Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

Abstract

Noncardiogenic pulmonary edema (NCPE) is a rare and less well-recognizable pulmonotoxic syndrome of anticancer therapy than pneumonitis/fibrosis. NCPE is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension/congestive heart failure. The diagnosis of drug-related NCPE relies upon documented exclusion of any infectious, metabolic, or cancer-related causes. The Oncologist 2001;6:153-161 www.TheOncologist.com Correspondence: Evangelos Briasoulis, M.D., Medical Oncology Department, Ioannina University, Ioannina, 45110, Greece. Telephone and Fax: 30-651-99394; e-mail: ebriasou@otenet.gr. Received August 15, 2000; accepted for publication November 30, 2000. ©AlphaMed Press 1083-7159/2001 INTRODUCTIONSeveral cancer therapeutic drugs are known to induce pulmonary damage, which may result in a variety of clinicopathologic syndromes with minor to severe clinical consequences [1]. Clinical syndromes associated with drug-induced pulmonary toxicity include pneumonitis/fibrosis, hypersensitivity lung disease, and noncardiogenic pulmonary edema (NCPE)/acute respiratory distress syndrome (ARDS). These syndromes share a similar symptomatology but differ in regard to the time-relation to cancer treatment, the radiographic findings, the duration of pulmonary damage, and the long-term outcome [2]. Non-specific symptomatology of cough, progressive dyspnea, and often a low-grade fever alert clinicians confronted with the diagnostic challenge to recognize subclinical syndromes and differentiate fully developed drug-induced pulmonary reactions from lung injuries caused by infectious, cardiac, and neoplastic causes.

Noncardiogenic Pulmonary Edema in Low-dose Oral Methotrexate Therapy

“…It is known that MTX injected intrathecally can be absorbed systemically, possibly causing the pathologic process occurring in the lungs. It is also a known fact that anticancer therapy can induce NCPE regardless of the route of administration (11). Therefore, MTX at a low dose, although never reported previously, could be considered as a cause for NCPE.…”

“…General laboratory results are non-specific and represent the underlying disease process. Since these findings are non-diagnostic, information such as the time proximity to administration of the offending drug, radiograph findings, exclusion of heart dysfunction and any infectious, metabolic causes, and possible response to corticosteroids may further support a more accurate diagnosis (11).…”

“…A direct toxicity of the drug to the alveolar type I pneumocytes or pulmonary vascular endothelial cells and the triggering of a cytokine-mediated inflammatory response is a popular hypothesis (11). These processes may result in increased vascular permeability accompanied by extravasation of fluids and proteins into the air spaces (13).…”

ARA-C associated pulmonary toxicity

“…Drug-induced pulmonary damage is an entity encompassing a broad spectrum of pulmonary syndromes with mild to severe symptomatology, including pneumonitis/fibrosis, hypersensitivity pneumonitis, NCPE, and ARDS [3]. ARA-C-induced pulmonary injury is usually overlooked among the turbulent circumstances of febrile leukemia patients.…”

“…ARA-C-induced pulmonary injury is usually overlooked among the turbulent circumstances of febrile leukemia patients. ARA-C was suggested to be a causative agent of distinct forms of pulmonary toxicity in several reports [1,[3][4][5][6][7][8]. The primary cause of ARA-C toxicity is considered to be a clinical consequence of cytokine network activation, which results in alveolar damage and increased vascular permeability, leading to capillary leakage syndrome [5,6,9].…”