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pazopanib is a multi - targeted tyrosine kinase inhibitor ( tki ) that inhibits vascular endothelial growth factor ( vegf ) and platelet - derived growth factor ( pdgf ) ( 1 ) .
a phase iii study on renal cell carcinoma ( 2 ) and soft - tissue sarcomas such as leiomyosarcoma and synovial sarcoma ( 3 ) showed that pazopanib prolonged progression - free survival .
additionally , in recent years , the activity of pazopanib in several types of solid tumors including tumors of the breast , thyroid , and cervix has been reported ( 1 ) .
the common adverse events of multikinase inhibitors ( including pazopanib ) are fatigue , diarrhea , nausea , weight loss , hand - foot skin reactions , and hypertension ( 4 ) ; pneumothorax has been reported as a pulmonary adverse event in patients treated with pazopanib ( 3,5,6 ) .
drug - induced interstitial lung disease ( dild ) has been reported as a serious adverse event in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors ( egfr - tkis ) such as gefitinib , erlotinib , and afatinib ( 7,8 ) .
furthermore , there have been several reports of dild due to sorafenib , another multikinase inhibitor , in recent years ( 9 - 13 ) .
three months previously , the patient had been diagnosed with left femoral vein leiomyosarcoma , and a chest computed tomography ( ct ) scan revealed multiple pulmonary metastases with bilateral mild reticular shadows ( fig .
1 ) . he was a current smoker with a 52 pack - year habit , and quit smoking after the diagnosis of leiomyosarcoma .
pazopanib ( 600 mg ) was administered ; at the same time , local radiation therapy was performed to treat the patient 's left femoral vein leiomyosarcoma .
twenty - five days after the start of pazopanib therapy , the patient 's treatment was interrupted because of fatigue and renal function failure ; pazopanib ( 200 mg ) was re - started on day 39 .
25 days after the re - starting pazopanib , the patient complained of fatigue , fever , and a nonproductive cough , and pazopanib treatment was interrupted again .
however , the symptoms and dyspnea became exacerbated on day 73 , and he was transferred to our hospital .
chest computed tomography from the start of pazopanib therapy . ( a ) lung metastases from leiomyosarcoma and ( b ) pre - existing interstitial lung disease are observed . the clinical course is shown in fig .
his body temperature was 36.4c , his blood pressure was 160/88 mmhg , his heart rate of 107 bpm , and his oxygen saturation was 95% ( with 5
the results of the laboratory tests that were performed on admission are shown in table .
a chest radiograph revealed bilateral peripheral reticular shadows and ground - glass opacity ( ggo ) , and a chest ct scan revealed bilateral ggo and traction bronchiectasis ( fig .
we diagnosed the patient with dild due to pazopanib based on the chest ct findings , the compatible clinical course , and because the laboratory tests for atypical pneumonia , opportunistic infections , and interstitial lung disease complicated by connective tissue diseases were all negative ( table ) .
a drug - induced lymphocyte stimulation test was not evaluable because the positive control was negative .
high - dose methylprednisolone ( 1,000 mg / day for 3 days ) was initiated on the day of admission , and tacrolimus was added on the 5th day after admission .
the results of a cytomegalovirus ( cmv ) antigenemia assay ( c7hrp ) changed to positive on the 9th day after admission , and ganciclovir treatment was initiated .
chest radiography and a ct scan showed partial improvement of the bilateral ggo ( fig .
3c ) , and he was transferred to another hospital on the 22nd day after admission . after tapering the patient 's prednisolone dose on the 34th day of treatment , hypoxia and bilateral reticular shadows developed again ( fig .
3d ) . since tests for c7hrp and -d - glucan were negative , steroid and tacrolimus therapy was re - started , and the patient 's dild improved .
he was transferred to a convalescent hospital to receive end - of - life care for leiomyosarcoma on the 90th day after admission .
wbc : white blood cells , rbc : red blood cells , hb : hemoglobin , hct : hematocrit , plt : platelet , tp : total protein , bun : blood urea nitrogen , cre : creatinine , t - bil : total bilirubin , ast : aspartate transaminase , alt : alanine transaminase , alp : alkaline phosphatase , ldh : lactate dehydrogenase , g - gtp : g - glutamyl transferase , glu : glucose , crp : c - reactive protein , bdg : -d - glucan , asp - ag : aspergillus antigen , cry - ag : cryptococcus antigen , cmv - ag : cytomegalovirus pp65 antigenemia , ana : anti - nuclear antibody , mpo - anca : myeloperoxidase - anti - neutrophil cytoplasmic antibody , pr3-anca : proteinase-3-anti - neutrophil cytoplasmic antibody , sp - a : surfactant protein - a , sp - d : surfactant protein - d .
