Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents

Fabien Maldonado, MD
Andrew H Limper, MD
James R Jett, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editors
Diane MF Savarese, MD
Helen Hollingsworth, MD


Adverse drug reactions (ADRs) due to antineoplastic agents are a common form of iatrogenic injury, and the lungs are a frequent target [1-3]. While some antineoplastic agent-induced ADRs are potentially preventable (particularly those that are related to cumulative dosing), many are idiosyncratic and unpredictable.

Increasingly, cancer treatment is selected based upon an individual tumor's molecular features, a practice termed molecularly targeted therapy. Examples include use of the monoclonal antibody trastuzumab for breast cancers that over-express HER2; imatinib, a tyrosine kinase (TK) inhibitor, for gastrointestinal stromal tumors with mutations in the KIT receptor TK, as well as chronic myelogenous leukemia (where the target is the Bcr-Abl fusion protein); and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab for metastatic colorectal tumors lacking mutations in the K ras oncogene. Many of these agents are associated with lung toxicity.

This topic review will provide an overview of the incidence and specific patterns of lung toxicity seen with molecularly targeted agents used for cancer therapy. A general discussion of the clinical presentation, pathogenesis, diagnosis, differential diagnosis, and treatment of pulmonary toxicity associated with the use of antineoplastic agents is covered separately, as is lung toxicity associated with conventional cytotoxic chemotherapy agents. (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents".)


Anti-EGFR agents — Gefitinib (Iressa), erlotinib (Tarceva), and osimertinib (Tagrisso) are orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). They are primarily used in the treatment of advanced non-small cell lung cancer (NSCLC).

Approximately 1 percent of patients treated with gefitinib or erlotinib and 3 percent of patients treated with osimertinib develop lung toxicity, usually within the first two to three months of therapy. The risk is higher in patients with preexisting lung disease and in smokers. Approximately one-third of patients who develop interstitial lung disease (ILD) while being treated with gefitinib die of this complication. The mortality rate among patients receiving osimertinib appears to be lower; in one review of 813 cases, 27 developed ILD/pneumonitis, and 4 cases (15 percent of the total) were fatal [4]. The mortality rate in patients who develop ILD while receiving erlotinib is not well characterized but is likely similar to gefitinib, based on available information.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Aug 22, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting. Ann Intern Med 2004; 140:795.
  2. Classen DC, Pestotnik SL, Evans RS, Burke JP. Computerized surveillance of adverse drug events in hospital patients. JAMA 1991; 266:2847.
  3. Ozkan M, Dweik RA, Ahmad M. Drug-induced lung disease. Cleve Clin J Med 2001; 68:782.
  4. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf (Accessed on November 20, 2015).
  5. Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 2008; 177:1348.
  6. Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 2004; 45:93.
  7. Haidl ID, Huber G, Eichmann K. An ADAM family member with expression in thymic epithelial cells and related tissues. Gene 2002; 283:163.
  8. Miettinen PJ, Warburton D, Bu D, et al. Impaired lung branching morphogenesis in the absence of functional EGF receptor. Dev Biol 1997; 186:224.
  9. Hardie WD, Prows DR, Leikauf GD, Korfhagen TR. Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-alpha. Am J Physiol 1999; 277:L1045.
  10. Cohen MH, Williams GA, Sridhara R, et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8:303.
  11. Endo M, Johkoh T, Kimura K, Yamamoto N. Imaging of gefitinib-related interstitial lung disease: multi-institutional analysis by the West Japan Thoracic Oncology Group. Lung Cancer 2006; 52:135.
  12. Ieki R, Saitoh E, Shibuya M. Acute lung injury as a possible adverse drug reaction related to gefitinib. Eur Respir J 2003; 22:179.
  13. Ohyanagi F, Ando Y, Nagashima F, et al. Acute gefitinib-induced pneumonitis. Int J Clin Oncol 2004; 9:406.
  14. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366:1527.
  15. Leidner RS, Fu P, Clifford B, et al. Genetic abnormalities of the EGFR pathway in African American Patients with non-small-cell lung cancer. J Clin Oncol 2009; 27:5620.
  16. Cleverley JR, Screaton NJ, Hiorns MP, et al. Drug-induced lung disease: high-resolution CT and histological findings. Clin Radiol 2002; 57:292.
  17. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2006; 24:2549.
  18. Inomata S, Takahashi H, Nagata M, et al. Acute lung injury as an adverse event of gefitinib. Anticancer Drugs 2004; 15:461.
  19. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361:137.
