Drug Safety

, Volume 36, Issue 6, pp 413–426 | Cite as

Tyrosine Kinase Inhibitors: Their On-Target Toxicities as Potential Indicators of Efficacy

  • Devron R. Shah
  • Rashmi R. ShahEmail author
  • Joel Morganroth
Review Article


Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, raising hopes for many patients with otherwise unresponsive tumours. While these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. Many of these toxic effects result from downstream inhibition of vascular endothelial growth factor or epidermal growth factor signalling in cells of normal organs. Many of these undesirable effects such as hypertension, hypothyroidism, skin reactions and possibly proteinuria are on-target effects. Since tyrosine kinases are widely distributed with specific functional roles in different organs, this association is not too surprising. Various studies suggest that the development of these on-target effects indicates clinically desirable and effective inhibition of the corresponding ligand-mediated receptor linked with oncogenesis. This is reflected as improved efficacy in the subgroup of patients who develop these on-target adverse effects compared with those who do not. Inevitably, issues arise with respect to the regulatory assessment of efficacy and risk/benefit of the TKIs as well as the clinical approach to managing patients who develop these effects. Routine subgroup analysis of efficacy data from clinical trials (patients with and without on-target toxicity) may enable more effective clinical use of TKIs since (i) discontinuing or reducing the dose of the TKI has a negative impact if the tumour is TKI-responsive; and (ii) it is usually possible to manage these undesirable on-target effects with conventional clinical approaches. Prospective studies are needed to investigate this proposition further.


Overall Survival Hypothyroidism Sorafenib Sunitinib Gefitinib 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The views expressed in this paper are those of the authors and do not necessarily reflect the views or opinions of their affiliates, any regulatory authorities or any of their advisory bodies.

The authors have not received any financial support for writing this commentary. Devron Shah is a first-year house officer at a district general hospital and has no consultancy relationships. Rashmi Shah was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and the ICH E14 Topic Leader, representing the EU. Joel Morganroth is the Chief Cardiac Consultant to eResearchTechnology Inc (eRT), Philadelphia, PA, USA, which provides cardiac safety services to the drug development community. Both Rashmi Shah and Joel Morganroth now provide expert consultancy services on the development of new drugs to a number of pharmaceutical companies.


