Therapy of mRCC beyond mTOR-inhibition in clinical practice: results of a retrospective analysis

  • Luise MauteEmail author
  • Viktor Grünwald
  • Steffen Weikert
  • Ulrich Kube
  • Thomas Gauler
  • Christoph Kahl
  • Iris Burkholder
  • Lothar Bergmann
Original Article – Clinical Oncology



Renal cell carcinoma (RCC) is the most common renal tumor and accounts for nearly 3 % of adult cancers. In the recent years, seven new targeted agents have been approved changing the treatment in metastatic RCC dramatically. So far, however, it remains unclear which sequence is best for those patients. This study analyzed retrospectively the outcome of patients treated with everolimus after failure of a vascular endothelial growth factor receptor-directed therapy and which therapies were used after everolimus.

Patients and methods

In a retrospective analysis, patients receiving everolimus after failure of first-line VEGFR-directed therapy have been analyzed in regard to response, duration of treatment and subsequent therapies. In total, the data of 81 patients have been analyzed.


The most observed first-line therapy was sunitinib followed by sorafenib. Thirty-two patients received everolimus as second-line therapy, and 49 as third-line therapy. The median duration of treatment with everolimus was 4.5 months. Seventy-seven of eighty-one patients (95 %) received a further therapy after discontinuation of everolimus. The agents administered beyond were sunitinib (28.6 %), sorafenib (28.6 %) and 42.8 % received other therapies. Twenty-seven patients received an additional sequence of therapy (fourth to fifth line). Fifty-eight percentage of patients have still been alive at time of analysis.


The duration of everolimus therapy beyond failure of anti-VEGF-directed therapy and the reported time to progression was in the range of the RECORD-1 trial in daily practice as well. After failure of everolimus, reexposure to tyrosine kinase inhibitors is a common clinical practice and demonstrates a clinical benefit of therapies beyond everolimus.


Renal cancer Everolimus Sequential treatment mTOR 



The authors would like to thank the following participating investigators: S. Weigert, K. Miller (Berlin); W. Hölzer (Berlin); U. Kube (Chemnitz); S. Zastrow (Dresden); T. Gauler (Essen); A. Becker (Hamburg), M. von Staden (Hamburg); V. Grünewald (Hannover); C. Kahl (Magdeburg); M. Staehler (München); S. Bierer (Münster); A. Lück (Rostock); A. Stenzl (Tübingen); and A. Schrader (Ulm). The retrospective analysis was partially supported by Novartis Pharma, Nürnberg, Germany.


  1. Bergmann L, Goebell PJ, Kube U et al (2013) Everolimus in metastatic renal cell carcinoma after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: results of an interim analysis of a non-interventional study. Onkologie 36(3):95–100CrossRefPubMedGoogle Scholar
  2. Bergmann L, Beck J, Bothe K et al (2014) Treatment algorithm for metastatic renal cell carcinoma. Recommendations based on evidence and clinical practice. Oncol Res Treat (in press)Google Scholar
  3. Bergmann L, Luise Maute L, Guschmann L (2014b) Drug profile of temsirolimus for advanced renal cell carcinoma. Expert Rev Anticancer Ther 14(1):9–21CrossRefPubMedGoogle Scholar
  4. Beuvink I, Boulay A, Fumagalli S et al (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120(6):747–759CrossRefPubMedGoogle Scholar
  5. Bukowski RM (2012) Temsirolimus: a safety and efficacy review. Expert Opin Drug Saf 11(5):861–879CrossRefPubMedGoogle Scholar
  6. Cho I, Chung J (2012) Current status of targeted therapy for advanced renal cell carcinoma. Korean J Urol 53:217–228CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr (1999) Rising incidence of renal cell cancer in the United States. JAMA 281(17):1628–1631CrossRefPubMedGoogle Scholar
  8. Del Bufalo D, Ciuffreda L, Trisciuoglio D et al (2006) Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66(11):5549–5554CrossRefPubMedGoogle Scholar
  9. Dutcher JP, de Souza P, McDermott D et al (2009) Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol 26(2):202–209CrossRefPubMedGoogle Scholar
  10. Escudier B, Albiges L, Sonpavde G (2013) Optimal management of metastatic renal cell carcinoma: current status. Drugs 73(5):427–438CrossRefPubMedGoogle Scholar
  11. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688CrossRefPubMedGoogle Scholar
  12. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674CrossRefPubMedGoogle Scholar
  13. Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK (2006) Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 98(18):1331–1334CrossRefPubMedGoogle Scholar
  14. Hutson TE, Escudier B, Esteban E et al (2013) Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol [Epub ahead of print]Google Scholar
  15. Janzen NK, Kim HL, Figlin RA, Belldegrun AS (2003) Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 30(4):843–852CrossRefPubMedGoogle Scholar
  16. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42CrossRefPubMedPubMedCentralGoogle Scholar
  17. Mathew A, Devesa SS, Fraumeni JF Jr, Chow WH (2002) Global increases in kidney cancer incidence, 1973–1992. Eur J Cancer Prev 11(2):171–178CrossRefPubMedGoogle Scholar
  18. 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(9637):449–456CrossRefPubMedGoogle Scholar
  19. Motzer RJ, Escudier B, Oudard S et al (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer 116(18):4256–4265CrossRefPubMedGoogle Scholar
  20. Motzer RJ, Barrios CH, Kim TM et al (2013) Record-3: phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 31(Suppl; abstr 4504)Google Scholar
  21. Pantuck AJ, Seligson DB, Klatte T et al (2007) Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer 109(11):2257–2267CrossRefPubMedGoogle Scholar
  22. Populo H, Lopes JM, Soares P (2012) The mTOR signalling pathway in human cancer. Int J Mol Sci 13(2):1886–1918CrossRefPubMedPubMedCentralGoogle Scholar
  23. Rini BI, Escudier B, Tomczak P et al (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378(9807):1931–1939CrossRefPubMedGoogle Scholar
  24. Shinohara ET, Cao C, Niermann K et al (2005) Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 24(35):5414–5422CrossRefPubMedGoogle Scholar
  25. Wu C, Wangpaichitr M, Feun L et al (2005) Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol Cancer 4(1):25CrossRefPubMedPubMedCentralGoogle Scholar
  26. Yuan R, Kay A, Berg WJ, Lebwohl D (2009) Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2:45CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Luise Maute
    • 1
    Email author
  • Viktor Grünwald
    • 2
  • Steffen Weikert
    • 3
  • Ulrich Kube
    • 4
  • Thomas Gauler
    • 5
  • Christoph Kahl
    • 6
  • Iris Burkholder
    • 7
  • Lothar Bergmann
    • 1
  1. 1.Department of Internal Medicine II, Hematology and OncologyJohann Wolfgang Goethe UniversityFrankfurt am MainGermany
  2. 2.Department of Hematology/OncologyMedical School HannoverHannoverGermany
  3. 3.Department of UrologyCharitéBerlinGermany
  4. 4.Practice for UrologyChemnitzGermany
  5. 5.Department of Medicine (Cancer Research)University HospitalEssenGermany
  6. 6.University Hospital MagdeburgMagdeburgGermany
  7. 7.Department of Nursing and HealthUniversity of Applied Sciences of the SaarlandSaarbrueckenGermany

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