  20. Hotta K, Kiura K, Tabata M, et al. Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib: an analysis of risk factors and treatment outcomes in Okayama Lung Cancer Study Group. Cancer J 2005; 11:417.
  21. Lim KH, Chang YH. Interstitial lung disease and gefitinib. N Engl J Med 2010; 363:1579; author reply 1579.
  22. Fukui T, Otani S, Hataishi R, et al. Successful rechallenge with erlotinib in a patient with EGFR-mutant lung adenocarcinoma who developed gefitinib-related interstitial lung disease. Cancer Chemother Pharmacol 2010; 65:803.
  23. Chang SC, Chang CY, Chen CY, Yu CJ. Successful erlotinib rechallenge after gefitinib-induced acute interstitial pneumonia. J Thorac Oncol 2010; 5:1105.
  24. Mok TS, Wu YL, Yu CJ, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 2009; 27:5080.
  25. Spigel DR, Lin M, O'Neill V, Hainsworth JD. Final survival and safety results from a multicenter, open-label, phase 3b trial of erlotinib in patients with advanced nonsmall cell lung cancer. Cancer 2008; 112:2749.
  26. Cohen MH, Johnson JR, Chen YF, et al. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist 2005; 10:461.
  27. Reck M, van Zandwijk N, Gridelli C, et al. Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study. J Thorac Oncol 2010; 5:1616.
  28. Yoshioka H, Komuta K, Imamura F, et al. Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer. Lung Cancer 2014; 86:201.
  29. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353:123.
  30. Liu V, White DA, Zakowski MF, et al. Pulmonary toxicity associated with erlotinib. Chest 2007; 132:1042.
  31. Makris D, Scherpereel A, Copin MC, et al. Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer. BMC Cancer 2007; 7:150.
  32. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23:5892.
  33. Yoneda KY, Shelton DK, Beckett LA, Gandara DR. Independent review of interstitial lung disease associated with death in TRIBUTE (paclitaxel and carboplatin with or without concurrent erlotinib) in advanced non-small cell lung cancer. J Thorac Oncol 2007; 2:537.
  34. Lind JS, Smit EF, Grünberg K, et al. Fatal interstitial lung disease after erlotinib for non-small cell lung cancer. J Thorac Oncol 2008; 3:1050.
  35. Kubota K, Nishiwaki Y, Tamura T, et al. Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study. J Thorac Oncol 2008; 3:1439.
  36. Tammaro KA, Baldwin PD, Lundberg AS. Interstitial lung disease following erlotinib (Tarceva) in a patient who previously tolerated gefitinib (Iressa). J Oncol Pharm Pract 2005; 11:127.
  37. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327.
  38. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15:213.
  39. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372:1689.
  40. Capri G, Chang J, Chen SC, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol 2010; 21:474.
  41. Goldsby R, Pulsipher M, Adams R, et al. Unexpected pleural effusions in 3 pediatric patients treated with STI-571. J Pediatr Hematol Oncol 2002; 24:694.
  42. Ishii Y, Shoji N, Kimura Y, Ohyashiki K. Prominent pleural effusion possibly due to imatinib mesylate in adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Intern Med 2006; 45:339.
  43. Breccia M, D'Elia GM, D'Andrea M, et al. Pleural-pericardic effusion as uncommon complication in CML patients treated with Imatinib. Eur J Haematol 2005; 74:89.
  44. Rosado MF, Donna E, Ahn YS. Challenging problems in advanced malignancy: Case 3. Imatinib mesylate-induced interstitial pneumonitis. J Clin Oncol 2003; 21:3171.
  45. Yokoyama T, Miyazawa K, Kurakawa E, et al. Interstitial pneumonia induced by imatinib mesylate: pathologic study demonstrates alveolar destruction and fibrosis with eosinophilic infiltration. Leukemia 2004; 18:645.
  46. Lin JT, Yeh KT, Fang HY, Chang CS. Fulminant, but reversible interstitial pneumonitis associated with imatinib mesylate. Leuk Lymphoma 2006; 47:1693.
  47. Ma CX, Hobday TJ, Jett JR. Imatinib mesylate-induced interstitial pneumonitis. Mayo Clin Proc 2003; 78:1578.
  48. Bergeron A, Bergot E, Vilela G, et al. Hypersensitivity pneumonitis related to imatinib mesylate. J Clin Oncol 2002; 20:4271.
  49. Ohnishi K, Sakai F, Kudoh S, Ohno R. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia 2006; 20:1162.
  50. Rajda J, Phatak PD. Reversible drug-induced interstitial pneumonitis following imatinib mesylate therapy. Am J Hematol 2005; 79:80.
