epidermal growth factor receptor ( egfr ) tyrosine kinase inhibitors are well - established treatments for advanced non - small cell lung cancer ( nsclc ) in many countries . they are generally well tolerated and not associated with the side effects typical of cytotoxic chemotherapy . gefitinib ( iressa , astrazeneca , london , uk ) is an orally administered , reversible tyrosine kinase inhibitor of egfr . in 2002 , it was approved for the treatment of inoperable or recurrent nsclc based on the results of two large - scale multicenter phase ii studies that yielded favorable responses and low toxicities . the iressa pan - asia study ( ipass ) found that gefitinib produced longer progression - free survival compared to carboplatin plus paclitaxel in patients with advanced pulmonary adenocarcinoma harboring egfr mutations . a more recent phase iii trial , conducted in metastatic nsclc patients with mutated egfr , confirmed these findings . common adverse events associated with gefitinib treatment are diarrhea , skin rashes , and nausea , but most of these are mild in severity and manageable . however , since the first report of gefitinib - induced interstitial lung disease ( ild ) from japan , ild associated with molecularly targeted agents has drawn considerable attention . the incidence of gefitinibinduced ild was approximately 1% in worldwide populations , while the frequency of ild in the japanese series was reported to be much higher than that in the rest of the world . in korean patients , several small prospective studies reported a high incidence ( 1.3%-3.7% ) of ild during gefitinib treatment [ 6 - 8 ] . gefitinib - induced ild is often life - threatening ; its mortality is approximately 30%-40% . however , investigation of predictive and prognostic factors for gefitinib - induced ild is limited . , we estimate the incidence of gefitinibinduced ild in a large korean population and describe the major clinical findings . a retrospective cohort study was performed with histology proven nsclc patients who were treated with gefitinib at seoul national university hospital from january 2002 through december 2011 . patient clinical data , including medical records , radiographic findings and laboratory results were reviewed . this study protocol was approved by the institutional review board ( irb ) of the seoul national university hospital ( irb protocol number : h 1308 - 047 - 511 ) . the following demographic data were abstracted : age , sex , comorbidities , smoking history , eastern cooperative oncology group ( ecog ) performance status , histologic type , previous anticancer treatment and concurrent pulmonary disease ( e.g. , pulmonary emphysema or interstitial pneumonitis ) . adverse events from gefitinib treatment were evaluated using the common terminology criteria for adverse events ( ctcae ) from the national cancer institute ver . 4.0 and a fatal adverse event was defined as being ctcae grade 4 or grade 5 . treatment response to gefitinib was assessed according to the criteria of the response evaluation criteria in solid tumors ( recist ) ver . laboratory results , including complete blood cell and differential counts , chemistry tests , and oxyhemoglobin saturation measured by pulse oximetry ( spo2 ) performed when gefitinib treatment began and when ild occurred were collected . overall survival was calculated from the initiation of gefitinib treatment to the date of death or last follow - up . new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as possible adverse pulmonary reactions . to identify the cause of an adverse pulmonary reaction , two of the investigators ( s .- h.b and s.h.s ) reviewed the data independently . if their opinions differed regarding the cause of an adverse pulmonary reaction , another investigator ( d .- w.k . ) made the decision . adverse pulmonary reactions were classified as non - infectious and infectious complications ; the causes of non - infectious complications were categorized using published classifications . the diagnosis of gefitinib - induced ild was based on published , generally accepted clinical criteria . in brief , for the diagnosis of ild , four specific findings were required : ( 1 ) progressive dyspnea with or without cough or fever , ( 2 ) lack of evidence of infection , ( 3 ) radiologic findings consistent with drug - induced ild ( i.e. , bilateral , diffuse , or patchy interstitial and/or alveolar opacifications without evidence of marked progression of underlying lung cancer ) , and ( 4 ) consistent pathologic findings , if available . categorical clinical variables were compared using a chi - squared test or fisher exact test . continuous variables were compared using an independent unpaired t test or the mann - whitney u test if the variables were not normally distributed . univariate analysis was performed to evaluate associations between the outcomes of gefitinib - induced ild and patient characteristics . variables with a p - value in the univariate analysis of less than 0.2 were selected for the multivariate analysis . overall survival was assessed by kaplan - meier method after onset of ild in different patient groups . two - sided null hypotheses of no difference were rejected if p - values were less than 0.05 , or , equivalently , if the 95% confidence intervals ( cis ) of risk point estimates excluded 1 . all statistical analyses were performed with spss ver . 