we analyzed the medical records of 39 patients with egfr mutation - positive nsclc who were newly diagnosed at our institute between january 2003 and august 2010 , underwent tki therapy , and died before february 2012 . this protocol was approved by the ethics committee of osaka prefectural medical center for respiratory and allergic diseases . exon 19 deletion , exon 21 point mutation ( l858r ) , or exon 18 point mutation ( g719c , g719s , and g719a)as determined by direct sequencing or the pna - lna pcr clamp method . patients with egfr exon 20 t790 m mutation before treatment were excluded from this study . the parameters measured in this study were overall survival ; first , second , and overall tki therapy duration ; first tki intensity ; and tki rate . overall survival was measured from the date of diagnosis ( or confirmed recurrence in postoperative cases ) to the date of death . first tki therapy duration was measured from the start to the end of tki therapy , or to the switch to another tki due to disease progression or toxicity . second tki therapy duration was calculated from the start of re - challenge to the end of therapy . overall tki therapy duration was defined as the first tki therapy duration plus the second or more tki therapy duration . first tki intensity was defined as ( actual dose of tki)/(normal dose of tki ) during first tki therapy . for example , for a patient who took gefitinib , 250 mg / day , for 100 days and then took it sequentially every other day over 100 days , the first tki intensity is ( 250  100 + 250  100  0.5)/(250  200 ) = 0.75 . similarly , for a patient who took erlotinib , 150 mg / day , over 100 days followed by continuous low - dose erlotinib , 100 mg / day , over 100 days , the first tki intensity is ( 150  100 + 100  100)/(150  200 ) = 0.83 . to evaluate the contribution of tki to overall survival , we evaluated correlation coefficients between overall survival and overall tki therapy duration , first tki duration , first tki intensity , and tki rate . the correlation coefficients ( r ) were interpreted as follows : -0.2  r  0.2 , no relationship ; 0.2 < r  0.4 ( -0.4  r < -0.2 ) , weak positive ( or negative ) linear relationship ; 0.4 < r  0.7 ( -0.7  r < < r  1.0 ( -1.0  r < -0.7 ) , strong positive ( or negative ) linear relationship . first tki durations were compared between groups with and without cytotoxic treatment using the mann - whitney u test . survival time from disease diagnosis to death was assessed by kaplan - meier survival analysis . all statistical analyses were performed using software r [ version 2.13.1 , r development core team ( 2011 ) , r : a language and environment for statistical computing , r foundation for statistical computing ; vienna , austria ] . we analyzed the medical records of 39 patients with egfr mutation - positive nsclc who were newly diagnosed at our institute between january 2003 and august 2010 , underwent tki therapy , and died before february 2012 . this protocol was approved by the ethics committee of osaka prefectural medical center for respiratory and allergic diseases . exon 19 deletion , exon 21 point mutation ( l858r ) , or exon 18 point mutation ( g719c , g719s , and g719a)as determined by direct sequencing or the pna - lna pcr clamp method . patients with egfr exon 20 t790 m mutation before treatment were excluded from this study . the parameters measured in this study were overall survival ; first , second , and overall tki therapy duration ; first tki intensity ; and tki rate . overall survival was measured from the date of diagnosis ( or confirmed recurrence in postoperative cases ) to the date of death . first tki therapy duration was measured from the start to the end of tki therapy , or to the switch to another tki due to disease progression or toxicity . second tki therapy duration was calculated from the start of re - challenge to the end of therapy . overall tki therapy duration was defined as the first tki therapy duration plus the second or more tki therapy duration . first tki intensity was defined as ( actual dose of tki)/(normal dose of tki ) during first tki therapy . for example , for a patient who took gefitinib , 250 mg / day , for 100 days and then took it sequentially every other day over 100 days , the first tki intensity is ( 250  100 + 250  100  0.5)/(250  200 ) = 0.75 . similarly , for a patient who took erlotinib , 150 mg / day , over 100 days followed by continuous low - dose erlotinib , 100 mg / day , over 100 days , the first tki intensity is ( 150  100 + 100  100)/(150  200 ) = 0.83 . to evaluate the contribution of tki to overall survival we evaluated correlation coefficients between overall survival and overall tki therapy duration , first tki duration , first tki intensity , and tki rate . the correlation coefficients ( r ) were interpreted as follows : -0.2  r  0.2 , no relationship ; 0.2 < r  0.4 ( -0.4  r < -0.2 ) , weak positive ( or negative ) linear relationship ; 0.4 < r  0.7 ( -0.7  r < -0.4 ) , moderate positive ( or negative ) linear relationship ; and 0.7 < r  1.0 ( -1.0  r < -0.7 ) , strong positive ( or negative ) linear relationship . the r values were analyzed using pearson 's correlation test . first tki durations were compared between groups with and without cytotoxic treatment using the mann - whitney u test . survival time from disease diagnosis to death was assessed by kaplan - meier survival analysis . all statistical analyses were performed using software r [ version 2.13.1 , r development core team ( 2011 ) , r : a language and environment for statistical computing , r foundation for statistical computing ; vienna , austria ] . of the 39 patients , 18 were males and 21 were females , with a median age of 66 years ( table 1 ) . the response rate was 50% , although this objective group included 7 cases that could not be evaluated because toxicity or death reduced the therapeutic period . a variety of egfr mutations were identified , including 19 exon 19 deletions , 17 exon 21 point mutations , and 3 exon 18 point mutations . we found a moderate relationship [ r = 0.534 , 95% confidential interval ( ci ) = 0.263 to 0.727 , p < 0.001 ] between overall survival and overall tki therapy duration ( figure 1a ) . for first tki intensity , the median was 0.928 , the mean was 0.831 , and the standard deviation was 0.2 . notably , one - third of patients ( 13/39 ) had tki intensity less than 0.8 . we found no relationship ( r = 0.073 , 95% ci = -0.380 to 0.247 , p = 0.657 ) between first tki intensity and overall survival ( figure 1b ) . as shown in figure 1c , there was a weak relationship between overall survival and first tki therapy duration ( r = 0.32 , 95% ci = -0.012 to 0.582 , p = 0.043 ) . there was no significant difference between first tki duration and cytotoxic agent use duration ( 159 days vs. 174 days , p = 0.93 ) . for tki rate , the median was 0.266 , the mean was 0.329 , and the standard deviation was 0.268 . we observed no relationship ( r = 0.0345 , 95% ci = -0.284 to 0.346 , p = 0.835 ) between tki rate and overall survival ( figure 1d ) . the estimated median survival time was 553 days ( 95% ci = 444 to 750 days ) . tki , tyrosine kinase inhibitor ; pr , partial response ; sd , stable disease ; pd , progressive disease ; ne , not evaluated . this study showed that there is no obvious relationship between overall survival and first tki intensity or tki rate in egfr mutation - positive nsclc patients . these patients took tki for one - third of the overall survival time in the mean . if the total duration of tki therapy , including the time after first progression while on tki , affects overall survival , physicians need to consider the use of tki , even beyond disease progression . for example , to reduce the dose of gefitinib , drug administration should be changed from everyday to once every 2 or 3 days . if there is a clear relation between tki dose intensity and overall survival , dose reduction can be accordingly monitored . we found that overall survival increased as the overall tki therapy duration increased , but there were insufficient data to determine a causal relationship between these parameters . in contrast , we observed no relationship between overall survival and first tki intensity . in a post - hoc analysis of large phase iii study , satoh et al . reported that low - dose gefitinib was superior to the usual dose of gefitinib . likewise , low - dose erlotinib ( 25 mg / day ) was found to be effective in cell lines and in clinical practice . our finding that tki intensity and overall survival were not significantly related agreed that reduced doses of tki did not directly affect overall survival . the effect of egfr mutations on patient response to cytotoxic agents remains controversial , . in this study anticancer agents , except for tki , appear to increase the survival of cancer patients . we previously reported that long - term chemotherapy might extend survival in responders to first - line chemotherapy . reported that the response rate and progression - free survival was 0% and 2.5 months , respectively , when gefinitib was re - administered after cytotoxic chemotherapy . koizumi et al . reported that the response rate and progression - free survival was 15% and 2 months , respectively , after gefitinib readministration . in our study , 15 patients ( 38.5% ) underwent tki re - challenge , and we observed a moderate relationship between overall survival and overall tki therapy duration . these results suggest that tki re - challenge may contribute to survival in selected cases . first , it was retrospective and conducted on a small population at a single institution . egfr mutation - positive patients who transferred to the palliative care unit or local hospitals were excluded from this study . second , only patients who died were followed ; long - term survivors were excluded . it remains unknown whether the two tkis ( gefitinib and erlotinib ) showed the same clinical effect or whether their serum concentrations differed among mutation - positive patients . thus , further investigation is needed to determine the relationship between overall survival and tki administration . in conclusion , we found no relationship between overall survival and first tki intensity or tki rate in the treatment of patients with egfr mutation - positive nsclc . egfr mutation - positive patients should not stick to using tkis . a prospective study to define the most effective duration of tki therapy and to reduce adverse effects is needed .
for patients with epidermal growth factor receptor ( egfr ) mutation - positive lung cancer , the relationship between the dose or duration of treatment with tyrosine kinase inhibitor ( tki ) and overall survival remains unclear . 
 here , we analyzed clinical data of 39 patients who were diagnosed with egfr mutation - positive non - small cell lung cancer and treated with tki , but subsequently died . 
 several parameters were measured in this study : overall survival ; first , second , and overall tki therapy durations ; first tki intensity ( actual dose / normal dose ) ; and tki rate ( overall tki therapy duration / overall survival ) . 
 the response rate to tki therapy was 50% , and the median survival was 553 days . 
 after tki therapy failed , 38.5% patients were re - challenged with tki . 
 we observed a moderate relationship [ r = 0.534 , 95% confidential interval ( ci ) = 0.263 to 0.727 , p < 0.001 ] between overall tki therapy duration and overall survival . 
 however , we found no relationship between overall survival and first tki intensity ( r = 0.073 , 95% ci = -0.380 to 0.247 , p = 0.657 ) or tki rate ( r = 0.0345 , 95% ci = 
 -0.284 to 0.346 , p = 0.835 ) . 
 non - small cell lung cancer patients with mutation - positive tumors remained on tki therapy for , on average , 33% of the overall survival time . 
 these findings suggest that patients with egfr mutation - positive tumors should not stick to using tkis .