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Cancer and Metastasis Reviews

, Volume 31, Supplement 1, pp 19–27 | Cite as

Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma

  • María José Méndez-VidalEmail author
  • Esther Martínez Ortega
  • Álvaro Montesa Pino
  • Begoña Pérez Valderrama
  • Ruth Viciana
Article

Abstract

Treatment options for metastatic renal cell carcinoma (mRCC) have evolved very rapidly, as reflected by the approval of the many drugs that have shown efficacy in phase III studies. Approved drugs include tyrosine kinase inhibitors (TKI) such as sunitinib, sorafenib and pazopanib, vascular endothelial growth factor inhibitors such as bevacizumab, and mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus and everolimus. These biological agents have toxicity profiles that differ from those accompanying current chemotherapeutic agents, but their novelty leads to a lack of exhaustive clinical data regarding related adverse events (AEs), whose symptoms may overlap with those of the chronic illnesses of patients with mRCC such as hypertension, hyperglycemia, and pneumonitis. Hypertension, hypothyroidism, hand–foot syndrome, and fatigue are AEs frequently associated with TKIs; whereas immunosuppression, stomatitis, metabolic alterations, and non-infectious pneumonitis are AEs of mTOR inhibitors. Recommendations for treating these adverse events in patients with mRCC are usually the same as those for the general population. Mild to moderate toxicities may be managed with supportive and pharmacologic interventions, but higher-grade toxicities usually require external specialist consultation, dose reductions, and treatment interruption or discontinuation. Some groups of patients with mRCC, such as frail, elderly patients, and patients with renal or liver dysfunction, require special management of AEs.

Keywords

Adverse events Tyrosine kinase inhibitors Mammalian target of rapamycin Vascular endothelial growth factor inhibitors Dose reduction Treatment interruption 

Notes

Acknowledgments

The authors acknowledge the support of Novartis Oncology Spain, which has facilitated the necessary meetings to evaluate and discuss all the data presented in this review, and Dr. Fernando Sánchez-Barbero from HealthCo SL (Madrid, Spain) for assistance in the preparation of this manuscript.

Conflicts of interest

The authors declare that they do not have any conflict of interest that may inappropriately influence this work.

