
  132. Martín G, Bellido L, Cruz JJ. Reversible posterior leukoencephalopathy syndrome induced by sunitinib. J Clin Oncol 2007; 25:3559.
  133. Govindarajan R, Adusumilli J, Baxter DL, et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol 2006; 24:e48.
  134. Chelis L, Souftas V, Amarantidis K, et al. Reversible posterior leukoencephalopathy syndrome induced by pazopanib. BMC Cancer 2012; 12:489.
  135. Dogan E, Aksoy S, Arslan C, et al. Probable sorafenib-induced reversible encephalopathy in a patient with hepatocellular carcinoma. Med Oncol 2010; 27:1436.
  136. Kapiteijn E, Brand A, Kroep J, Gelderblom H. Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol 2007; 18:1745.
  137. Allen JA, Adlakha A, Bergethon PR. Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer. Arch Neurol 2006; 63:1475.
  138. Seet RC, Rabinstein AA. Clinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment. QJM 2012; 105:69.
  139. Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007; 99:81.
  140. Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006; 145:660.
  141. Feldt S, Schüssel K, Quinzler R, et al. Incidence of thyroid hormone therapy in patients treated with sunitinib or sorafenib: a cohort study. Eur J Cancer 2012; 48:974.
  142. Torino F, Corsello SM, Longo R, et al. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 2009; 6:219.
  143. Mannavola D, Coco P, Vannucchi G, et al. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 2007; 92:3531.
  144. Grossmann M, Premaratne E, Desai J, Davis ID. Thyrotoxicosis during sunitinib treatment for renal cell carcinoma. Clin Endocrinol (Oxf) 2008; 69:669.
  145. Faris JE, Moore AF, Daniels GH. Sunitinib (sutent)-induced thyrotoxicosis due to destructive thyroiditis: a case report. Thyroid 2007; 17:1147.
  146. Sakurai K, Fukazawa H, Arihara Z, Yoshida K. Sunitinib-induced thyrotoxicosis followed by persistent hypothyroidism with shrinkage of thyroid volume. Tohoku J Exp Med 2010; 222:39.
  147. Alexandrescu DT, Popoveniuc G, Farzanmehr H, et al. Sunitinib-associated lymphocytic thyroiditis without circulating antithyroid antibodies. Thyroid 2008; 18:809.
  148. Tamaskar I, Bukowski R, Elson P, et al. Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 2008; 19:265.
  149. Miyake H, Kurahashi T, Yamanaka K, et al. Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: a prospective evaluation. Urol Oncol 2010; 28:515.
  150. Escudier B, Eisen T, Stadler WM, 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.
  151. Robinson SI, Hobday TJ, Sathananthan A, et al. Can sorafenib cause hypothyroidism? J Chemother 2007; 19:352.
  152. Haraldsdottir S, Li Q, Villalona-Calero MA, et al. Case of sorafenib-induced thyroid storm. J Clin Oncol 2013; 31:e262.
  153. Barbaro D. Sorafenib and thyrotoxicosis. J Endocrinol Invest 2010; 33:436.
  154. van Doorn L, Eskens FA, Visser TJ, et al. Sorafenib induced thyroiditis in two patients with hepatocellular carcinoma. Thyroid 2011; 21:197.
  155. Fujiwara Y, Kiyota N, Chayahara N, et al. Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients. Invest New Drugs 2012; 30:1055.
  156. Figlin RA, de Souza P, McDermott D, et al. Analysis of PTEN and HIF-1alpha and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-alpha. Cancer 2009; 115:3651.
  157. Sternberg CN, Davis ID, Mardiak 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.
  158. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf?et_cid=35470087&et_rid=907466112&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2015%2f206947s000lbl.pdf (Accessed on February 20, 2015).
  159. Kumar R, Crouthamel MC, Rominger DH, et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 2009; 101:1717.
  160. Funakoshi T, Latif A, Galsky MD. Risk of hematologic toxicities in cancer patients treated with sunitinib: a systematic review and meta-analysis. Cancer Treat Rev 2013; 39:818.
  161. Heath EI, Blumenschein GR Jr, Cohen RB, et al. Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results. Cancer Chemother Pharmacol 2011; 68:703.
  162. van Erp NP, Mathijssen RH, van der Veldt AA, et al. Myelosuppression by sunitinib is flt-3 genotype dependent. Br J Cancer 2010; 103:757.
  163. van Erp NP, Eechoute K, van der Veldt AA, et al. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 2009; 27:4406.
