pemetrexed is a potent inhibitor of thymidylate synthase , dihydrofolate reductase , and glycinamide ribonucleotide formyltransferase . the us food and drug administration approved pemetrexed as a single agent or in association with cisplatin as a treatment for patients with locally advanced or metastatic non - small cell lung cancer ( nsclc ) . pemetrexed has been approved for maintenance treatment in patients with locally advanced or metastatic nonsquamous nsclc whose disease has not shown progression after four cycles of platinum - based doublet induction chemotherapy . pemetrexed has a modest toxicity profile and has not traditionally been regarded as a cause of interstitial pneumonitis . seven months before admission , he was diagnosed with stage iv lung adenocarcinoma ( ct3n2m1 for metastases of bone ) . he was an ex - smoker ( 45 packs / yr ) , and his performance status was eastern cooperative oncology group ( ecog ) 1 . he was treated with first - line chemotherapy , including gemcitabine ( 1,000 mg / m , days 1 and 8) and carboplatin ( area under the curve , 5.5 ) , every three weeks for six cycles . after four weeks from the last gemcitabine and carboplatin administration , the patient started second - line treatment with pemetrexed ( 500 mg / m , day 1 , every three weeks ) with vitamin supplementation and steroid pre - medication . on admission , his vital signs were as follows : blood pressure , 110/70 mm hg ; pulse rate , 74/min ; respiration rate , 24/min ; and body temperature , 36.8. no abnormal heart sounds were detected on chest auscultation ; however , fine crackles were detected in the bilateral lower lung fields . results of arterial blood gas analysis showed severe hypoxia ( ph , 7.470 ; pco2 , 28.2 mm hg ; po2 , 39.5 mm hg ; hco , 20.7 mm ; and o2 saturation , 84.6% ) ; thus , the patient received 4 l / min oxygen through a nasal cannula . peripheral blood tests showed the following : white blood cells , 7,600/l ; hemoglobin , 11.0 g / dl ; and platelets , 170,000/l . the patient 's c - reactive protein concentration increased to 3.991 mg / dl , and routine chemistry showed the following : na , 135 mm ; k , 4.1 mm ; cl , 103 mm ; aspartate transaminase , 26 iu / l ; alanine aminotransferase , 17 iu / l ; alkaline phosphatase , 113 iu / l ; gamma glutamyl transferase , 29 iu / l ; total bilirubin , 0.8 mg / dl ; blood urea nitrogen , 8.8 mg / dl ; and creatinine , 0.6 mg / dl . due to the patient 's immunocompromised status , treatment with broad - spectrum antibiotics ( levofloxacin ) and trimethoprim - sulfamethoxazole against pneumocystis jiroveci was started . a microbiological culture obtained from bronchoalveolar lavage fluid showed no evidence of bacterial , viral , or fungal pathogens . sputum cultures , acid - fast staining for bacilli , blood cultures , and p. jiroveci pneumonia polymerase chain reaction all showed negative results . an extensive microbiological investigation , including bronchoscopy , excluded the possibility of infection , including opportunistic infections . treatment with pemetrexed , which was suspected as the cause of the drug - induced pneumonitis , was stopped , and high - dose prednisolone was administered . we performed a tissue biopsy via video - assisted thoracoscopic surgery in order to confirm interstitial pneumonitis . a diagnosis of drug - induced interstitial pneumonitis caused by pemetrexed was ultimately made ; in response , antibiotic therapy was discontinued , and high - dose prednisolone therapy was continued for two weeks . treatment with oral prednisolone resulted in improvement of the patient 's clinical presentation and interstitial infiltration in both lung fields ( fig . here , we report on a case of pemetrexed - induced pneumonitis in a patient with nsclc . pemetrexed has a modest toxicity profile and is frequently used in patients with locally advanced or metastatic nsclc . the most frequently reported pemetrexed - related toxicity was fatigue ; other adverse events were less frequent . clinical studies of pemetrexed have reported a lack of patients with grade 3 - 4 pulmonary toxicity [ 1 - 4 ] . one phase ii study ( n=244 ) reported eight cases , including one death from pneumonitis without definite clinical data , and three cases occurred in the arm that received 1,000 mg / m pemetrexed , which is greater than the usual 500 mg / m dosage . symptoms of drug - associated ild , as with all forms of the condition , include rapidly developing breathlessness and a dry and unproductive cough , together with fever . such symptoms are nonspecific and can occur with a large number of common illnesses often associated with nsclc . the onset of drug - associated ild during therapy for treatment of advanced nsclc usually occurs within a few weeks after the start of treatment . our patient presented with acute dyspnea and pulmonary infiltration on chest x - ray after three weeks of first - cycle pemetrexed treatment without evidence of an infectious cause . the time interval between the last gemcitabine cycle and the first pemetrexed cycle was four weeks , and no lesion indicative of penumonitis was observed on ct scans taken before the start of pemetrexed chemotherapy , therefore , the possibility of gemcitabine - related pneumonitis was low . no specific parenchymal change in the radiological pattern is observed with drug - associated ild ; however , common findings include the presence of ground - glass shadows and/or linear opacities on high - resolution ct ( hrct ) . it seemed reasonable to approach the radiological manifestations of drug - associated lung disease using the underlying histological pattern . the patient 's tissue showed the nonspecific interstitial pneumonia pattern of idiopathic interstitial pneumonia , according to the clinical - radiological - pathological diagnosis classification . nonspecific interstitial pneumonia is one of the most common forms of drug - associated pneumonitis . nonspecific interstitial pneumonia is characterized histologically by homogeneous alveolar wall thickening with fibrous tissue and the presence of mononuclear inflammatory cells . corresponding radiographical and hrct findings usually consist of patchy or diffuse ground - glass opacities . as the disease progresses , there may be evidence of fibrosis with development of a reticular pattern and traction bronchiectasis . drug - induced injury to the lungs is thought to result from either a direct toxic effect or an indirect effect by way of a hypersensitivity reaction . anticancer agents such as bleomycin , methotrexate , procarbazine hydrochloride , and paclitaxel can cause pulmonary opacities as part of a hyper - sensitivity reaction ; however , the pathophysiology of pemetrexed - related pneumonitis is unknown . in many instances , chemotherapy - associated lung disease may respond to withdrawal of the offending agent and the judicious application of corticosteroid therapy . in summary , we report on a rare case of pemetrexed - induced pneumonitis in a patient with nsclc , including radiological and pathological documentation . diagnosis of chemotherapy - associated lung disease remains an exclusionary process , particularly with respect to infections and recurrence of the underlying neoplastic process in immuno - compromised patients . given the increasing use of pemetrexed for treatment of lung cancer , physicians must be aware of this potential toxicity .
pemetrexed is approved as a first - line treatment for advanced non - squamous non - small cell lung cancer ( nsclc ) with cisplatin and as a single agent for second - line treatment or for patients who show no disease progression after four cycles of platinum - based doublet induction chemotherapy as maintenance therapy . 
 pemetrexed has a modest toxicity profile and has not traditionally been regarded as a cause of interstitial pneumonitis . here 
 , we report on a rare case of pemetrexed - induced pneumonitis in a patient with nsclc .