  1. 1.
    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–87.PubMedCrossRefGoogle Scholar
  2. 2.
    Chen MH, Kerkela R, Force T. Mechanisms of cardiomyopathy associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118(1):84–95.PubMedCrossRefGoogle Scholar
  3. 3.
    Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarization (QT interval). Drug Saf. doi: 10.1007/s40264-013-0047-5
  4. 4.
    Keefe D, Bowen J, Gibson R, et al. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist. 2011;16(4):432–44.PubMedCrossRefGoogle Scholar
  5. 5.
    Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010;60(4):222–43.Google Scholar
  6. 6.
    Gotlink KJ, Verheul HMW. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13(1):1–14.Google Scholar
  7. 7.
    Laurent-Puig P, Lievre A, Blons H. Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res. 2009;15(4):1133–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Elice F, Rodeghiero F, Falanga A, et al. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol. 2009;22(1):115–28.PubMedCrossRefGoogle Scholar
  9. 9.
    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. 2012;14(4):295–306.PubMedCrossRefGoogle Scholar
  10. 10.
    Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29(18):2543–9.PubMedCrossRefGoogle Scholar
  11. 11.
    van Cruijsen H, van der Veldt A, Hoekman K. Tyrosine kinase inhibitors of VEGF receptors: clinical issues and remaining questions. Front Biosci. 2009;14(1):2248–68.PubMedCrossRefGoogle Scholar
  12. 12.
    Roodhart JM, Langenberg MH, Witteveen E, et al. The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol. 2008;3(2):132–43.PubMedCrossRefGoogle Scholar
  13. 13.
    Eaby B, Culkin A, Lacouture ME. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors. Clin J Oncol Nurs. 2008;12(2):283–90.PubMedCrossRefGoogle Scholar
  14. 14.
    Asnacios A, Naveau S, Perlemuter G. Gastrointestinal toxicities of novel agents in cancer therapy. Eur J Cancer. 2009;45(Suppl. 1):332–42.PubMedCrossRefGoogle Scholar
  15. 15.
    Steeghs N, Gelderblom H, Roodt JO, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14(11):3470–6.PubMedCrossRefGoogle Scholar
  16. 16.
    GlaxoSmilthKline. Clinical Study Register. A meta-analysis of the cumulative incidence of hypertension in the first month of treatment with pazopanib across three RCC studies: VEG102616, VEG105192 and VEG107769 (Study number 115227). Available from URL: Accessed 25 Oct 2012.
  17. 17.
    FDA. Label for INLYTA (axitinib) approved on 27 January 2012. Available from URL: Accessed 7 Oct 2012.
  18. 18.
    FDA. Label for BOSULIF (bosutinib) approved on 4 September 2012. Available from URL: Accessed 7 Oct 2012.
  19. 19.
    FDA. Label for XALKORI (crizotinib) approved on 24 February 2012. Available from URL: Accessed 7 Oct 2012.
  20. 20.
    FDA. Label for SPRYCEL (dasatinib) approved on 7 October 2011. Available from URL: Accessed 7 Oct 2012.
  21. 21.
    FDA. Label for TARCEVA (erlotinib) approved on 17 April 2012. Available from URL: Accessed 7 Oct 2012.
  22. 22.
    FDA. Label for IRESSA (gefitinib) approved on 17 June 2005. Available from URL: Accessed 7 Oct 2012.
  23. 23.
    FDA. Label for GLEEVEC (imatinib) approved on 31 January 2012. Available from URL: Accessed 7 Oct 2012.
  24. 24.
    FDA. Label for TYKERB (lapatinib) approved on 14 February 2012. Available from URL: Accessed 7 Oct 2012.
  25. 25.
    FDA. Label for TASIGNA (nilotinib) approved on 1 May 2012. Available from URL: Accessed 7 Oct 2012.
  26. 26.
    FDA. Label for VOTRIENT (pazopanib) approved on 26 April 2012. Available from URL: Accessed 7 Oct 2012.
  27. 27.
    FDA. Label for STIVARGA (regorafenib) approved on 27 September 2012. Available from URL: Accessed 7 Oct 2012.
  28. 28.
    FDA. Label for JAKAFI (ruxolitinib) approved on 21 June 2012. Available from URL: Accessed 7 Oct 2012.
  29. 29.
    FDA. Label for NEXAVAR (sorafenib) approved on 14 October 2011. Available from URL: Accessed 7 Oct 2012.
  30. 30.
    Label for SUTENT (sunitinib) approved on 20 April 2012. Available from URL: Accessed 7 Oct 2012.
  31. 31.
    FDA. Label for CAPRELSA (vandetanib) approved on 22 June 2011. Available from URL: Accessed 7 Oct 2012.
  32. 32.
    FDA. Label for ZELBORAF (vemurafenib) approved on 17 August 2011. Available from URL: Accessed 7 Oct 2012.
  33. 33.
    Nazer B, Humphreys BD, Moslehi J. Effects of novel angiogenesis inhibitors for the treatment of cancer on the cardiovascular system: focus on hypertension. Circulation. 2011;124(15):1687–91.PubMedCrossRefGoogle Scholar
  34. 34.