21.0 ( ibm spss statistics , ibm co. , armonk , ny ) . a retrospective cohort study was performed with histology proven nsclc patients who were treated with gefitinib at seoul national university hospital from january 2002 through december 2011 . patient clinical data , including medical records , radiographic findings and laboratory results were reviewed . this study protocol was approved by the institutional review board ( irb ) of the seoul national university hospital ( irb protocol number : h 1308 - 047 - 511 ) . the following demographic data were abstracted : age , sex , comorbidities , smoking history , eastern cooperative oncology group ( ecog ) performance status , histologic type , previous anticancer treatment and concurrent pulmonary disease ( e.g. , pulmonary emphysema or interstitial pneumonitis ) . adverse events from gefitinib treatment were evaluated using the common terminology criteria for adverse events ( ctcae ) from the national cancer institute ver . 4.0 and a fatal adverse event was defined as being ctcae grade 4 or grade 5 . treatment response to gefitinib was assessed according to the criteria of the response evaluation criteria in solid tumors ( recist ) ver . laboratory results , including complete blood cell and differential counts , chemistry tests , and oxyhemoglobin saturation measured by pulse oximetry ( spo2 ) performed when gefitinib treatment began and when ild occurred were collected . overall survival was calculated from the initiation of gefitinib treatment to the date of death or last follow - up . new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as possible adverse pulmonary reactions . to identify the cause of an adverse pulmonary reaction , two of the investigators ( s .- h.b and s.h.s ) reviewed the data independently . if their opinions differed regarding the cause of an adverse pulmonary reaction , another investigator ( d .- w.k . ) made the decision . adverse pulmonary reactions were classified as non - infectious and infectious complications ; the causes of non - infectious complications were categorized using published classifications . the diagnosis of gefitinib - induced ild was based on published , generally accepted clinical criteria . in brief , for the diagnosis of ild , four specific findings were required : ( 1 ) progressive dyspnea with or without cough or fever , ( 2 ) lack of evidence of infection , ( 3 ) radiologic findings consistent with drug - induced ild ( i.e. , bilateral , diffuse , or patchy interstitial and/or alveolar opacifications without evidence of marked progression of underlying lung cancer ) , and ( 4 ) consistent pathologic findings , if available . categorical clinical variables were compared using a chi - squared test or fisher exact test . continuous variables were compared using an independent unpaired t test or the mann - whitney u test if the variables were not normally distributed . univariate analysis was performed to evaluate associations between the outcomes of gefitinib - induced ild and patient characteristics . variables with a p - value in the univariate analysis of less than 0.2 were selected for the multivariate analysis . overall survival was assessed by kaplan - meier method after onset of ild in different patient groups . two - sided null hypotheses of no difference were rejected if p - values were less than 0.05 , or , equivalently , if the 95% confidence intervals ( cis ) of risk point estimates excluded 1 . all statistical analyses were performed with spss ver . 21.0 ( ibm spss statistics , ibm co. , armonk , ny ) . the medical records of the 1,114 patients who received gefitinib from january 2002 through december 2011 were reviewed and abstracted ( fig . 1 ) . among these patients , 128 patients ( 11.5% ) developed symptomatic pulmonary infiltrates after treatment initiation . an infectious pulmonary complication occurred in 98 patients ( 8.8% ) , and 30 patients ( 2.7% ) experienced a non - infectious pulmonary complication . fifteen patients ( 1.3% ) with gefitinib - induced ild were identified . in multivariate analysis , only a lower serum albumin level was significantly associated with the development of gefitinib - induced ild after adjusting for sex , hypertension and coincidence of ild ( odds ratio , 3.91 ; 95% ci , 1.20 to 12.71 ) ( tables 1 and 2 ) . the association between the coincidence of ild before treatment and the development of gefitinibinduced ild was not significant statistically . the model fit was confirmed with the hosmer - lemeshow goodness of fitness test ( p=0.419 ) . the median time interval from the start of gefitinib administration to onset of ild was 29.0 days ( range , 3 to 1,953 days ) ( fig . gefitinib was used as second or later line treatment . in three patients ( 20.0% ) , the computed tomography ( ct ) findings at the time of ild diagnosis revealed combined lung cancer