Targeted Oncology

, Volume 6, Issue 4, pp 235–243

Pulmonary toxicities from targeted therapies: a review



Pulmonary toxicity is rarely seen with most commonly used targeted therapies. The endothelial growth factor receptor (EGFR) small-molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib can cause interstitial lung disease (ILD). BCR-ABL tyrosine kinase inhibitors imatinib and dasatinib can cause pleural effusions. Infusion-related bronchospasm is common with the monoclonal antibodies to EGFR cetuximab and panitumumab, and case reports of bronchiolitis and pulmonary fibrosis have been described. Up to one-sixth of patients taking mammalian target of rapamycin (mTOR) inhibitors get a reversible interstitial pneumonitis. Bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), has been associated with hemoptysis and pulmonary embolism particularly in patients with squamous cell lung cancer. Infusion-related bronchospasms, acute respiratory distress syndrome (ARDS), and interstitial pneumonitis can be seen with the anti-lymphocyte monoclonal antibodies rituximab, ofatumumab, and alemtuzumab. While most pulmonary toxicities from these therapies are mild and resolve promptly with dose reduction or discontinuation, it is important for the clinician to recognize these potential toxicities when faced with treatment-related complications. Discerning these pulmonary adverse effects may help in making decisions on diagnostic testing and therapy, particularly for those with pulmonary and cardiovascular co-morbidities.


Pulmonary toxicity Targeted therapy Erlotinib Gefitinib mTOR inhibitors Dasatinib Interstitial pneumonitis Non-specific acute interstitial lung disease 