References

  1. 1.
    Schutzm, F. A., Je, Y., Richards, C. J., & Choueiri, T. K. (2012). 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. Journal of Clinical Oncology. Feb 6.Google Scholar
  2. 2.
    EMA. Sunitinib (Sutent®)—Summary of product characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000687/WC500057737.pdf (accessed on October 2011).
  3. 3.
    Motzer, R. J., Hutson, T. E., Tomczak, P., Michaelson, M. D., Bukowski, R. M., Rixe, O., et al. (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. The New England Journal of Medicine, 356(2), 115–124. Jan 11.PubMedCrossRefGoogle Scholar
  4. 4.
    Rini, B. I., Tamaskar, I., Shaheen, P., Salas, R., Garcia, J., Wood, L., et al. (2007). Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. Journal of the National Cancer Institute, 99(1), 81–83. Jan 3.PubMedCrossRefGoogle Scholar
  5. 5.
    Chen, A., & Agarwal, N. (2009). Reversible posterior leucoencephalopathy syndrome associated with sunitinib. Internal Medicine Journal, 39(5), 341–342.PubMedCrossRefGoogle Scholar
  6. 6.
    Padhy, B. M., Shanmugam, S. P., Gupta, Y. K., & Goyal, A. (2011). Reversible posterior leucoencephalopathy syndrome in an elderly male on sunitinib therapy. British Journal of Clinical Pharmacology, 71(5), 777–779.PubMedCrossRefGoogle Scholar
  7. 7.
    Marschner, N. (2010). Sunitinib in clinical practice: the expanded access program for metastatic renal cell carcinoma. Onkologie, 33(Suppl 1), 12–14.PubMedCrossRefGoogle Scholar
  8. 8.
    EMA. Sorafenib (Nexavar®)—Summary of product characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000690/WC500027704.pdf (accessed on October, 2011).
  9. 9.
    Escudier, B., Eisen, T., Stadler, W. M., Szczylik, C., Oudard, S., Siebels, M., et al. (2007). Sorafenib in advanced clear-cell renal-cell carcinoma. The New England Journal of Medicine, 356(2), 125–134. Jan 11.PubMedCrossRefGoogle Scholar
  10. 10.
    Beck, J., Procopio, G., Bajetta, E., Keilholz, U., Negrier, S., Szczylik, C., et al. (2011). Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Annals of Oncology, 22(8), 1812–1823.PubMedCrossRefGoogle Scholar
  11. 11.
    EMA. Pazopanib (Votrient®)—Summary of product characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001141/WC500094272.pdf (accessed on October, 2011).
  12. 12.
    Sternberg, C. N., Davis, I. D., Mardiak, J., Szczylik, C., Lee, E., Wagstaff, J., et al. (2010). Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. Journal of Clinical Oncology, 28(6), 1061–1068. Feb 20.PubMedCrossRefGoogle Scholar
  13. 13.
    Rini, B. I., Escudier, B., Tomczak, P., Kaprin, A., Szczylik, C., Hutson, T. E., et al. (2011). Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. Nov 3.Google Scholar
  14. 14.
    EMA. Bevacizumab (Avastin®)—Summary of product characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf (accessed on October 2011).
  15. 15.
    Escudier, B., Pluzanska, A., Koralewski, P., Ravaud, A., Bracarda, S., Szczylik, C., et al. (2007). Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet, 370(9605), 2103–2111. Dec 22.PubMedCrossRefGoogle Scholar
  16. 16.
    EMA (Ed.) Temsirolimus (Torisel®)—Summary of product characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000799/WC500039912.pdf (accessed on October 2011).
  17. 17.
    Hudes, G., Carducci, M., Tomczak, P., Dutcher, J., Figlin, R., Kapoor, A., et al. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. The New England Journal of Medicine, 356(22), 2271–2281. May 31.PubMedCrossRefGoogle Scholar
  18. 18.
    Maroto, J. P., Hudes, G., Dutcher, J. P., Logan, T. F., White, C. S., Krygowski, M., et al. (2011). Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. Journal of Clinical Oncology, 29(13), 1750–1756. May 1.PubMedCrossRefGoogle Scholar
  19. 19.
    EMA. Everolimus (Afinitor®)—Summary of product characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001038/WC500022814.pdf (accessed on October, 2011).
  20. 20.
    Motzer, R. J., Escudier, B., Oudard, S., Hutson, T. E., Porta, C., Bracarda, S., et al. (2010). Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer, 116(18), 4256–4265. Sep 15.PubMedCrossRefGoogle Scholar
  21. 21.
    Muriel, C., Esteban, E., Corral, N., Fonseca, P. J., Luque, M., Berros, J. P., et al. (2010). Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias. Clinical and Translational Oncology, 12(8), 562–567.PubMedCrossRefGoogle Scholar
  22. 22.
    Kollmannsberger, C., Soulieres, D., Wong, R., Scalera, A., Gaspo, R., & Bjarnason, G. (2007). Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects. Canadian Urology Association Journal, 1(2 Suppl), S41–S54.Google Scholar