progression . the most common clinical presentation of gefitinib - induced ild was dyspnea ( 100% ) , followed by cough ( 60.0% ) . leukocytosis and elevated level of c - reactive protein ( crp ) were common ; mean leukocytes count was 13.9010/l and mean crp level was 12.01 mg / dl . the mean albumin level at the time of ild development was 3.03 g / dl . in two patients ( 13.3% ) , the patient treated with erlotinib began medication 3 months after development of gefitinib - induced ild . she received erlotinib treatment for 1 month but had to stop the medication due to newly appeared multifocal patch ground - glass opacities in both lungs on chest ct . in microbiologic examinations , sputum pneumocystis jirovecii polymerase chain reaction was positive , and the patient was treated with intravenous sulfamethoxazole , trimethoprim , and steroid . after pneumocystis pneumonia developed , she was transferred to another hospital near her hometown for hospice care because of worsened general condition . the mean dose was equivalent to 0.87 mg / kg / day methylprednisolone initially and was gradually tapered . among the 15 patients with gefitinib - induced ild , nine patients ( 60.0% ) had a fatal clinical course and six patients ( 40.0% ) died directly from ild . the other three patients ( 20.0% ) recovered from the potentially fatal ild condition after stopping the medication or steroid treatment . however , nosocomial respiratory superinfection developed in two patients and uncontrolled infection caused their death . one patient expired from sudden cardiac arrest of unknown cause when he under observation in a general ward as gefitinib - induced ild improving after steroid treatment . we compared the clinical and laboratory variables of the fatal and non - fatal cases of ild and found that patients in the fatal group developed ild after a shorter median length of gefitinib administration and had lower mean spo2 and lower albumin level at the time of ild development than did the non - fatal group ( table 3 ) . however , the fatal and nonfatal groups did not differ significantly in underlying comorbidities , pulmonary disease , types of previous cancer treatment , time interval from onset of ild to cessation of gefitinib or administration of corticosteroids , and methylprednisolone dosage . the medical records of the 1,114 patients who received gefitinib from january 2002 through december 2011 were reviewed and abstracted ( fig . 1 ) . among these patients , 128 patients ( 11.5% ) developed symptomatic pulmonary infiltrates after treatment initiation . an infectious pulmonary complication occurred in 98 patients ( 8.8% ) , and 30 patients ( 2.7% ) experienced a non - infectious pulmonary complication . in multivariate analysis , only a lower serum albumin level was significantly associated with the development of gefitinib - induced ild after adjusting for sex , hypertension and coincidence of ild ( odds ratio , 3.91 ; 95% ci , 1.20 to 12.71 ) ( tables 1 and 2 ) . the association between the coincidence of ild before treatment and the development of gefitinibinduced ild was not significant statistically . the model fit was confirmed with the hosmer - lemeshow goodness of fitness test ( p=0.419 ) . the median time interval from the start of gefitinib administration to onset of ild was 29.0 days ( range , 3 to 1,953 days ) ( fig . gefitinib was used as second or later line treatment . in three patients ( 20.0% ) , the computed tomography ( ct ) findings at the time of ild diagnosis revealed combined lung cancer progression . the most common clinical presentation of gefitinib - induced ild was dyspnea ( 100% ) , followed by cough ( 60.0% ) . leukocytosis and elevated level of c - reactive protein ( crp ) were common ; mean leukocytes count was 13.9010/l and mean crp level was 12.01 mg / dl . the mean albumin level at the time of ild development was 3.03 g / dl . in two patients ( 13.3% ) , the patient treated with erlotinib began medication 3 months after development of gefitinib - induced ild . she received erlotinib treatment for 1 month but had to stop the medication due to newly appeared multifocal patch ground - glass opacities in both lungs on chest ct . in microbiologic examinations , sputum pneumocystis jirovecii polymerase chain reaction was positive , and the patient was treated with intravenous sulfamethoxazole , trimethoprim , and steroid . after pneumocystis pneumonia developed , she was transferred to another hospital near her hometown for hospice care because of worsened general condition . the mean dose was equivalent to 0.87 mg / kg / day methylprednisolone initially and was gradually tapered . among the 15 patients with gefitinib - induced ild , nine patients ( 60.0% ) had a fatal clinical course and six patients ( 40.0% ) died directly from ild . the other three patients ( 20.0% ) recovered from the potentially fatal ild condition after stopping the medication or steroid treatment . however , nosocomial respiratory superinfection developed in two patients and uncontrolled infection caused their death . one patient expired from sudden cardiac arrest of unknown cause