Targeted Oncology

, Volume 9, Issue 3, pp 287–291 | Cite as

Diagnostic challenges of respiratory adverse events during everolimus treatment

  • Annelieke E. C. A. B. Willemsen
  • Filip Y. De Vos
  • Anne Jansen
  • Maaike de Boer
  • Vivianne C. G. Tjan-Heijnen
  • Carla M. L. van Herpen
Day-to-Day Practice


Everolimus has important clinical activity in various malignancies, but its use can be complicated by respiratory adverse events. Important everolimus-induced respiratory adverse events are interstitial lung disease (ILD) and infections, either typical or opportunistic. Furthermore, non-everolimus-related respiratory events can occur. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. Considering the potential fatal nature of opportunistic infections, these are especially important to recognize. To be able to distinguish between ILD and (opportunistic) infections as the underlying cause, an aggressive diagnostic workup, including bronchoalveolar lavage, should be performed in patients treated with everolimus who develop respiratory disease. We report three cases of severe opportunistic pulmonary infections during everolimus treatment, concerning two Pneumocystis jirovecii pneumonia infections. These cases illustrate the diagnostic challenges of respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.


Everolimus Pneumocystis jirovecii pneumonia Pulmonary infection Immunosuppression 


  1. 1.
    Hudes GR (2009) Targeting mTOR in renal cell carcinoma. Cancer 115(10 Suppl):2313–2320. doi:10.1002/cncr.24239 PubMedCrossRefGoogle Scholar
  2. 2.
    Vitko S, Margreiter R, Weimar W, Dantal J, Kuypers D, Winkler M, Oyen O, Viljoen HG, Filiptsev P, Sadek S, Li Y, Cretin N, Budde K, Group RBS (2005) Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Trans: Off J Am Soc Trans Am Soc Trans Surg 5(10):2521–2530. doi:10.1111/j.1600-6143.2005.01063.x CrossRefGoogle Scholar
  3. 3.
    Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A, Group R-S (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer 116(18):4256–4265. doi:10.1002/cncr.25219 PubMedCrossRefGoogle Scholar
  4. 4.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K, Rad001 in Advanced Neuroendocrine Tumors TTSG (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6):514–523. doi:10.1056/NEJMoa1009290 PubMedCrossRefGoogle Scholar
  5. 5.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529. doi:10.1056/NEJMoa1109653 PubMedCrossRefGoogle Scholar
  6. 6.
    Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K (2013) Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381(9869):817–824. doi:10.1016/S0140-6736(12)61767-X PubMedCrossRefGoogle Scholar
  7. 7.
    Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, Davies SF, Dismukes WE, Hage CA, Marr KA, Mody CH, Perfect JR, Stevens DA, American Thoracic Society Fungal Working G (2011) An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 183(1):96–128. doi:10.1164/rccm.2008-740ST PubMedCrossRefGoogle Scholar
  8. 8.
    National Comprehensive Cancer Network (NCCN) Clinical practice guidelines in oncology. Prevention and treatment of cancer-related infections. Version 1.2013. Accessed 21 Jul 2013
  9. 9.
    White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, Uemura H, Kpamegan E, Kay A, Robson M, Ravaud A, Motzer RJ (2010) Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 182(3):396–403. doi:10.1164/rccm.200911-1720OC PubMedCrossRefGoogle Scholar
  10. 10.
    Weichhart T, Costantino G, Poglitsch M, Rosner M, Zeyda M, Stuhlmeier KM, Kolbe T, Stulnig TM, Horl WH, Hengstschlager M, Muller M, Saemann MD (2008) The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29(4):565–577. doi:10.1016/j.immuni.2008.08.012 PubMedCrossRefGoogle Scholar
  11. 11.
    Kawahara T, Asthana S, Kneteman NM (2011) m-TOR inhibitors: what role in liver transplantation? J Hepatol 55(6):1441–1451. doi:10.1016/j.jhep.2011.06.015 PubMedCrossRefGoogle Scholar
  12. 12.
