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Pemetrexed and interstitial lung disease

Pemetrexed is an antifolate chemotherapy agent that acts by inhibiting thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase [1,2]. The US Food and Drug Administration (FDA) first approved it in February 2004 for treatment of malignant pleural mesothelioma. It is also used as treatment of metastatic non-small cell lung cancer [3–5]. Pemetrexed is structurally and mechanistically similar to methotrexate, and methotrexate is known to cause severe pulmonary toxicity. A number of studies have been conducted to evaluate methotrexate-induced lung toxicity. However, limited information is available regarding the risk factors and clinical course of pemetrexed-induced interstitial lung disease (ILD), with only 12 reported cases in published literature [1,2,6–10]. This study was conducted to evaluate the demographics and outcomes of ILD associated with pemetrexed therapy. A retrospective analysis of pemetrexed-related adverse events reported to the FDA MedWatch database from February 2004 to February 2014 was performed using the keywords interstitial lung disease, pneumonitis, dyspnea, chest pain, cough, lung infiltrate, acute lung injury, respiratory failure, and acute respiratory distress syndrome [11]. Duplicate reports were excluded by comparing report numbers, age, gender, concomitant medication(s), diagnosis, and dose. Inclusion criteria included the receipt of at least one dose of pemetrexed and a radiographic or computerized tomographic (CT) confirmed ILD diagnosis. Cases meeting the study criteria were characterized with regard to age, gender, ethnicity, treatment, risk factors, and outcome. Our database search returned 1915 pemetrexed adverse event reports including 423 pulmonary events and 44 cases of ILD. The majority of events occurred in patients with non-small cell lung cancer (75%), followed by mesothelioma (22.7%). The median age was 66 years, and 68% of the patients were men. Over half (59%) of the reports were from those of Asian ethnicity, primarily of Japanese descent. The remaining third (34%) were Caucasian. Patients received a median of three (1–11) doses of pemetrexed prior to the reported adverse event. The median interval between the initiation of treatment and ILD presentation was 70 days (1–403 days). Delayed presentations of ILD had a median of 24.5 days (1–83 days) following completion of therapy. The majority of the patients (n1⁄4 36, 81.6%) received concomitant chemotherapy. A little over one third of the patients were smokers (34%), 23% had a history of radiotherapy, 16% had a history of asbestos exposure, 11% had a history of chronic obstructive pulmonary disease, and 7% had pre-existing ILD (Table I). Treatment with intravenous or oral pulse dose steroids plus supportive therapy was noted in 35 reports resulting in improvement or recovery in eight patients. There were 20 reported deaths. Case fatality rate was 46%. A total of 15 (34%) of ILD cases presented with severe ILD at their initial presentation, resulting in 12 deaths (80%). ILD refers to a heterogeneous group of conditions affecting the interstitium, i.e. the tissue and space around the air sacs of the lungs. Its clinical course can progress from mild dyspnea to the development of respiratory failure often leading to death. It is the most common form of drug-induced pulmonary toxicity [12]. However, the symptoms of ILD are non-specific and multiple causative agents/conditions can lead to this disease with majority of cases being idiopathic in nature. Hence, drug-induced ILD is a diagnosis of exclusion and is often difficult to diagnose. Drug-induced ILD accounts for about 2.5–3% of total cases [13,14]. Several chemotherapeutic agents have been associated with ILD, the most common ones being bleomycin, carmustine, busulfan, and cyclophosphamide [12]. Lung damage occurs as a direct effect of the drug or its metabolites on the pulmonocytes or by means of immune mechanisms [15]. Methotrexate-induced pneumonitis occurs in the form of a hypersensitivity reaction or a direct toxic injury to alveolar epithelial walls [16]. Toxicity is mediated by the release of free oxygen radicals and various cytokines [17]. Although unclear, the mechanism of pemetrexed-induced ILD may be similar to methotrexate as both these drugs act by common mechanism of blocking tetrahydrofolate synthesis [1]. Risk factors for development of drug-induced ILD are age, dose, concomitant chemotherapy, radiation exposure, preexisting lung disease, smoking, etc. [14]. Also pre-existing renal dysfunction and presence of other comorbid inflammatory conditions can lead to the development of drug-induced ILD. A study of malignant pleural mesothelioma patients in 2012 found that the incidence of pemetrexedand cisplatin-related pulmonary toxicity was 0.9% (eight cases in total 903 patients).