  1. 1.
    Cohen MH, Williams GA et al (2003) FDA drug approval summary: gefitinib (ZD 1839) (Iressa®) tablets. Oncologist 8:303–306PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen MH et al (2005) FDA drug approval summary: erlotinib (Tarceva®) tablets. Oncologist 10:461–466PubMedCrossRefGoogle Scholar
  3. 3.
    O’Brien SG et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004PubMedCrossRefGoogle Scholar
  4. 4.
    Druker BJ et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417PubMedCrossRefGoogle Scholar
  5. 5.
    Kantarjian H et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270PubMedCrossRefGoogle Scholar
  6. 6.
    Saglio G et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259PubMedCrossRefGoogle Scholar
  7. 7.
    Cutsem EV et al (2009) Cetuximab and chemotherapy as initial treatment for colorectal cancer. N Eng J Med 360:1408–1417CrossRefGoogle Scholar
  8. 8.
    Cutsem EV et al (2007) Open-labeled phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664PubMedCrossRefGoogle Scholar
  9. 9.
    Motzer R 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
  10. 10.
    Motzer R et al (2010) Phase III trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116:4256–4265PubMedCrossRefGoogle Scholar
  11. 11.
    Fukuoka M, Yano S et al (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237–2246PubMedCrossRefGoogle Scholar
  12. 12.
    Kris MG, Natale RB et al (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. JAMA 290:2149–2158PubMedCrossRefGoogle Scholar
  13. 13.
    Mok TS, Wu YL et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957PubMedCrossRefGoogle Scholar
  14. 14.
    Maemondo M, Inoue A et al (2010) Gefitinib or chemotherapy for non-small cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388PubMedCrossRefGoogle Scholar
  15. 15.
    Cohen MH et al (2003) FDA drug approval summary: gefitinib (ZD1839) (Iressa®) tablets. Oncologist 8:303–306PubMedCrossRefGoogle Scholar
  16. 16.
    Ando M, Okamoto I et al (2006) Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 24:2549–2556PubMedCrossRefGoogle Scholar
  17. 17.
    Paez JG et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedCrossRefGoogle Scholar
  18. 18.
    Inoue A et al (2003) Severe acute interstitial pneumonia and gefitinib. Lancet 361:137–139PubMedCrossRefGoogle Scholar
  19. 19.
    Dimopoulou I et al (2006) Pulmonary toxicity from novel antineoplastic agents. Ann Onc 17:372–379CrossRefGoogle Scholar
  20. 20.
    Danson S et al (2005) Interstitial lung disease in lung cancer: separating disease progression from treatment effects. Drug Saf 28:103–113PubMedCrossRefGoogle Scholar
  21. 21.
    Suzuki M et al (2008) Recurrent gefitinib-induced interstitial lung disease. Intern Med 47:533–536PubMedCrossRefGoogle Scholar
  22. 22.
    Herbst RS et al (2005) 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 23:5892–5899PubMedCrossRefGoogle Scholar
  23. 23.
    Gatzemeier U et al (2007) Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the tarceva lung cancer investigation trial. J Clin Oncol 25:1545–1552PubMedCrossRefGoogle Scholar
  24. 24.
    Moore MJ et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol 25:1960–1966PubMedCrossRefGoogle Scholar
  25. 25.
    Liu V et al (2007) Pulmonary toxicity associated with erlotinib. Chest 132:1042–1044PubMedCrossRefGoogle Scholar
  26. 26.
    Makris D et al (2007) Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer. BMC Cancer 7:150PubMedCrossRefGoogle Scholar
  27. 27.
    Geyer CE et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRefGoogle Scholar
  28. 28.
    Bokemeyer C et al (2008) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671PubMedCrossRefGoogle Scholar
  29. 29.
    Vermorken JB et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Eng J Med 359:1116–1127CrossRefGoogle Scholar
  30. 30.
    Lenz HJ (2007) Management and preparedness for infusion and hypersensitivity reactions. Oncologist 12:601–609PubMedCrossRefGoogle Scholar
  31. 31.
    Chua W et al (2009) Cetuximab-associated pulmonary toxicity. Clin Colorectal Cancer 8:118–120PubMedCrossRefGoogle Scholar
  32. 32.
    Giusti RM et al (2008) 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 14:1296–1302PubMedCrossRefGoogle Scholar
  33. 33.
    Slamon DJ et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  34. 34.
    Romond EH et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRefGoogle Scholar
  35. 35.
    DeMatteo RP et al (2009) Placebo-controlled randomized trial of adjuvant imatinib mesylate following the resection of localized, primary gastrointestinal stromal tumor (GIST). Lancet 373:1097–1104PubMedCrossRefGoogle Scholar
  36. 36.
    Demetri GD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480PubMedCrossRefGoogle Scholar
  37. 37.
    Quintás-Cardama A et al (2007) Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 25:3908–3914PubMedCrossRefGoogle Scholar
  38. 38.
    Kantarjian H et al (2007) Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 109:5143–5150PubMedCrossRefGoogle Scholar
  39. 39.
    Stephens J et al (2010) The burden of managing pleural effusions in patients with chronic myelogenous leukemia post-imatinib failure: a literature-based economic analysis. Int J Gen Med 3:31–36PubMedGoogle Scholar
  40. 40.
    Rajda J, Phatak PD (2005) Reversible drug-induced interstitial pneumonitis following imatinib mesylate therapy. Amer J Hem 79:80–81CrossRefGoogle Scholar
  41. 41.
    Yamasawa H et al (2008) Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary fibrosis. Respiration 75:350–354PubMedCrossRefGoogle Scholar
  42. 42.
    Isshiki I et al (2004) Interstitial pneumonitis during imatinib therapy. Brit J Haemat 125:420PubMedCrossRefGoogle Scholar
  43. 43.
    Bergeron A et al (2007) Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Res Crit Care Med 176:814–818CrossRefGoogle Scholar
  44. 44.
    Kaelin W (2004) The von hippel-lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 10:6290S–6295SPubMedCrossRefGoogle Scholar
  45. 45.
    Pham P et al (2004) Sirolimus-associated pulmonary toxicity. Clin Transplant 77:1215–1220Google Scholar
  46. 46.
    Miwa Y et al (2008) Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis. Mod Rheumat 18:208–211CrossRefGoogle Scholar
  47. 47.
    Vandewiele B et al (2010) Diffuse alveolar hemorrhage induced by everolimus. Chest 137:456–459PubMedCrossRefGoogle Scholar
  48. 48.