    Saito Y, Nagayama M, Miura Y, Ogushi S, Suzuki Y, Noro R, Minegishi Y, Kimura G, Kondo Y, Gemma A (2013) A case of pneumocystis pneumonia associated with everolimus therapy for renal cell carcinoma. Jpn J Clin Oncol 43(5):559–562. doi:10.1093/jjco/hyt019 PubMedCrossRefGoogle Scholar
  13. 13.
    Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, Niccoli P, Guimbaud R, Chougnet CN, Goichot B, Rohmer V, Borson-Chazot F, Baudin E, French Group of Endocrine T (2013) Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia. Eur J Endocrinol / Eur Fed Endocr Soc 168(5):665–674. doi:10.1530/EJE-12-1101 CrossRefGoogle Scholar
  14. 14.
    Suzuki T, Tada Y, Tsushima K, Terada J, Sakurai T, Watanabe A, Kasahara Y, Tanabe N, Tatsumi K (2013) Pneumocystis pneumonia in everolimus therapy: an indistinguishable case from drug induced interstitial lung disease. Respir Med Case Rep 10:4Google Scholar
  15. 15.
    Ponce CA, Gallo M, Bustamante R, Vargas SL (2010) Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population. Clin Infect Dis: Off Publ Infect Dis Soc Am 50(3):347–353. doi:10.1086/649868 CrossRefGoogle Scholar
  16. 16.
    Thomas CF Jr, Limper AH (2004) Pneumocystis pneumonia. N Engl J Med 350(24):2487–2498. doi:10.1056/NEJMra032588 PubMedCrossRefGoogle Scholar
  17. 17.
    Limper AH, Offord KP, Smith TF, Martin WJ 2nd (1989) Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis 140(5):1204–1209. doi:10.1164/ajrccm/140.5.1204 PubMedCrossRefGoogle Scholar
  18. 18.
    Azoulay E, Bergeron A, Chevret S, Bele N, Schlemmer B, Menotti J (2009) Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates. Chest 135(3):655–661. doi:10.1378/chest.08-1309 PubMedCrossRefGoogle Scholar
  19. 19.
    Alanio A, Desoubeaux G, Sarfati C, Hamane S, Bergeron A, Azoulay E, Molina JM, Derouin F, Menotti J (2011) Real-time PCR assay-based strategy for differentiation between active Pneumocystis jirovecii pneumonia and colonization in immunocompromised patients. Clin Microbiol Infect: Off Publ Eur Soc Clin Microbiol Infect Dis 17(10):1531–1537. doi:10.1111/j.1469-0691.2010.03400.x CrossRefGoogle Scholar
  20. 20.
    Reid AB, Chen SC, Worth LJ (2011) Pneumocystis jirovecii pneumonia in non-HIV-infected patients: new risks and diagnostic tools. Curr Opin Infect Dis 24(6):534–544. doi:10.1097/QCO.0b013e32834cac17 PubMedCrossRefGoogle Scholar
  21. 21.
    Fijalkowska-Morawska JB, Jagodzinska M, Nowicki M (2011) Pulmonary embolism and reactivation of tuberculosis during everolimus therapy in a kidney transplant recipient. Ann Transpl: Q Pol Transpl Soc 16(4):107–110Google Scholar
  22. 22.
    Mizuno S, Yamagishi Y, Ebinuma H, Nakamoto N, Katahira M, Sasaki A, Sakamoto M, Suzuki H, Kanai T, Hibi T (2013) Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier. Clin J Gastroenterol 6(2):188–192. doi:10.1007/s12328-013-0371-4 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Sezgin Goksu S, Bilal S, Coskun HS (2013) Hepatitis B reactivation related to everolimus. World J Hepatol 5(1):43–45. doi:10.4254/wjh.v5.i1.43 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Azar AE, Ballas ZK (2007) Evaluation of the adult with suspected immunodeficiency. Am J Med 120(9):764–768. doi:10.1016/j.amjmed.2006.12.013 PubMedCrossRefGoogle Scholar
  25. 25.
    Morice WG, Brunn GJ, Wiederrecht G, Siekierka JJ, Abraham RT (1993) Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. J Biol Chem 268(5):3734–3738PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Annelieke E. C. A. B. Willemsen
    • 1
  • Filip Y. De Vos
    • 2
  • Anne Jansen
    • 1
  • Maaike de Boer
    • 3
  • Vivianne C. G. Tjan-Heijnen
    • 3
  • Carla M. L. van Herpen
    • 1
  1. 1.Department of Medical Oncology (452)Radboud University Medical CentreNijmegenThe Netherlands
  2. 2.Department of Medical OncologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  3. 3.Division of Medical Oncology, Department of Internal Medicine, GROW—School for Oncology and Developmental BiologyMaastricht University Medical CentreMaastrichtThe Netherlands

Personalised recommendations