doi:10.1378/chest.07-0050
(Chest. 2007; 132:1042-1044)
© 2007 American College of Chest Physicians
Pulmonary Toxicity Associated With Erlotinib*
Vincent Liu, MD;
Dorothy A. White, MD, FCCP;
Maureen F. Zakowski, MD;
William Travis, MD, FCCP;
Mark G. Kris, MD, FCCP;
Michelle S. Ginsberg, MD;
Vincent A. Miller, MD and
Christopher G. Azzoli, MD
* From the Thoracic Oncology Service (Drs. Liu, Kris, Miller, and Azzoli), Division of Solid Tumor Oncology, Department of Medicine, the Pulmonary Service (Dr. White), Division of General Medicine, Department of Medicine, and the Departments of Pathology (Drs. Zakowski and Travis) and Radiology (Dr. Ginsberg), Memorial Sloan-Kettering Cancer Center, New York, NY.
Correspondence to: Vincent Liu, MD, 300 Pasteur Dr, H3143, Stanford, CA 94305; e-mail: vinliu{at}stanford.edu
 |
Abstract
|
|---|
Interstitial lung disease (ILD) related to therapy with the drug gefitinib has been well reported. The adverse pulmonary effects of erlotinib are less well known. We report a case of fatal pulmonary toxicity in a patient with advanced non-small cell lung cancer who received erlotinib. He had been found to have pathologic findings of usual interstitial pneumonia (UIP) on the resected lung cancer specimen prior to receiving erlotinib. This case and other published evidence should alert physicians to the possibility of fatal erlotinib-induced ILD. Similar to reports in patients receiving gefitinib, those with pathologic findings of UIP on resected lung specimens or known pulmonary fibrosis may be at particular risk for erlotinib pulmonary toxicity.
Key Words: epidermal growth factor receptor • erlotinib • gefitinib • idiopathic pulmonary fibrosis • interstitial lung disease • pulmonary toxicity • tyrosine kinase inhibitor • usual interstitial pneumonia
|
Introduction
|
|---|
Erlotinib (OSI-774, Tarceva; Genentech; South San Francisco, CA) is an adenosine triphosphate-competitive inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It shares a chemical structure with gefitinib (ZD1839, Iressa; AstraZeneca; London, UK). Both medications have been studied in patients with non-small cell lung cancer (NSCLC), in whom they induce radiographic regression, alleviate lung cancer-related symptoms, and improve survival in some patients.
The common adverse effects of gefitinib and erlotinib are rash, diarrhea, and nausea, which are usually well tolerated. Interstitial lung disease (ILD), which is sometimes fatal, associated with gefitinib use has been reported in approximately 1% of patients worldwide.1 The propensity of erlotinib to lead to ILD is not well documented, but we report here on a patient in whom fatal ILD developed following erlotinib use and discuss the implications of this case.
|
Case Report
|
|---|
A 60-year-old former smoker with atrial fibrillation who was receiving warfarin therapy was found to have cancer of the left lung (Fig 1
, top, A). Pathology results from a specimen obtained by video-assisted thoracoscopy showed a well-differentiated adenocarcinoma, with acinar and mucinous bronchioloalveolar patterns, involving both lobes of the left lung. The biopsy specimen also revealed patchy interstitial fibrosis in the lung parenchyma adjacent to the cancer, with honeycombing and fibroblastic foci demonstrating the pattern of usual interstitial pneumonia. Preoperative pulmonary function studies showed normal volumes and spirometry results, and a diffusing capacity of 73% predicted. The patient began therapy with erlotinib, 150 mg daily.
View larger version (97K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1.. A CT scan through the lung bases demonstrates consolidation with air bronchograms in the left lower lobe, an adjacent 2.4-cm nodule, and smaller nodules as well as ground-glass densities in the right lower lobe (top, A). A CT scan through a similar section of the lung 1 month later demonstrates extensive ground-glass and airspace densities throughout most of the lungs (bottom, B). Previous consolidation at the left base is still present.
|
|
In his fourth week of treatment, he had acutely worsening dyspnea and hypoxemia without fever, chills, or cough. He was afebrile and tachypneic with a resting oxygen saturation of 94% while breathing ambient air, which decreased to 88% with ambulation. Breath sounds were decreased with crackles bilaterally, and he had a maculopapular rash that was consistent with a drug effect. The WBC count was 21,600 cells/µL (92% neutrophils) and a prothrombin time international normalized ratio of 4.2. A chest CT scan revealed new extensive bilateral ground-glass opacities and alveolar airspace densities throughout both lungs (Fig 1, bottom, B). Erlotinib therapy was discontinued, and therapy with methylprednisolone, ticarcillin/clavulanate, and vitamin K was initiated. Despite therapy, respiratory failure developed, requiring mechanical ventilation. No pathogens were cultured from blood, urine, or bronchial secretions. Echocardiography was nonrevealing. After several weeks of intensive care, the patient died.