  51. Wagner U, Staats P, Moll R, et al. Imatinib-associated pulmonary alveolar proteinosis. Am J Med 2003; 115:674.
  52. Yamasawa H, Sugiyama Y, Bando M, Ohno S. Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary fibrosis. Respiration 2008; 75:350.
  53. Grimison P, Goldstein D, Schneeweiss J, Murray N. Corticosteroid-responsive interstitial pneumonitis related to imantinib mesylate with successful rechallenge, and potential causative mechanisms. Intern Med J 2005; 35:136.
  54. Seki N, Ito A, Watanabe K, et al. Irreversible imatinib-induced pneumonitis following long-term imatinib administration. Intern Med 2007; 46:1941.
  55. Izumiyama N, Noguchi K, Takahashi H, et al. [Successful reintroduction of mesylate imatinib after pneumonitis in two patients with gastrointestinal stromal tumor (GIST)]. Nihon Kokyuki Gakkai Zasshi 2009; 47:918.
  56. Brixey AG, Light RW. Pleural effusions due to dasatinib. Curr Opin Pulm Med 2010; 16:351.
  57. Goldblatt M, Huggins JT, Doelken P, et al. Dasatinib-induced pleural effusions: a lymphatic network disorder? Am J Med Sci 2009; 338:414.
  58. Latagliata R, Breccia M, Fava C, et al. Incidence, risk factors and management of pleural effusions during dasatinib treatment in unselected elderly patients with chronic myelogenous leukaemia. Hematol Oncol 2013; 31:103.
  59. Masiello D, Gorospe G 3rd, Yang AS. The occurrence and management of fluid retention associated with TKI therapy in CML, with a focus on dasatinib. J Hematol Oncol 2009; 2:46.
  60. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362:2260.
  61. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol 2016; 34:2333.
  62. Porkka K, Khoury HJ, Paquette RL, et al. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer 2010; 116:377.
  63. Quintás-Cardama A, Kantarjian H, O'brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 2007; 25:3908.
  64. Kathula SK. Dasatinib in chronic myelogenous leukemia. N Engl J Med 2006; 355:1062; author reply 1063.
  65. Orlandi EM, Rocca B, Pazzano AS, Ghio S. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res 2012; 36:e4.
  66. Dumitrescu D, Seck C, ten Freyhaus H, et al. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J 2011; 38:218.
  67. Mattei D, Feola M, Orzan F, et al. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transplant 2009; 43:967.
  68. Rasheed W, Flaim B, Seymour JF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res 2009; 33:861.
  69. Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125:2128.
  70. Quilot FM, Georges M, Favrolt N, et al. Pulmonary hypertension associated with ponatinib therapy. Eur Respir J 2016; 47:676.
  71. Force T. Double-edged sword of the new cancer therapeutics. Circulation 2012; 125:2057.
  72. Bergeron A, Réa D, Levy V, et al. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med 2007; 176:814.
  73. Radaelli F, Bramanti S, Fantini NN, et al. Dasatinib-related alveolar pneumonia responsive to corticosteroids. Leuk Lymphoma 2006; 47:1180.
  74. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362:2251.
  75. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12:841.
  76. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012; 119:3403.
  77. Crizotinib prescribing information available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7#nlm34084-4 (Accessed on July 15, 2016).
  78. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205755s003s004lbl.pdf s/label/2015/205755s003s004lbl.pdf (Accessed on July 16, 2016).
  79. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014; 370:1189.
  80. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.pdf (Accessed on December 15, 2015).
  81. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204114s004lbl.pdf (Accessed on July 16, 2016).
  82. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205858lbl.pdf (Accessed on July 30, 2014).
  83. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370:1008.
  84. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 2014; 123:3406.
  85. Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 2007; 13:1367.
  86. US FDA-approved manufacturer's product information available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=43a4d7f8-48ae-4a63-9108-2fa8e3ea9d9c#S5.6 (Accessed on August 21, 2012).
  87. Horiuchi-Yamamoto Y, Gemma A, Taniguchi H, et al. Drug-induced lung injury associated with sorafenib: analysis of all-patient post-marketing surveillance in Japan. Int J Clin Oncol 2013; 18:743.
  88. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379:1879.
  89. Verschoor AJ, Gelderblom H. Pneumothorax as adverse event in patients with lung metastases of soft tissue sarcoma treated with pazopanib: a single reference centre case series. Clin Sarcoma Res 2014; 4:14.
  90. Chua W, Peters M, Loneragan R, Clarke S. Cetuximab-associated pulmonary toxicity. Clin Colorectal Cancer 2009; 8:118.