    Qi WX, Shen Z, Lin F, et al. Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials. Br J Clin Pharmacol. 2013;75(4):919–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763–73.PubMedCrossRefGoogle Scholar
  36. 36.
    George S, Reichardt P, Lechner T, et al. Hypertension as a potential biomarker of efficacy in patients with gastrointestinal stromal tumor treated with sunitinib. Ann Oncol. 2012;23(12):3180–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17(11):3841–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol (Epub 2012 Apr 27).Google Scholar
  39. 39.
    Kim JJ, Vaziri SA, Rini BI, et al. Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib. Cancer. 2012;118(7):1946–54.PubMedCrossRefGoogle Scholar
  40. 40.
    Li XS, Wu X, Zhao PJ, et al. Efficacy and safety of sunitinib in the treatment of metastatic renal cell carcinoma. Chin Med J (Engl). 2011;124(18):2920–4.Google Scholar
  41. 41.
    Clemons J, Gao D, Naam M, et al. Thyroid dysfunction in patients treated with sunitinib or sorafenib. Clin Genitourin Cancer. 2012;10(4):225–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Daimon M, Kato T, Kaino W, et al. Thyroid dysfunction in patients treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, for metastatic renal cell carcinoma. Jpn J Clin Oncol. 2012;42(8):742–7.PubMedCrossRefGoogle Scholar
  43. 43.
    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(4):219–28.PubMedCrossRefGoogle Scholar
  44. 44.
    Sakurai K, Fukazawa H, Arihara Z, et al. Sunitinib-induced thyrotoxicosis followed by persistent hypothyroidism with shrinkage of thyroid volume. Tohoku J Exp Med. 2010;222(1):39–44.PubMedCrossRefGoogle Scholar
  45. 45.
    Krouse RS, Royal RE, Heywood G, et al. Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. J Immunother Emphasis Tumor Immunol. 1995;18(4):272–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Schwartzentruber DJ, White DE, Zweig MH, et al. Thyroid dysfunction associated with immunotherapy for patients with cancer. Cancer. 1991;68(11):2384–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid. 2007;17(4):351–5.PubMedCrossRefGoogle Scholar
  48. 48.
    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(9):3531–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Abdulrahman RM, Verloop H, Hoftijzer H, et al. Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination. J Clin Endocrinol Metab. 2010;95(8):3758–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Kappers MH, van Esch JH, Smedts FM, et al. Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab. 2011;96(10):3087–94.PubMedCrossRefGoogle Scholar
  51. 51.
    Vesely D, Astil J, Lastuvka P, et al. Serum levels of IGF-I, HGF, TGFβ1, bFGF and VEGF in thyroid gland tumors. Physiol Res. 2004;53(1):83–9.PubMedGoogle Scholar
  52. 52.
    Makita N, Miyakawa M, Fujita T, et al. Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid. 2010;20(3):323–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Sato S, Muraishi K, Tani J, et al. Clinical characteristics of thyroid abnormalities induced by sunitinib treatment in Japanese patients with renal cell carcinoma. Endocr J. 2010;57(10):873–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Kitajima K, Takahashi S, Maeda T, et al. Thyroid size change by CT monitoring after sorafenib or sunitinib treatment in patients with renal cell carcinoma: comparison with thyroid function. Eur J Radiol. 2012;81(9):2060–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Riesenbeck LM, Bierer S, Hoffmeister I, et al. Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol. 2011;29(6):807–13.PubMedCrossRefGoogle Scholar
  56. 56.
    Schmidinger M, Vogl UM, Bojic M, et al. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer. 2011;117(3):534–44.PubMedCrossRefGoogle Scholar
  57. 57.
    Robinson ES, Matulonis UA, Ivy P, et al. Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor. Clin J Am Soc Nephrol. 2010;5(3):477–83.PubMedCrossRefGoogle Scholar
  58. 58.
    Eskens FA, de Jonge MJ, Bhargava P, et al. Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin Cancer Res. 2011;17(22):7156–63.PubMedCrossRefGoogle Scholar
  59. 59.
    Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36.PubMedCrossRefGoogle Scholar
  60. 60.
    Eremina V, Quaggin SE. Biology of anti-angiogenc therapy-induced thrombotic microangiopathy. Semin Nephrol. 2010;30(6):582–90.PubMedCrossRefGoogle Scholar
  61. 61.
    Izzedine H, Massard C, Spano JP, et al. VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. Eur J Cancer. 2010;46(2):439–48.PubMedCrossRefGoogle Scholar
  62. 62.
    Hattori S, Kanda S, Harita Y. Tyrosine kinase signalling in kidney glomerular podocytes. J Signal Transduct. 2011;2011:317852. doi: 10.1155/2011/317852.PubMedGoogle Scholar