when he under observation in a general ward as gefitinib - induced ild improving after steroid treatment . we compared the clinical and laboratory variables of the fatal and non - fatal cases of ild and found that patients in the fatal group developed ild after a shorter median length of gefitinib administration and had lower mean spo2 and lower albumin level at the time of ild development than did the non - fatal group ( table 3 ) . however , the fatal and nonfatal groups did not differ significantly in underlying comorbidities , pulmonary disease , types of previous cancer treatment , time interval from onset of ild to cessation of gefitinib or administration of corticosteroids , and methylprednisolone dosage . gefitinib is recognized as an acceptably safe oral agent , given that the most common toxicities associated with its use are mild and self - limiting , such as skin toxicities and diarrhea . however , the development of ild during gefitinib treatment is a drug - related toxicity that sometimes has serious consequences . in 2003 , an food and drug administration ( fda ) analysis of 50,000 patients who received gefitinib reported a 1% worldwide incidence of ild . notably , the incidence of ild in japanese populations was reported to range between 2.4% and 5.4% in clinical trials [ 9,13 - 18 ] . in other asian studies , the incidence of ild also exceeds the global incidence ; in taiwanese patients , it was reported at 2.3% . however , the incidence of ild in our study was 1.3% , similar to values reported worldwide . this is much lower than reported in other asian populations , including studies of japanese and taiwanese patients ( table 4 ) . risk factors for ild have been identified in several japanese studies ( table 4 ) , but the findings from the reported studies are inconsistent . in the present study , we attempted to identify risk factors for ild in gefitinib - treated nsclc patients by collecting all possible risk factors , including laboratory results and clinical factors that were evaluated in previous studies . unlike the previous results , a lower serum albumin level at the time of gefitinib treatment initiation was the only risk factor for developing gefitinib - induced ild . a smaller japanese study evaluated the association between ild and several laboratory values including albumin level , but did not find a significant association . however , decreased egfr phosphorylation resulting in a decrease in regenerative epithelial proliferation could augment pulmonary fibrosis . we found that a lower serum albumin level might be an important surrogate marker for predicting gefitinib - induced ild . notably , the albumin level at the time of ild development decreased compared to that before gefitinib administration ( from a mean of 3.51 to 3.03 g / dl ) . hypoalbuminemia is a predisposing factor for methotrexate - induced pulmonary toxicity ( either before or during therapy ) . it has been hypothesized that a lower degree of protein binding of methotrexate and higher levels of free methotrexate resulting from hypoalbuminemia could enhance drug - induced pulmonary toxicity in methotrexate - treated patients . gefitinib is also primarily bound to plasma proteins including human serum albumin ( 90% ) and alpha-1 acid glycoprotein ( 78% ) . ter heine et al .   reported a case of fatal ild associated with another egfr tyrosine kinase inhibitor erlotinib , with high erlotinib and metabolite plasma levels , and suggested that high drug and metabolite levels result in severe adverse pulmonary reactions . with these drugs , a lower albumin level might lead to higher levels of free gefitinib and enhance pulmonary toxicity . in a study of another target agent , monoclonal antibodies , low albumin level was identified as a risk factor for developing adverse pulmonary reactions in cancer patients . however , the cause for gefitinib - associated ild is multifactorial and it is difficult to demonstrate causation between hypoalbuminemia and the development of gefitinib - induced ild from the results in our study . in addition , hypoalbuminemia in itself is a marker for illness severity and malnutrition , and many confounding clinical factors can influence the development of hypoalbuminemia . another possible predisposing factor for gefitinib - induced ild is ethnic differences in susceptibility to ild . notably , the incidence of gefitinib - induced ild in japanese patients was higher than the incidence found in our study ; the incidence in our study was similar to values reported in worldwide populations . forsythe and faulkner   suggest that the reason for the observed difference in susceptibility to ild is related to population or environmental differences or differences in diagnostic or clinical practice . a higher risk of ild has been noted in japan than elsewhere with other medications . in fact , the frequency of coincidence with interstitial pneumonitis before gefitinib treatment was much higher ( 5.0%-13.6% ) [ 13 - 17 ] than that observed in our korean population ( 1.6% ) . of note , comorbid interstitial pneumonitis was found to be a major risk factor for gefitinib - induced ild in many japanese studies ( table 4 ) . gefitinib - induced ild usually occurs during the first 3 months of treatment ; the range to onset is 24 to 42 days . in our study , the median time to development of ild was 29 days , and 80.0% of ild cases presented within the first 8 weeks of starting gefitinib treatment ( fig . the main manifestations of gefitinib - induced ild were dyspnea ( 100.0% ) and cough ( 60.0% ) , sequentially , while only two patients ( 13.3% ) presented with fever , a commonly recognized sign of infectious pneumonia . the prognosis for gefitinib - induced ild was consistent with other studies ( table 4 ) . in the present study , among patients diagnosed with ild , six patients had an ild related death ( mortality , 40.0% ) . treatment of gefitinib - induced ild is largely supportive , including supplemental oxygen , empirical antibiotics and mechanical ventilation . immediate discontinuation of the drug is strongly recommended and systemic corticosteroids are usually prescribed , although no controlled trials have been conducted to evaluate their efficacy . we investigated the association between clinical factors at the time of onset and fatality from gefitinib - induced ild . in this study , the treatment for gefitinib - induced ild was not significantly different between the fatal and non - fatal groups . the time interval from onset of symptoms to cessation of gefitinib was similar between groups . among the 15 patients who developed ild , 12 patients ( 80.0% ) the median dose of corticosteroids at the time of onset of ild , treatment duration and the time interval from ild onset to administration of corticosteroids were not significantly associated with the prognosis of ild . no patient was rechallenged with gefitinib after recovery from ild . in univariate analysis , patients with fatal ild were more likely to develop ild within a shorter interval , to have lower spo2 and lower serum albumin compared to those with non - fatal ild . although not confirmed by multivariate analysis , due to small sample size , ild with abrupt onset after gefitinib treatment and severe pneumonitis requiring high o2 demand apparently has a poor prognosis despite appropriate treatment . also lower albumin level might be a prognostic factor as well as a predictive factor . this is the first study that evaluated predictive factors for gefitinib - induced ild and examined prognostic factors for ild with the same data set in a large scale of korean patients treated with gefitinib . another concern was misdiagnosis of ild , but we believe that the independent review of clinical data by investigators minimized this problem . it was based on ct findings and clinical characteristics , and biopsies  generally considered the gold standard for ild diagnosis  were not performed in all cases . nevertheless the clinical features of gefitinib - induced ild found in our study were similar to those previously reported . in summary , the incidence of gefitinib - induced ild in korean nsclc patients was similar to that of worldwide reports but lower than values reported for japanese population . a lower serum albumin level (  3.0 g / dl ) at baseline was the only predictive factor for gefitinib - induced ild . ild is a serious adverse effect and clinicians should give attention to the possibility of gefitinib - induced ild , particularly among patients with a lower serum albumin level .
purposeinterstitial lung disease ( ild ) is a serious adverse effect of gefitinib . 
 we examined the incidence and clinical characteristics of drug - induced ild in korean non - small cell lung carcinoma patients treated with gefitinib.materials and methodsa retrospective cohort study was performed in non - small cell lung cancer ( nsclc ) patients who started gefitinib treatment at seoul national university hospital from january 2002 through december 2011 . 
 patients who developed new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as having possible adverse pulmonary reactions . 
 the patients medical records were reviewed independently by investigators to identify the causes of pulmonary toxicities.resultsamong the 1,114 patients evaluated , 128 patients ( 11.5% ) developed pulmonary adverse reactions after taking gefitinib . 
 an infectious complication occurred in 98 patients ( 8.8% ) and 15 patients ( 1.3% ) developed ild . 
 nine of the 15 patients ( 60.0% ) with gefitinib - induced ild experienced a fatal clinical course that met either the common terminology criteria for adverse events grade 4 ( n=3 ) or grade 5 ( n=6 ) . in the multivariate analysis , 
 a lower serum albumin level (  3.0 g / dl ) at baseline was significantly associated with the development of gefitinib - induced ild ( odds ratio , 3.91 ; 95% confidence interval , 1.20 to 12.71).conclusionthe incidence of gefitinib - induced ild in korean nsclc patients was similar to that reported worldwide , but lower than values reported for japanese population . 
 ild was usually a life - threatening adverse effect of gefitinib , and the development of ild was significantly associated with a lower baseline serum albumin level .