    White D et al (2010) Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Res Crit Care Med 182:396–403CrossRefGoogle Scholar
  49. 49.
    Porta C, et al. (2009) Recommendations for adverse event management in patients with renal cell carcinoma treated with everolimus: safety data from the RECORD-1 Trial: Poster Presented at the 8th International Kidney Cancer Symposium, Chicago, IL, September 25–26, 2009Google Scholar
  50. 50.
    Hudes G et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Eng J Med 356:2271–2281CrossRefGoogle Scholar
  51. 51.
    Bellmunt J et al (2008) Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Onc 19:1387–1392CrossRefGoogle Scholar
  52. 52.
    Maroto JP et al (2011) Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J Clin Onc. doi:10.1200/JCO.2010.29.2235
  53. 53.
    Duran I et al (2006) Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus. Euro J Cancer 42:1875–1880CrossRefGoogle Scholar
  54. 54.
    Hurwitz H et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Eng J Med 350:2335–2342CrossRefGoogle Scholar
  55. 55.
    Sandler A et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for Non-small-cell lung cancer. N Eng J Med 355:2542–2550CrossRefGoogle Scholar
  56. 56.
    Rini B et al (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Onc 26:5422–5428CrossRefGoogle Scholar
  57. 57.
    Johnson D et al (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Onc 22:2184–2191CrossRefGoogle Scholar
  58. 58.
    Myung HJ et al (2010) Sorafenib-induced interstitial pneumonitis in a patient with hepatocellular carcinoma: a case report. Gut and Liver 4:543–546PubMedCrossRefGoogle Scholar
  59. 59.
    Seidel C et al (2010) Recall pneumonitis during systemic treatment with sunitinib. Ann Oncol 21(10):2119–2120PubMedCrossRefGoogle Scholar
  60. 60.
    Leon RJ et al (1994) Rituximab-induced acute pulmonary fibrosis: letters to the editor. Mayo Clin Proc 79:949–950CrossRefGoogle Scholar
  61. 61.
    Burton C et al (2003) Interstitial pneumonitis related to rituximab therapy: to the editor. N Eng J Med 348:2690–2691CrossRefGoogle Scholar
  62. 62.
    Kim KM et al (2008) Rituximab-CHOP induced interstitial pneumonitis in patients with disseminated extranodal marginal zone B cell lymphoma. Yonsei Med J 49:155–158PubMedCrossRefGoogle Scholar
  63. 63.
    Herishanu Y et al (2006) Fatal interstitial pneumonitis related to rituximab-containing regimen. Clin Lymphoma Myeloma 6:407–409PubMedCrossRefGoogle Scholar
  64. 64.
    Lim KH et al (2010) Severe pulmonary adverse effects in lymphoma patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus rituximab. Korean J Intern Med 25:86–92PubMedCrossRefGoogle Scholar
  65. 65.
    Swords R et al (2004) Interstitial pneumonitis following rituximab therapy for immune thrombocytopenic purpura (ITP). Amer J Hem 77:103–104CrossRefGoogle Scholar
  66. 66.
    Kishi J et al (2009) A case of rituximab-induced interstitial pneumonitis observed in systemic lupus erythematosus. Rheumatology 48:447–448PubMedCrossRefGoogle Scholar
  67. 67.
    Lioté H et al (2010) Rituximab-induced lung disease: a systematic literature review. Eur Respir J 35:681–687PubMedCrossRefGoogle Scholar
  68. 68.
    Ofatumumab CBD (2010) A novel anti-CD20 monoclonal antibody for the treatement of B-cell malignancies. J Clin Oncol 28:1–6CrossRefGoogle Scholar
  69. 69.
    Osterborg A et al (2008) Ofatumumab (HuMax-CD20), a novel CD20 monoclonal antibody, is an active treatment for patients with CLL refractory to both fludarabine and alemtuzumab or bulky fludarabine-refractory disease: results from the planned interim analysis of an international pivotal trial. Blood 112:126–127Google Scholar
  70. 70.
    Coiffier B et al (2008) Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood 111:1094–1100PubMedCrossRefGoogle Scholar
  71. 71.
    Keating MJ et al (2002) Therapeutic role of alemtuzumab (campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 99:3554–3561PubMedCrossRefGoogle Scholar
  72. 72.
    Lozanski G et al (2004) Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 103:3278–3281PubMedCrossRefGoogle Scholar
  73. 73.
    Sachdeva A, Matuschak GM (2008) Diffuse alveolar hemorrhage following alemtuzumab. Chest 133:1476–1478PubMedCrossRefGoogle Scholar
  74. 74.
    San Miguel JF et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917PubMedCrossRefGoogle Scholar
  75. 75.
    Goy A, et al. (2006) Bortezomib in relapsed or refractory mantle cell lymphoma (MCL): Results of the PINNACLE study. J Clin Oncol. 2006 ASCO Annual Meeting Proceedings PartI. Vol 24, No. 18S (June 20 Supplement):7512Google Scholar
  76. 76.
    Miyakoshi S et al (2006) Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma. Blood 107:3492–3494PubMedCrossRefGoogle Scholar
  77. 77.
    Zappasodi P et al (2007) Rapid response to high-dose steroids of severe bortezomib-related pulmonary complications in multiple myeloma. J Clin Oncol 25:3380–3381PubMedCrossRefGoogle Scholar
  78. 78.
    Rajkumar SV et al (2005) Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the eastern cooperative group. J Clin Oncol 24:431–436PubMedCrossRefGoogle Scholar
  79. 79.
    Rajkumar SC et al (2005) Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106:4050–4053PubMedCrossRefGoogle Scholar
  80. 80.
    List A et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355:1456–1465PubMedCrossRefGoogle Scholar
  81. 81.
    Bennett CL et al (2006) Thalidomide and lenalidomide-associated thromboembolism among patients with cancer. JAMA 296:2558–2560PubMedCrossRefGoogle Scholar
  82. 82.
    Onozawa M, et al. (2005) Thalidomide-induced interstitial pneumonitis. J Clin Oncol 2425–2426Google Scholar
  83. 83.
    Sasaki M et al (2008) Thalidomide may induce interstitial pneumonia preferentially in Japanese patients. Euro J Haem 82:73–74CrossRefGoogle Scholar
  84. 84.
    Feaver AA et al (2006) Thalidomide-induced organizing pneumonia. So Med J 99:1292–1294CrossRefGoogle Scholar
  85. 85.
    Tilluckdharry L et al (2008) Thalidomide-related eosinophilic pneumonia: a case report and brief literature review. Cases Journal 1:1–4CrossRefGoogle Scholar
  86. 86.
    Chen C et al (2009) Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Brit J Haemat 146:164–170PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of Internal MedicineUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Internal MedicineVA-Nebraska Western Iowa Health Care SystemOmahaUSA

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