  63. 63.
    Bertuccio C, Veron D, Aggarwal PK, et al. Vascular endothelial growth factor receptor 2 direct interaction with nephrin links VEGF-A signals to actin in kidney podocytes. J Biol Chem. 2011;286(46):39933–44.PubMedCrossRefGoogle Scholar
  64. 64.
    Sugimoto H, Hamano Y, Charytan D, et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem. 2003;278(15):12605–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Blanco S, Bonet J, López D, et al. ACE inhibitors improve nephrin expression in Zucker rats with glomerulosclerosis. Kidney Int Suppl. 2005;67(S93):S10-4.Google Scholar
  66. 66.
    Agabiti-Rosei E. Structural and functional changes of the microcirculation in hypertension: influence of pharmacological therapy. Drugs. 2003;63(Spec No 1):19–29.Google Scholar
  67. 67.
    Rosen AC, Wu S, Damse A, et al. Risk of rash in cancer patients treated with vandetanib: systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(4):1125–33.PubMedCrossRefGoogle Scholar
  68. 68.
    Lacouture ME, Laabs SM, Koehler M, et al. Analysis of dermatologic events in patients with cancer treated with lapatinib. Breast Cancer Res Treat. 2009;114(3):485–93.PubMedCrossRefGoogle Scholar
  69. 69.
    Choi NM. Chemotherapy-induced iatrogenic injury of skin: new drugs and new concepts Clin Dermatol. 2011;29(6):587–601.Google Scholar
  70. 70.
    Hirsh V. Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol. 2011;18(3):126–38.PubMedCrossRefGoogle Scholar
  71. 71.
    Suzumura T, Kimura T, Kudoh S, et al. Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer. BMC Cancer. 2012;4(12):568.CrossRefGoogle Scholar
  72. 72.
    Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98(23):1714–23.PubMedCrossRefGoogle Scholar
  73. 73.
    Pérez-Soler R, Zou Y, Li T, et al. The phosphatase inhibitor menadione (vitamin K3) protects cells from EGFR inhibition by erlotinib and cetuximab. Clin Cancer Res. 2011;17(21):6766–77.PubMedCrossRefGoogle Scholar
  74. 74.
    Mitra SS, Simcock R. Erlotinib induced skin rash spares skin in previous radiotherapy field. J Clin Oncol. 2006;24(16):e28–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Pérez-Soler R. Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? Oncology (Williston Park). 2003;17(11 Suppl. 12):23–8.Google Scholar
  76. 76.
    Pérez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer. 2006;8(Suppl. 1):S7–14.PubMedCrossRefGoogle Scholar
  77. 77.
    Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res. 2007;13(13):3913–21.PubMedCrossRefGoogle Scholar
  78. 78.
    Liu G, Gurubhagavatula S, Zhou W, et al. Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib. Pharmacogenomics J. 2008;8(2):129–38.PubMedCrossRefGoogle Scholar
  79. 79.
    Vincenzi B, Santini D, Russo A, et al. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist. 2010;15(1):85–92.PubMedCrossRefGoogle Scholar
  80. 80.
    Petrelli F, Borgonovo K, Cabiddu M, et al. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer. 2012;78(1):8–15.PubMedCrossRefGoogle Scholar
  81. 81.
    Stepanski EJ, Reyes C, Walker MS, et al. The association of rash severity with overall survival: findings from patients receiving erlotinib for pancreatic cancer in the community setting. Pancreas. 2013;42(1):32–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Fiala O, Pesek M, Finek J, et al. Skin rash as useful marker of erlotinib efficacy in NSCLC and its impact on clinical practice. Neoplasma. 2013;60(1):26–32.PubMedCrossRefGoogle Scholar
  83. 83.
    Mita AC, Papadopoulos K, de Jonge MJA, et al. Erlotinib ‘dosing-to-rash’: a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer. Br J Cancer. 2011;105(7):938–44.Google Scholar
  84. 84.
    Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2013;8(1):e55128.PubMedCrossRefGoogle Scholar
  85. 85.
    Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.PubMedCrossRefGoogle Scholar
  87. 87.
    Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012;30(23):2861–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374–9.PubMedCrossRefGoogle Scholar
  89. 89.
    FDA. Oncologic Drugs Advisory Committee meeting (24 September 2002). Clinical review: IRESSA NDA 21-399. Available from URL: Accessed 22 Oct 2012.
  90. 90.
    European Medicines Agency. NEXAVAR public assessment report (4 March 2007). Available from URL: Accessed 22 Oct 2012.
  91. 91.
    European Medicines Agency. VOTRIENT public assessment report (EMA/CHMP/248579/2010) [14 June 2010]. Available from URL: Accessed 22 Oct 2012.
  92. 92.
