Research Article| Volume 42, ISSUE 12, P1875-1880, August 2006

Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus


      The aims of this study were reviewing our experience regarding the pulmonary toxicity of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, discussing potential pathogenic mechanisms and proposing management strategies. Medical records and radiological reports of 22 patients treated with weekly doses of temsirolimus 25 mg were reviewed. Eight (36%) out of 22 patients developed pulmonary abnormalities compatible with drug-induced pneumonitis. Half were asymptomatic and in those with symptoms, dyspnea and dry cough were the most common. Radiologically two different patterns, ground glass opacities and lung parenchymal consolidation, were described. The management of this toxicity was variable, ranging from no intervention to discontinuation of the drug. In our experience temsirolimus may cause drug-induced pneumonitis at a higher incidence than that previously reported. The presentation and its severity are variable. The risk of developing this toxicity may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Vignot S.
        • Faivre S.
        • Aguirre D.
        • Raymond E.
        mTOR-targeted therapy of cancer with rapamycin derivatives.
        Ann Oncol. 2005; 16: 525-537
        • Hidalgo M.
        • Rowinsky E.K.
        The rapamycin-sensitive signal transduction pathway as a target for cancer therapy.
        Oncogene. 2000; 19: 6680-6686
        • Podsypanina K.
        • Lee R.T.
        • Politis C.
        • Hennessy I.
        • Crane A.
        • Puc J.
        • et al.
        An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice.
        Proc Natl Acad Sci USA. 2001; 98: 10320-10325
        • Guba M.
        • von Breitenbuch P.
        • Steinbauer M.
        • Koehl G.
        • Flegel S.
        • Hornung M.
        • et al.
        Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor.
        Nat Med. 2002; 8: 128-135
        • Shi Y.
        • Frankel A.
        • Radvanyi L.G.
        • Penn L.Z.
        • Miller R.G.
        • Mills G.B.
        Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro.
        Cancer Res. 1995; 55: 1982-1988
        • Pham P.T.
        • Pham P.C.
        • Danovitch G.M.
        • Ross D.J.
        • Gritsch H.A.
        • Kendrick E.A.
        • et al.
        Sirolimus-associated pulmonary toxicity.
        Transplantation. 2004; 77: 1215-1220
        • Morelon E.
        • Stern M.
        • Kreis H.
        Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients.
        N Engl J Med. 2000; 343: 225-226
        • Singer S.J.
        • Tiernan R.
        • Sullivan E.J.
        Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients.
        N Engl J Med. 2000; 343: 1815-1816
        • Morelon E.
        • Mamzer-Bruneel M.F.
        • Peraldi M.N.
        • Kreis H.
        Sirolimus: a new promising immunosuppressive drug. Towards a rationale for its use in renal transplantation.
        Nephrol Dial Transplant. 2001; 16: 18-20
        • Yu K.
        • Toral-Barza L.
        • Discafani C.
        • Zhang W.G.
        • Skotnicki J.
        • Frost P.
        • et al.
        mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer.
        Endocr Relat Cancer. 2001; 8: 249-258
      1. Ha L. The rapamycin derivative RADOO1 in oncology: What is the endpoint? In: AACR-NCI-EORTC Internal Conference. Molecular Cancer and Cancer therapeutics; 17–21 November 2003; Boston, MA; 2003. p. 259–60.

      2. Mita MM, Goldston ML, et al. Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of AP 23573, an mTOR inhibitor administered IV daily × 5 every other week in patients with refractory or advanced malignancies. In: Proc Am Soc Clin Oncol; 2004; New Orleans: Meeting proceedings American Society of Clinical Oncology; 2004.

        • Chan S.
        Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer.
        Br J Cancer. 2004; 91: 1420-1424
        • Grunwald V.
        • DeGraffenried L.
        • Russel D.
        • Friedrichs W.E.
        • Ray R.B.
        • Hidalgo M.
        Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells.
        Cancer Res. 2002; 62: 6141-6145
        • Dudkin L.
        • Dilling M.B.
        • Cheshire P.J.
        • Harwood F.C.
        • Hollingshead M.
        • Arbuck S.G.
        • et al.
        Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition.
        Clin Cancer Res. 2001; 7: 1758-1764
        • Shi Y.
        • Gera J.
        • Hu L.
        • Hsu J.H.
        • Bookstein R.
        • Li W.
        • et al.
        Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779.
        Cancer Res. 2002; 62: 5027-5034
        • Geoerger B.
        • Kerr K.
        • Tang C.B.
        • Fung K.M.
        • Powell B.
        • Sutton L.N.
        • et al.
        Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.
        Cancer Res. 2001; 61: 1527-1532
        • Raymond E.
        • Alexandre J.
        • Faivre S.
        • Vera K.
        • Materman E.
        • Boni J.
        • et al.
        Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer.
        J Clin Oncol. 2004; 22: 2336-2347
        • Baselga J.F.P.
        • Gil M.
        • et al.
        Phase 2-3 study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: preliminary results.
        Proc Am Soc Clin Oncol. 2004; 23 (Abstract 544): 13
        • Atkins M.B.
        • Hidalgo M.
        • Stadler W.M.
        • Logan T.F.
        • Dutcher J.P.
        • Hudes G.R.
        • et al.
        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. 2004; 22: 909-918
        • Tabernero J.R.
        • Burris H.
        • Casado E.
        • Macarulla T.
        • Jones S.
        • Dimitrijevic S.
        • et al.
        A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced solid tumors.
        Proc Am Soc Clin Oncol. 2005; 23 (Abstract 3007): 193s
        • Chawla S.P.
        • Chua V.
        • Menendez L.R.
        • Eilber F.C.
        • Eckardt J.J.
        • Daly S.T.
        • et al.
        A phase II study of AP23573 (an mTOR inhibitor) in patients (pts) with advanced sarcomas.
        Proc Am Soc Clin Oncol. 2005; 23 (Abstract 9068): 833s
        • Feldman E.
        • Roboz G.
        • Yee K.
        • Curcio T.
        • Rivera V.M.
        • Albitar M.
        • et al.
        A phase 2 clinical trial of AP23573, an mTOR inhibitor, in patients with relapsed or refractory hematologic malignancies.
        Proc Am Soc Clin Oncol. 2005; 23 (Abstract 6631): 592s
        • Mahalati K.
        Bronchiolitis obliterans and organizing pneumonia in renal transplant recipients.
        Transplantation. 2000; 69: 1581
        • Morelon E.
        • Stern M.
        • Israel-Biet D.
        • Correas J.M.
        • Danel C.
        • Mamzer-Bruneel M.F.
        • et al.
        Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients.
        Transplantation. 2001; 72: 787-790
        • Chan S.
        • Scheulen M.E.
        • Johnston S.
        • Mross K.
        • Cardoso F.
        • Dittrich C.
        • et al.
        Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer.
        J Clin Oncol. 2005; 23: 5314-5322
        • Galanis E.
        • Buckner J.C.
        • Maurer M.J.
        • Kreisberg J.I.
        • Ballman K.
        • Boni J.
        • et al.
        Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study.
        J Clin Oncol. 2005; 23: 5294-5304
        • Witzig T.E.
        • Geyer S.M.
        • Ghobrial I.
        • Inwards D.J.
        • Fonseca R.
        • Kurtin P.
        • et al.
        Phase II trial of single-agent Temsirolimus (CCI-779) for relapsed mantle cell lymphoma.
        J Clin Oncol. 2005; 23: 5347-5356