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Targeted Oncology

, Volume 6, Issue 2, pp 125–129 | Cite as

Common toxicities of mammalian target of rapamycin inhibitors

  • Scott A. Soefje
  • Anand Karnad
  • Andrew J. Brenner
Review

Abstract

The toxicities of newer targeted therapies are different from those seen with the traditional chemotherapy. Mammalian target of rapamycin (mTOR) inhibitors are evolving into an important class of drugs in oncology, and this class of drugs presents with a variety of different toxicities. Although similar to the toxicities seen in transplantation, these rapamycin analogs have unique side effects when compared to traditional chemotherapy agents. While most of the toxicities are mild, few can be severe and require routine monitoring. Mucositis and rash are the most common side effects. The metabolic toxicities, hyperglycemia, hyperlipidemia, and hypophosphatemia are different from the side effects traditionally seen with chemotherapy. This review will focus on the common toxicities seen with the mTOR inhibitors.

Keywords

mTOR inhibitors Toxicity Temsirolmus Everolimus Radaforolimus 

Notes

Acknowledgements

Supported in part by the CTRC P30 Cancer Center Support Grant from the National Cancer Institute (CA054174).

Conflict of interest statement

The authors have no financial relationship with or sponsorship to disclose. No original data is being published in this review.

References

  1. 1.
    Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281PubMedCrossRefGoogle Scholar
  2. 2.
    Raymond E, Alexandre J, Faivre S et al (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336–2347PubMedCrossRefGoogle Scholar
  3. 3.
    Atkins MB, Hildalgo M, Stadler WM et al (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909–918PubMedCrossRefGoogle Scholar
  4. 4.
    Motzer RJ, Escudier B, Oudard S et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456PubMedCrossRefGoogle Scholar
  5. 5.
    O’Donnell A, Faivre S, Burris HA III et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595PubMedCrossRefGoogle Scholar
  6. 6.
    Hartford CM, Berk L, Loewry JW et al (2009) A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies. Clin Cancer Res 15:1428–1434PubMedCrossRefGoogle Scholar
  7. 7.
    Mita MM, Mita AC, Chu QS et al (2008) Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26:361–367PubMedCrossRefGoogle Scholar
  8. 8.
    Mahe E, Morelon E, Lechaton S et al (2005) Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 79:476–482PubMedCrossRefGoogle Scholar
  9. 9.
    Sonis S, Treister N, Chawla S, Demetri G, Haluska F (2010) Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 116:210–215PubMedGoogle Scholar
  10. 10.
    Campistol JM, de Fijter JW, Flechner SM et al (2010) mTOR inhibitor-associated dermatologic and mucosal problems. Clin Transplant 24:149–156PubMedCrossRefGoogle Scholar
  11. 11.
    Fouladi M, Lanningham F, Wu J et al (2007) Phase I study of everolimus in pediatric patients with refractory solid tumors. J Clin Oncol 25:4806–4812PubMedCrossRefGoogle Scholar
  12. 12.
    Chuang P, Langone AJ (2007) Clobetasol ameliorates aphthous ulceration in renal transplant patients on sirolimus. Am J Transplant 7:714–717PubMedCrossRefGoogle Scholar
  13. 13.
    Morelon E, Stern M, Israël-Biet D et al (2001) Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 72:787–790PubMedCrossRefGoogle Scholar
  14. 14.
    Pham PT, Pham PC, Danovitch GM et al (2004) Sirolimus-associated pulmonary toxicity. Transplantation 77:1215–1220PubMedCrossRefGoogle Scholar
  15. 15.
    Duran I, Sui LL, Oza AM et al (2004) Characterization of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer 42:1875–1880CrossRefGoogle Scholar
  16. 16.
    Aparicio G, Calvo MB, Medina V et al (2009) Comprehensive lung injury pathology induced by mTOR inhibitors. Clin Transl Oncol 11:499–510PubMedCrossRefGoogle Scholar
  17. 17.
    Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent Glioblastoma Multiforme: a north central cancer treatment group study. J Clin Oncol 23:5294–5304PubMedCrossRefGoogle Scholar
  18. 18.
    Beretta L, Gingras AC, Svitkin YV et al (1996) Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 15:658–664PubMedGoogle Scholar
  19. 19.
    Taha C, Liu Z, Jin J et al (1999) Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin. J Biol Chem 274(46):33085–33091PubMedCrossRefGoogle Scholar
  20. 20.
    Rizzieri DA, Feldman E, DiPersio JF et al (2008) A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 14:2756–2762PubMedCrossRefGoogle Scholar
  21. 21.
    Executive Summary: Standards of Medical Care in Diabetes—2011. Diabetes Care 34:S4–S10Google Scholar
  22. 22.
    Brattstrom C, Wilczek H, Tyden G et al (1998) Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation 65:1272–1274PubMedCrossRefGoogle Scholar
  23. 23.
    Gaasbeek A, Meinders AE (2005) Hypophosphatemia: an update on its etiology and treatment. Am J Med 118:1094–1101PubMedCrossRefGoogle Scholar
  24. 24.
    Torisel (2010) Package insert. Wyeth Pharmaceuticals, PhiladelphiaGoogle Scholar
  25. 25.
    Afinitor (2010) Package insert. Novartis Pharmaceuticals Corporation, East HanoverGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Scott A. Soefje
    • 1
  • Anand Karnad
    • 1
  • Andrew J. Brenner
    • 1
  1. 1.Cancer Therapy & Research Center at The University of Texas Health Science Center San AntonioSan AntonioUSA

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