  164. Schutz FA, Je Y, Choueiri TK. Hematologic toxicities in cancer patients treated with the multi-tyrosine kinase sorafenib: a meta-analysis of clinical trials. Crit Rev Oncol Hematol 2011; 80:291.
  165. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013; 31:412.
  166. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, et al. Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 2012; 17:135.
  167. Yuan A, Kurtz SL, Barysauskas CM, et al. Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors. Oral Oncol 2015; 51:1026.
  168. Lee JS, Hirsh V, Park K, et al. Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 2012; 30:1114.
  169. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 2012; 13:897.
  170. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115.
  171. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368:1329.
  172. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011; 29:1059.
  173. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364:501.
  174. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27:3584.
  175. Fischer A, Wu S, Ho AL, Lacouture ME. The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs 2013; 31:787.
  176. Massey PR, Okman JS, Wilkerson J, Cowen EW. Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature. Support Care Cancer 2015; 23:1827.
  177. Poprach A, Pavlik T, Melichar B, et al. Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study. Ann Oncol 2012; 23:3137.
  178. FDA-approved manufacturer's package insert for sorafenib available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b50667e4-5ebc-4968-a646-d605058dbef0#section-2 (Accessed on January 31, 2013).
  179. Ghatalia P, Je Y, Mouallem NE, et al. Hepatotoxicity with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2015; 93:257.
  180. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125.
  181. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367:2075.
  182. Ghatalia P, Morgan CJ, Choueiri TK, et al. Pancreatitis with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Crit Rev Oncol Hematol 2015; 94:136.
  183. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021938s027lbl.pdf (Accessed on January 05, 2015).
  184. Billemont B, Medioni J, Taillade L, et al. Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 2008; 99:1380.
  185. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract 2011; 17:197.
  186. Mailliez A, Baldini C, Van JT, et al. Nasal septum perforation: a side effect of bevacizumab chemotherapy in breast cancer patients. Br J Cancer 2010; 103:772.
  187. Ramiscal JA, Jatoi A. Bevacizumab-induced nasal septal perforation: incidence of symptomatic, confirmed event(s) in colorectal cancer patients. Acta Oncol 2011; 50:578.
  188. http://www.medscape.com/viewarticle/545083 (Accessed on January 31, 2013).
  189. Ramiscal JA, Jatoi A. Nasal septal perforation from bevacizumab: a discussion of outcomes, management, and pharmacovigilance. Curr Oncol Rep 2012; 14:307.
  190. Diamantopoulos II, Jones NS. The investigation of nasal septal perforations and ulcers. J Laryngol Otol 2001; 115:541.
  191. Watson D, Barkdull G. Surgical management of the septal perforation. Otolaryngol Clin North Am 2009; 42:483.
  192. Fakih MG, Lombardo JC. Bevacizumab-induced nasal septum perforation. Oncologist 2006; 11:85.
  193. Ruiz N, Fernandez-Martos C, Romero I, et al. Invasive fungal infection and nasal septum perforation with bevacizumab-based therapy in advanced colon cancer. J Clin Oncol 2007; 25:3376.
  194. Antoun S, Baracos VE, Birdsell L, et al. Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann Oncol 2010; 21:1594.
  195. Antoun S, Birdsell L, Sawyer MB, et al. Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study. J Clin Oncol 2010; 28:1054.
  196. Mir O, Coriat R, Blanchet B, et al. Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma. PLoS One 2012; 7:e37563.
  197. Poterucha T, Burnette B, Jatoi A. A decline in weight and attrition of muscle in colorectal cancer patients receiving chemotherapy with bevacizumab. Med Oncol 2012; 29:1005.
  198. Parsons HA, Tsimberidou AM, Pontikos M, et al. Evaluation of the clinical relevance of body composition parameters in patients with cancer metastatic to the liver treated with hepatic arterial infusion chemotherapy. Nutr Cancer 2012; 64:206.
  199. Hescot S, Vignaux O, Goldwasser F. Pancreatic atrophy--a new late toxic effect of sorafenib. N Engl J Med 2013; 369:1475.
  200. Shinagare AB, Steele E, Braschi-Amirfarzan M, et al. Sunitinib-associated Pancreatic Atrophy in Patients with Gastrointestinal Stromal Tumor: A Toxicity with Prognostic Implications Detected at Imaging. Radiology 2016; 281:140.
  201. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5b7b3a4-c3a4-4722-8ca5-8f6a5c622553 (Accessed on March 04, 2015).