A postmortem examination revealed heavy lungs (right lung, 1,340 g; left lung, 950 g). Histologic analysis showed residual mucinous adenocarcinoma of mixed subtype, in both the upper and lower lobes of the left lung with a background of severe interstitial fibrosis, acute bronchopneumonia, edema, and acute and chronic hemorrhage. An acute infarct was present in the right lung, and alveolar edema and fibrin accumulation with early hyaline membrane formation, with a pattern of diffuse alveolar damage, was present (Fig 2
).
View larger version (168K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2.. The lung shows alveolar edema and fibrin accumulation with early hyaline membrane formation with the pattern of diffuse alveolar damage. Pneumocyte hyperplasia is also present, but the cells are detached from the alveolar walls (bottom left) [hematoxylin-eosin, original x250].
|
|
|
Discussion
|
|---|
The worldwide reported incidence of ILD following gefitinib administration is estimated at 1%1 (Japan, approximately 2%; United States, 0.3%).2 Takano et al,3 however, reported a small series from Japan in which ILD developed in 5.4% of 112 patients receiving gefitinib therapy, leading to four deaths. All deaths occurred in current or former smokers, and preexisting pulmonary fibrosis was the most significant risk factor for the development of gefitinib-induced ILD.3 AstraZeneca Japan has reported4 that 29% of patients with gefitinib-induced ILD had an underlying diagnosis of pulmonary fibrosis with a significantly higher mortality rate when compared to those patients without fibrosis.
Ours is the first individual case reported of erlotinib-associated pulmonary toxicity. However, a phase 3 trial5 of erlotinib in combination with carboplatin and paclitaxel in patients with advanced NSCLC has reported five fatal ILD-like events in the erlotinib arm (1.0%) vs one event in the placebo arm (0.2%).
The etiology of ILD related to EGFR-tyrosine kinase inhibitor therapy is poorly understood. Based on case reports, common histopathologic evaluations have revealed diffuse alveolar damage with hyaline membrane formation, which is a pattern that is often seen in patients with acute interstitial pneumonia, ARDS, and drug-induced pulmonary toxicity. The molecular mechanisms leading to pulmonary toxicity are also unclear. Suzuki et al6 have suggested that gefitinib therapy may augment any underlying pulmonary fibrosis via a decrease in EGFR phosphorylation with a coincident decrease in regenerative epithelial proliferation. Regenerative epithelial cells, following bleomycin-induced pulmonary fibrosis, demonstrated the activation of EGFR-dependent proliferation. This proliferation was inhibited following the administration of gefitinib, potentially augmenting the pulmonary fibrosis.
The case presented here highlights the potential for erlotinib to induce ILD and the possible association of this complication with the presence of underlying pulmonary fibrosis. To date, pulmonary fibrosis is not an absolute contraindication to treatment with erlotinib. Given the data for gefitinib, and the results of our case, the authors recommend that patients with evidence of usual interstitial pneumonia present on resected lung specimens or a clinical diagnosis of pulmonary fibrosis should not be treated with gefitinib or erlotinib. Several cytotoxic chemotherapy agents commonly used in the treatment of NSCLC, including mitomycin, docetaxel, and gemcitabine, are also known to cause pulmonary toxicity with distinct clinical characteristics and should be used with caution.78910
Patients receiving erlotinib should have their baseline respiratory symptoms well documented prior to the administration of medication. Should pulmonary symptoms worsen, erlotinib therapy should be stopped immediately, and empiric corticosteroids should be administered until erlotinib-induced ILD can be excluded as the cause.
|
Footnotes
|
|---|
Abbreviations: EGFR = epidermal growth factor receptor; ILD = interstitial lung disease; NSCLC = non-small cell lung cancer
This article contains original material that has not been reported, presented, or published elsewhere. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication January 7, 2007.
Accepted for publication March 29, 2007.
|
References
|
|---|
- Cohen, MH, Williams, GA, Sridhara, R, et al (2003) FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8,303-306[Abstract/Free Full Text]
- Iressa [package insert]. London, UK: AstraZeneca, 2003
- 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;45,93-104[CrossRef][ISI][Medline]
- AstraZeneca Japan.. Final report on interstitial lung disease (ILD) related to gefitinib (Iressa Tablet 250) by Iressa Expert Committee. 2003 AstraZeneca Japan. Tokyo, Japan:
- 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;23,5892-5899[Abstract/Free Full Text]
- Suzuki, H, Aoshiba, K, Yokohori, N, et al Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res 2003;63,5054-5059[Abstract/Free Full Text]
- Castro, M, Veeder, MH, Mailliard, JA, et al A prospective study of pulmonary function in patients receiving mitomycin. Chest 1996;109,939-944[Abstract/Free Full Text]
- Read, WL, Mortimer, JE, Picus, J Severe interstitial pneumonitis associated with docetaxel administration. Cancer 2002;94,847-853[CrossRef][ISI][Medline]
- Semb, KA, Aamdal, S, Oian, P Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment. J Clin Oncol 1998;16,3426-3432[Abstract]
- Vander Els, NJ, Miller, V Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy. Chest 1998;114,1779-1781[Abstract/Free Full Text]
eLetters:
Read all eLetters
- First case of fatal ILD, histologically prouved, associated with erlotinib
- Colin Guillaume
- Chest Online, 21 Sep 2007
[Full text]
TOP
Abstract
Introduction