  23. 23.
    Dettmer, A. (1994). Loperamide oxide in the treatment of acute diarrhea in adults. Clinical Therapeutics, 16(6), 972–980. Nov-Dec.PubMedGoogle Scholar
  24. 24.
    Rusthoven, J., Obrien, B., & Rocchi, A. (1992). Ondansetron versus metoclopramide in the prevention of chemotherapy-induced nausea and vomiting—a metaanalysis. International Journal of Oncology, 1(4), 443–450.PubMedGoogle Scholar
  25. 25.
    Yeh, S. S., & Schuster, M. W. (2006). Megestrol acetate in cachexia and anorexia. International Journal of Nanomedicine, 1(4), 411–416.PubMedCrossRefGoogle Scholar
  26. 26.
    Fraenkel, M., Ketzinel-Gilad, M., Ariav, Y., Pappo, O., Karaca, M., Castel, J., et al. (2008). mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes, 57(4), 945–957.PubMedCrossRefGoogle Scholar
  27. 27.
    Neumiller, J. J., & Setter, S. M. (2009). Pharmacologic management of the older patient with type 2 diabetes mellitus. The American Journal of Geriatric Pharmacotherapy, 7(6), 324–342.PubMedCrossRefGoogle Scholar
  28. 28.
    Gaw, A. (2002). A new reality: achieving cholesterol-lowering goals in clinical practice. Atherosclerosis Supplements, 2(4), 5–8. discussion -11.PubMedCrossRefGoogle Scholar
  29. 29.
    Hudes, G. R. (2009). Targeting mTOR in renal cell carcinoma. Cancer, 115(10 Suppl), 2313–2320. May 15.PubMedCrossRefGoogle Scholar
  30. 30.
    NCCN Clinical Pratice Guidelines in Oncology. (2011). Cancer Related Fatigue. National Comprehensive Cancer Network Web Site. http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf (accessed on 10th October).
  31. 31.
    Minton, O., Richardson, A., Sharpe, M., Hotopf, M., & Stone, P. (2008). A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. Journal of the National Cancer Institute, 100(16), 1155–1166. Aug 20.PubMedCrossRefGoogle Scholar
  32. 32.
    Bukowski, R. M., Stadler, W. M., McDermott, D. F., Dutcher, J. P., Knox, J. J., Miller, W. H., Jr., et al. (2010). Safety and efficacy of sorafenib in elderly patients treated in the North American advanced renal cell carcinoma sorafenib expanded access program. Oncology, 78(5–6), 340–347.PubMedCrossRefGoogle Scholar
  33. 33.
    Gore, M. E., Hariharan, S., Porta, C., Bracarda, S., Hawkins, R., Bjarnason, G. A., et al. (2011). Sunitinib in metastatic renal cell carcinoma patients with brain metastases. Cancer, 117(3), 501–509. Feb 1.PubMedCrossRefGoogle Scholar
  34. 34.
    Stadler, W. M., Figlin, R. A., McDermott, D. F., Dutcher, J. P., Knox, J. J., Miller, W. H., Jr., et al. (2010). Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer, 116(5), 1272–1280. Mar 1.PubMedCrossRefGoogle Scholar
  35. 35.
    Staehler, M., Haseke, N., Nuhn, P., Tullmann, C., Karl, A., Siebels, M., et al. (2011). Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma. BJU International, 108(5), 673–678.PubMedGoogle Scholar
  36. 36.
    Khan, G., Golshayan, A., Elson, P., Wood, L., Garcia, J., Bukowski, R., et al. (2010). Sunitinib and sorafenib in metastatic renal cell carcinoma patients with renal insufficiency. Annals of Oncology, 21(8), 1618–1622.PubMedCrossRefGoogle Scholar
  37. 37.
    Gupta, S., Parsa, V., Heilbrun, L. K., Smith, D. W., Dickow, B., Heath, E., et al. (2011). Safety and efficacy of molecularly targeted agents in patients with metastatic kidney cancer with renal dysfunction. Anti-Cancer Drugs, 22(8), 794–800.PubMedCrossRefGoogle Scholar
  38. 38.
    Bello, C. L., Garrett, M., Sherman, L., Smeraglia, J., Ryan, B., & Toh, M. (2010). Pharmacokinetics of sunitinib malate in subjects with hepatic impairment. Cancer Chemotherapy and Pharmacology, 66(4), 699–707.PubMedCrossRefGoogle Scholar
  39. 39.
    Di Gion, P., Kanefendt, F., Lindauer, A., Scheffler, M., Doroshyenko, O., Fuhr, U., et al. (2011). Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clinical Pharmacokinetics, 50(9), 551–603. Sep 1.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • María José Méndez-Vidal
    • 1
    • 6
    Email author
  • Esther Martínez Ortega
    • 2
  • Álvaro Montesa Pino
    • 3
  • Begoña Pérez Valderrama
    • 4
  • Ruth Viciana
    • 5
  1. 1.Hospital Provincial de CórdobaCórdobaSpain
  2. 2.Complejo Hospitalario de JaénJaénSpain
  3. 3.Hospital Carlos Haya MálagaMálagaSpain
  4. 4.Hospital Universitario Virgen del RocíoSevillaSpain
  5. 5.Hospital de Jerez de la FronteraCádizSpain
  6. 6.Medical Oncology ServiceHospital Universitario Reina SofíaCórdobaSpain

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