Gemcitabine (2′, 2′-difluoro-2′-deoxycytidine) is a new nucleoside analog that is used for the treatment of non-small cell lung cancer, pancreatic cancer, urothelial cancer, breast cancer and ovarian cancer. Though it is thought that gemcitabine is relatively safe, various pulmonary toxicities have been reported (1–7). We report the autopsy of a non-small cell lung cancer patient who died because of acute respiratory distress syndrome (ARDS) 14 days after administration of gemcitabine.

A 75-year-old man with a 2 pack-per-day smoking history was admitted to our hospital on October 5, 2000, because of persistent cough and bloody sputum for over three months. The chest radiograph and CT film showed a giant mass with a cavity in the right lung lower lobe, and multiple small nodules in both of the lungs without apparent interstitial pneumonia (Figs. 1, 2). Oxygen saturation was 97%. Examination of the blood showed a white cell count of 7,200/μl, blood chemistry showed C-reactive protein of 1.4 mg/dl and lactate dehydrogenase (LDH) 290 IU/l. Bronchoscopic examination revealed that the right intermediate bronchus was obstructed by a polypoid lesion. The specimens obtained by brushings revealed non-small cell carcinoma. Further examination revealed distant metastases, including multiple bone and brain metastases, that were in stage T3N3M1 (stage IV). Taking his age into consideration, single-agent systemic chemotherapy with gemcitabine 1,000 mg/m² was started on October 23, 2000. On day three, the patient had a high fever and dyspnea at rest. Oxygen saturation in the room air was 84%. Chest radiograph showed dense infiltration mainly in the right upper lobe (Fig. 3). Examination of the blood showed a white cell count of 10,000/μl, platelet count of 388,000/μl, blood chemistry showed C-reactive protein of 24.8 mg/dl, and LDH 378 IU/l. Though repeated cultures of sputum and blood were negative for bacteria and fungi, these clinical and radiological findings with an acute onset were consistent with nosocomial pneumonia in the immunocompromised host. Thus, he was given several antibiotics including meropenem trihydrate and pentamidine isetionate, but his general condition deteriorated with progressive dyspnea. On day 8, chest radiograph (Fig. 4) and a high resolution computed tomographic scan (Fig. 5) revealed bilateral perihilar ground-glass opacity consistent with acute respiratory distress syndrome (ARDS). From day 8 to day 14, the patient was given 20 mg/day of betamethasone intravenously. However, his general condition worsened rapidly, and he died of respiratory failure on day 14. Both of the lungs at autopsy were heavy and congestive, and microscopic examination of the lungs revealed hyaline membrane formation, compatible with diffuse alveolar damage (Fig. 6). In addition, multiple microscopic fibroid thromboses were observed in arterioles and capillaries of the lungs, liver, kidney. These findings were compatible with disseminated intravascular coagulation (DIC). No pathogens were detected in cultures of blood and lung specimens obtained at autopsy.

Various pulmonary toxicities of gemcitabine have been reported. Transient dyspnea is reported to occur within hours after its administration in about 8–10 % of patients (1, 2). This transient dyspnea is often associated with bronchospasm and is usually a self-limiting event. Severe dyspnea associated with gemcitabine occurred in 3–5% of the patients (1, 3). Most of these cases could be cured by withdrawing gemcitabine, and/or by administration of diuretics and corticosteroids. Another recent report evaluated that in the clinical database the incidence rates of dyspnea and the other serious pulmonary toxicities associated with gemcitabine were 0.45% and 0.27% (4). According to an analysis of published reports (1–7), several cases including the present case have resulted in a fatal outcome (Table 1). Other reported autopsy findings revealed diffuse alveolar damage that was consistent with ARDS. The incidence rate of ARDS associated with gemcitabine is reported to be 0.002% (4). The number of doses of gemcitabine before the onset of symptoms that induced pulmonary toxicity was on average 5.4, and the latent period from starting gemcitabine to developing pulmonary toxicity was 44.4 days (3–84 days). Neither prior chemotherapy nor radiation therapy was performed on our patient, and the latent period from the initial administration of gemcitabine was three days. Compared to other reports in the literature, our case constitutes the briefest onset of fatal pulmonary toxicity after starting gemcitabine.

The diagnosis of drug-induced lung disease is made by exclusion of other potential causes, including congestive heart failure, infections, auto-immune disease, or lymphangitic carcinomatosis. At the beginning the clinical course of our patient was consistent with nosocomial pneumonia, so he was given some antibiotics. But his condition deteriorated in spite of the large amount of additional corticosteroids for ARDS. No pathogens were detected in cultures of sputum and blood obtained during the lifetime of our patient, or from blood and lung specimens obtained at autopsy. Invasion of carcinoma on the field of ground-glass opacity on the chest radiograph and CT films was ruled out at autopsy. Thus, the present case is probably gemcitabine-induced ARDS, pathologically diffuse alveolar damage and DIC, all of which occurred acutely following the initial administration of gemcitabine.

We present a case of fatal pulmonary toxicity that developed following intravaneous gemcitabine monotherapy for non-small cell lung cancer. Although most of the pulmonary toxicities associated with gemcibanine are transient and mild, they can occur acutely and can be fatal.