    Marshall JL. Maximum-tolerated dose, optimum biologic dose, or optimum clinical value: dosing determination of cancer therapies. J Clin Oncol. 2012;30(23):2815–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Mukohara T, Nakajima H, Mukai H, et al. Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients. Cancer Sci. 2010;101(4):963–8.PubMedCrossRefGoogle Scholar
  94. 94.
    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(3):1055–64.PubMedCrossRefGoogle Scholar
  95. 95.
    European Medicines Agency. IRESSA public assessment report (EMEA/CHMP/563746/2008) [22 July 2009]. Available from URL:0 Accessed 22 Oct 2012.
  96. 96.
    FDA. Clinical pharmacology and biopharmaceutics review(s) – INLYTA NDA. Application number 203324Orig1s000. Available from URL: Accessed 22 Oct 2012.
  97. 97.
    Girardi F, Franceschi E, Brandes AA. Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies. Oncologist. 2010;15(7):683–94.PubMedCrossRefGoogle Scholar
  98. 98.
    Franklin PH, Banfor PN, Tapang P, et al. Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N’-(2-fluoro-5-methylphenyl)urea], on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition. J Pharmacol Exp Ther. 2009;329(3):928–37.PubMedCrossRefGoogle Scholar
  99. 99.
    Izzedine H, Ederhy S, Goldwasser F, et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. 2009;20(5):807–15.PubMedCrossRefGoogle Scholar
  100. 100.
    Molteni A, Heffelfinger S, Moulder JE, et al. Potential deployment of angiotensin I converting enzyme inhibitors and of angiotensin II type 1 and type 2 receptor blockers in cancer chemotherapy. Anticancer Agents Med Chem. 2006;6(5):451–60.PubMedCrossRefGoogle Scholar
  101. 101.
    Wolter P, Stefan C, Decallonne B, et al. The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer. 2008;99(3):448–54.PubMedCrossRefGoogle Scholar
  102. 102.
    Garfield DH, Wolter P, Schöffski P, et al. Documentation of thyroid function in clinical studies with sunitinib: why does it matter? J Clin Oncol. 2008;26(31):5131–2.PubMedCrossRefGoogle Scholar
  103. 103.
    Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610–21.PubMedCrossRefGoogle Scholar
  104. 104.
    Thatcher N, Nicolson M, Groves RW, for the UK Erlotinib Skin Toxicity Management Consensus Group, et al. Expert consensus on the management of erlotinib-associated cutaneous toxicity in the UK. Oncologist. 2009;14(8):840–7.Google Scholar
  105. 105.
    Potthoff K, Hofheinz R, Hassel JC, et al. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion. Ann Oncol. 2011;22(3):524–35.PubMedCrossRefGoogle Scholar
  106. 106.
    Abdullah SE, Haigentz M Jr, Piperdi B. Dermatologic toxicities from monoclonal antibodies and tyrosine kinase inhibitors against EGFR: pathophysiology and management. Chemother Res Pract. 2012;2012:351210.PubMedGoogle Scholar
  107. 107.
    Robert C, Sibaud V, Mateus C, et al. Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol. 2012;39(2):227–40.PubMedCrossRefGoogle Scholar
  108. 108.
    Hassel JC, Kripp M, Al-Batran S, et al. Treatment of epidermal growth factor receptor antagonist-induced skin rash: results of a survey among German oncologists. Onkologie. 2010;33(3):94–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Bidoli P, Cortinovis DL, Colombo I, et al. Isotretinoin plus clindamycin seem highly effective against severe erlotinib-induced skin rash in advanced non-small cell lung cancer. J Thorac Oncol. 2010;5(10):1662–3.PubMedCrossRefGoogle Scholar
  110. 110.
    Requena C, Llombart B, Sanmartín O. Acneiform eruptions induced by epidermal growth factor receptor inhibitors: treatment with oral isotretinoin. Cutis. 2012;90(2):77–80.PubMedGoogle Scholar
  111. 111.
    Blanchetot C, Tertoolen LG, den Hertog J. Regulation of receptor protein-tyrosine phosphatase alpha by oxidative stress. EMBO J. 2002;21(4):493–503.PubMedCrossRefGoogle Scholar
  112. 112.
    Talon Therapeutics, Inc. Safety, tolerability and systemic absorption of menadione topical lotion for epidermal-growth-factor-receptor (EGFR) inhibitor-associated rash [ identifier NCT00656786]. US National Institutes of Health, Available from URL: Accessed 29 Oct 2012.
  113. 113.
    Mayo Clinic. Menadione topical lotion in treating skin discomfort and psychological distress in patients with cancer receiving panitumumab, erlotinib hydrochloride, or cetuximab [ identifier NCT01393821]. Available from URL: Accessed 29 Oct 2012.

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Devron R. Shah
    • 1
  • Rashmi R. Shah
    • 1
    Email author
  • Joel Morganroth
    • 2
  1. 1.Rashmi Shah Consultancy LtdBuckinghamshireUK
  2. 2.eResearch TechnologyPhiladelphiaUSA

Personalised recommendations