Amiodarone and cyclophosphamide: potential for enhanced lung toxicity

Abstract

Summary:Antineoplastic therapy can be associated with druginduced lung toxicity. With the increasing use of amiodarone for cardiac dysrhythmias there is an increasing possibility of its combined use with chemotherapies for various malignancies. We report a patient on long-term amiodarone who developed biopsy-proven druginduced lung toxicity after receiving high-dose cyclophosphamide, at a time-frame much shorter than would have been predicted with cyclophosphamide alone. The potential for enhanced lung toxicity secondary to combination of amiodarone and cyclophosphamide is discussed. Bone Marrow Transplantation (2001) 27, 1109-1111. Keywords: amiodarone; cyclophosphamide; oxidative stress; drug-induced lung toxicity; interstitial pneumonitis Treatment-related lung toxicity has been reported in 10-64% of patients who undergo antineoplastic chemotherapy for various malignancies. 1 In many cases it can be difficult to differentiate acute infectious processes from non-infectious conditions, such as drug toxicity. Several mechanisms for the development of drug-induced lung toxicity have been proposed. For example, antineoplastic drugs such as busulphan, cyclophosphamide, bleomycin and BCNU may promote an imbalance in lung oxidants/antioxidants, resulting in enhanced oxidative stress and lung injury. 1.2 Mechanisms by which these drugs interact with other potentially pneumotoxic drugs like amiodarone are poorly understood and lung protective strategies are lacking. Case reportA 59-year-old Caucasian male with dendritic cell sarcoma was admitted to hospital with a 2 day history of progressive shortness of breath. He denied any cough, hemoptysis, fever or phlegm. At the time of admission he was being evaluated for a bone marrow transplant and had received a single dose of cyclophosphamide (4000 mg/m 2 ) 18 days before, for progenitor cell mobilization. His past history was significant for dendritic cell sarcoma diagnosed a year ago. He had initially received six cycles of cyclophosphamide (1400 mg), vincristine (2 mg), VP-16 (100 mg) and prednisone (80 mg) on days 1-4, followed by four cycles of cisplatin (100 mg/m 2 ) on day 1, high-dose ara-C (2000 mg/m 2 ) on day 2, and dexamethasone (40 mg/day) on days 1-4. Eighteen months before admission he was diagnosed with sick sinus syndrome and a pacemaker was placed. During that hospitalization he also underwent cardioversion followed by initiation of amiodarone therapy for new onset atrial fibrillation.An admission physical examination revealed a dyspneic man with a blood pressure of 160/80 mm Hg, pulse 90, temperature 37.1°C and a respiratory rate of 20. Palpable lymph nodes were present bilaterally in the anterior triangle of the neck, as was a mildly enlarged spleen. Chest examination was significant for end inspiratory crackles in the right infrascapular region with absent breath sounds on the left side posteriorly below the mid interscapular region. A complete blood count showed a hemoglobin of 10.0 g/dl, platelet count of 101 × 10 9 /l and white cell count of 12.3 ×...

Fatal Pulmonary Toxicity After a Single Dose of Cyclophosphamide

“…Another case report describes accelerated pulmonary toxicity with the combination of cyclophosphamide plus amiodarone. 6 The frequency of cyclophosphamideinduced pulmonary toxicity is reported as approximately 1%. 1 This may be an underestimate, as it is difficult to diagnose cyclophosphamideinduced pulmonary toxicity when cyclophosphamide is used with other drugs that can cause lung injury or in the presence of pulmonary infections or malignancies.…”

“…It has the potential to cause pulmonary toxicity, most commonly in the form of diffuse alveolar damage. [1][2][3][4][5][6] Cyclophosphamideinduced pulmonary toxicity is extremely rare and often difficult to recognize because of presence of confounding factors, including use of other cytotoxic drugs, radiation pneumonitis, oxygen toxicity, pulmonary infections, and malignancies. Cyclophosphamide-induced pulmonary toxicity is accelerated when combined with amiodarone, an antiarrhythmic agent also capable of such toxicity.…”

“…Cyclophosphamide-induced pulmonary toxicity is accelerated when combined with amiodarone, an antiarrhythmic agent also capable of such toxicity. 6 We describe a patient with non-Hodgkin' s lymphoma who developed fatal pulmonary toxicity after a single dose of cyclophosphamide in the setting of long-term amiodarone use.…”

Cyclophosphamide‐induced acute respiratory distress syndrome

“…More than 25 cases have been reported in the English literature since 1976 and two reviews have addressed those from 1967 to 1976 12,13 . Some reports were of patients with a second potential cause for interstitial pneumonitis such a second drug regime or an opportunistic infection 14–16 . The interval between the administration and the onset of respiratory symptoms is extremely variable, from a few weeks to 13 years after exposure 13,17–24 .…”

Pulmonary Toxicity Caused by Cytotoxic Drugs

“…24 It has been suggested that the use of amiodarone to treat cardiac dysrhythmias in patients under chemotherapy could enhance potential chemotherapy-induced lung toxicity. 25 …”