chest computed tomography demonstrates bilateral diffuse ground - glass opacity and the progression of traction bronchiectasis ( b ) on the day of admission , ( c ) partial improvement on the 8th day of treatment , and ( d ) recurrence of interstitial pneumonia on the 42nd day .
the present patient developed dild due to the re - administration of pazopanib for vein leiomyosarcoma .
he had mild chronic interstitial lung disease and lung metastasis when pazopanib therapy was initiated ; however , chest radiography was not performed during pazopanib treatment .
dild may occur when a multikinase inhibitor , such as pazopanib , sorafenib , or sunitinib , targets the vegf receptor ( vegfr ) and pdgf receptor ( pdgfr ) ; however this occurs less frequently than dild due to egfr - tki - although it should be noted that dild due to sorafenib has been reported in recent years ( as described above ) ( 12 ) .
only one case of grade 1 dild was reported among 246 patients in a phase iii study on pazopanib for soft - tissue sarcoma ; however , the clinical course is unknown . to our knowledge , this is the first report to describe the clinical course of a patient with dild associated with pazopanib .
physicians should pay attention not only to pneumothorax , but also to dild during pazopanib therapy .
although the impairment of the alveolar repair mechanisms due to the inhibition of epidermal growth factor receptor phosphorylation may affect interstitial lung damage ( 15,16 ) , the mechanisms and risk factors of dild due to vegfr / pdgfr - tki are controversial .
the risk factors for dild due to egfr - tki have been reported to include older age , smoking , preexisting interstitial lung disease , and a poor performance status ( 17 - 19 ) .
a post - marketing analysis of sorafenib in japan reported that pre - existing interstitial pneumonia and pulmonary fibrosis were observed in 14% ( 9/62 cases ) of patients with dild ( 12 ) .
our case is consistent with these characteristics ; especially , pre - existing interstitial pneumonia may be associated with the development of dild , and suggests that the application of pazopanib therapy to patients with pre - existing interstitial lung disease should be considered carefully . in the current case
, we could not completely exclude an opportunistic infection because we could not perform bronchoscopy .
the c7hrp was negative on admission , but changed to positive on the 9th day after admission .
the acute progression of traction bronchiectasis and ggo on chest ct implied diffuse alveolar damage ( dad ) ; however , if dad was induced by the reactivation of cmv , the c7hrp test should have already been positive on the day of admission . additionally , laboratory tests such as -d - glucan , aspergillus antigen , rheumatoid factor , anti - nuclear antibody , and antineutrophil cytoplasmic antibody were all negative . after tapering the patient 's prednisolone dose to 7.5 mg on the 39th day ,
at that point , laboratory tests for opportunistic infections , including cmv , were all negative , and methylprednisolone pulse therapy was effective .
the guidelines for dild in japan recommend that the initial prednisolone dose should be continued for 2 - 4 weeks and then be tapered ( 20 ) - thus , the early tapering of prednisolone might have led to the recurrence of dild in the present case .
the clinical course supports a diagnosis of dild due to pazopanib ; however , it was difficult to distinguish whether the patient 's condition represented a recurrence of dild or an exacerbation of pre - existing interstitial pneumonia . in conclusion ,
the present case suggests dild due to pazopanib developed in an older patient with pre - existing interstitial lung disease .
physicians should consider the indications of pazopanib for these patients , and carefully observe their respiratory symptoms during pazopanib treatment .
although pneumothorax has been reported to be a major pulmonary adverse event in patients treated with pazopanib , a multikinase inhibitor , drug - induced interstitial lung disease ( dild ) has not been reported . a 74-year - old japanese man who received pazopanib for the treatment of femoral leiomyosarcoma and lung metastasis presented with dyspnea and fatigue . 
 he had mild interstitial pneumonia when pazopanib treatment was initiated . 
 chest computed tomography revealed progressive bilateral ground - glass opacity ( ggo ) and traction bronchiectasis . 
 we diagnosed dild due to pazopanib . 
 the patient 's pazopanib treatment was interrupted and a steroid was administered . 
 the symptoms and ggo were improved with treatment . 
 physicians should be aware of dild due to pazopanib in patients with pre - existing interstitial lung disease .