  91. Neyns B, Aerts M, Van Nieuwenhove Y, et al. Cetuximab with hepatic arterial infusion of chemotherapy for the treatment of colorectal cancer liver metastases. Anticancer Res 2008; 28:2459.
  92. Satoh T, Gemma A, Kudoh S, et al. Incidence and clinical features of drug-induced lung injury in patients with advanced colorectal cancer receiving cetuximab: results of a prospective multicenter registry. Jpn J Clin Oncol 2014; 44:1032.
  93. Giusti RM, Shastri K, Pilaro AM, et al. U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clin Cancer Res 2008; 14:1296.
  94. Vahid B, Mehrotra A. Trastuzumab (Herceptin)-associated lung injury. Respirology 2006; 11:655.
  95. Radzikowska E, Szczepulska E, Chabowski M, Bestry I. Organising pneumonia caused by transtuzumab (Herceptin) therapy for breast cancer. Eur Respir J 2003; 21:552.
  96. Bettini AC, Tondini C, Poletti P, et al. A case of interstitial pneumonitis associated with Guillain-Barré syndrome during administration of adjuvant trastuzumab. Tumori 2008; 94:737.
  97. Pepels MJ, Boomars KA, van Kimmenade R, Hupperets PS. Life-threatening interstitial lung disease associated with trastuzumab: case report. Breast Cancer Res Treat 2009; 113:609.
  98. Herceptin (trastuzumab for injection). FDA approved package insert. US National Library of Medicine. www.dailymed.nlm.nih.gov (Accessed on December 02, 2010).
  99. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/103792s5330lbl.pdf (Accessed on July 16, 2016).
  100. FDA-approved prescribing information for trastuzumab emtansine available online at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf?et_cid=31141095&et_rid=463638624&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2013%2f125427lbl.pdf (Accessed on February 25, 2013).
  101. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125427s094lbledt.pdf (Accessed on July 16, 2016).
  102. Burton C, Kaczmarski R, Jan-Mohamed R. Interstitial pneumonitis related to rituximab therapy. N Engl J Med 2003; 348:2690.
  103. Liu X, Hong XN, Gu YJ, et al. Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma. Leuk Lymphoma 2008; 49:1778.
  104. Ennishi D, Terui Y, Yokoyama M, et al. Increased incidence of interstitial pneumonia by CHOP combined with rituximab. Int J Hematol 2008; 87:393.
  105. Bitzan M, Anselmo M, Carpineta L. Rituximab (B-cell depleting antibody) associated lung injury (RALI): a pediatric case and systematic review of the literature. Pediatr Pulmonol 2009; 44:922.
  106. Iacovelli R, Palazzo A, Mezi S, et al. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trials. Acta Oncol 2012; 51:873.
  107. Willemsen AE, van Herpen CM. mTOR inhibitor-related pulmonary toxicity; incidence even higher. Acta Oncol 2013; 52:1234.
  108. Duran I, Siu LL, Oza AM, et al. Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Eur J Cancer 2006; 42:1875.
  109. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372:449.
  110. Atkins MB, Hidalgo M, Stadler WM, 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.
  111. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271.
  112. Chan S, Scheulen ME, Johnston S, 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.
  113. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005; 23:5347.
  114. Bellmunt J, Szczylik C, Feingold J, et al. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 2008; 19:1387.
  115. Atkinson BJ, Cauley DH, Ng C, et al. Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes. BJU Int 2014; 113:376.
  116. Dabydeen DA, Jagannathan JP, Ramaiya N, et al. Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer 2012; 48:1519.
  117. Dimopoulou I, Bamias A, Lyberopoulos P, Dimopoulos MA. Pulmonary toxicity from novel antineoplastic agents. Ann Oncol 2006; 17:372.
  118. White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010; 182:396.
  119. White DA, Schwartz LH, Dimitrijevic S, et al. Characterization of pneumonitis in patients with advanced non-small cell lung cancer treated with everolimus (RAD001). J Thorac Oncol 2009; 4:1357.
  120. Ellard SL, Clemons M, Gelmon KA, et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 2009; 27:4536.
  121. Soria JC, Shepherd FA, Douillard JY, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 2009; 20:1674.
  122. Mizuno R, Asano K, Mikami S, et al. Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma. Jpn J Clin Oncol 2012; 42:442.
  123. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378:2005.
  124. Sakamoto S, Kikuchi N, Ichikawa A, et al. Everolimus-induced pneumonitis after drug-eluting stent implantation: a case report. Cardiovasc Intervent Radiol 2013; 36:1151.
  125. Porta C, Osanto S, Ravaud A, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011; 47:1287.
  126. Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumors. Chest 2008; 133:528.