tyrosine kinase inhibitors ( tkis ) of epidermal growth factor receptor ( egfr ) , including gefitinib and erlotinib , have considerably improved survival in non - small cell lung cancer ( nsclc ) patients ( 1 , 2 ) .
the dramatic efficacies of egfr tkis have been noted in selected subgroups , including women , never - smokers , those with histological adenocarcinoma , and those of asian ethnicity ( 3 , 4 ) . most tumors in these sensitive subgroups were related to egfr sensitizing mutations ( 5 , 6 ) , and these tumors responded better to egfr tkis than to conventional cytotoxic chemotherapies ( 7 , 8) . in several studies ,
tkis are associated with a response rate according to response evaluation criteria in solid tumors of approximately 70% as well as a progression - free survival ( pfs ) rate of 8 - 14 months in lung cancer patients who harbor egfr activating mutations ( 8 - 12 ) .
these results were very encouraging , and no controversy surrounds the use of tkis in nsclc patients with features that suggest a clinical response or egfr activating mutations . even with activating egfr mutations , however , patients inevitably develop disease progression during tki treatment .
this secondary or acquired resistance to tkis has become an issue from the point of view of subgroup characteristics and underlying mechanisms that could lead to overcoming .
some suggestions regarding the consensus of clinical criteria for the definition of acquired resistance to egfr tki in nsclc were recently put forth ( 13 , 14 ) . the post - progression survival ( pps ) of nsclc patients with acquired resistance to egfr tkis who were treated with supportive care and placebo was reported to be11 months , which was longer than expected in the lux - lung1 trial ( 15 ) .
although the intrinsic good prognosis of egfr - mutated nsclc patients is assumed to result in a relatively long pps , various attempts have been made to overcome acquired resistance to egfr tkis and improve pps in nsclc patients , including the use of second - generation irreversible tkis or resuming tki use .
furthermore , most oncologists still believe that these tumors remain " oncogene addicted " to egfr ( 16 ) .
17 ) reported that some patients who experienced disease progression after gefitinib response were sensitive to gefitinib re - administration following temporary cessation and other treatments
. therefore , we reviewed the patient group deemed likely to develop acquired resistance to gefitinib in order to investigate pps and the factors that influence pps , with a focus on resuming tki use .
the medical records and radiological images of 1,328 stage iiib or iv nsclc patients who began gefitinib treatment at the national cancer center hospital ( goyang , korea ) between june 2001 and october 2008 were retrospectively reviewed .
we selected patients who were administered gefitinib as first - line or second - line therapy and who had eastern cooperative oncology group ( ecog ) performance status ( ps ) of 0 - 2 at the time of diagnosis , as shown in fig . 1 .
to select the group with acquired resistance , we identified 81 patients with pfs > 6 months and confirmed progressive disease ( pd ) during gefitinib treatment .
pd in the central nervous system alone was an exclusion criterion because poor drug penetration could influence the results ( 13 ) .
pearson 's chi - square test or fisher 's exact test was used to compare the baseline characteristics and administered treatments between patients who resumed tki treatment ( the tki - resumed group ) and those who did not resume tki treatment ( tki - not - resumed group ) .
pps was assessed from the date of first documentation of pd during gefitinib treatment until death or the most recent follow - up .
pfs was calculated from the first day of gefitinib treatment to the first documentation of disease progression or death , and the same method was used for cases in which gefitinib treatment was resumed .
the pps time was estimated according to the kaplan - meier method , and survival differences between the groups were assessed using the cox proportional hazard model .
this study was approved by the institutional review board of the national cancer center hospital in goyang , korea ( irb number : nccncs-11 - 443 ) .
this study was approved by the institutional review board of the national cancer center hospital in goyang , korea ( irb number : nccncs-11 - 443 ) .
a total of 81 patients with confirmed pd after responding to gefitinib and minimum stable disease duration > 6 months were investigated .
the median patient age was 60 yr ( range , 36 - 82 yr ) , and the proportion of patients > 65 of age was 30.9% .
the proportions of patients who were female , never - smokers , had adenocarcinoma , and had initial stage iv disease were 77.8% , 72.8% , 95.1% , and 91.4% , respectively ( table 1 ) .
sixteen patients who resumed tki treatment included 12 treated with gefitinib and 4 treated with erlotinib .
the tki - resumed and tki - not - resumed groups did not significantly differ with regard to baseline characteristics , including pfs after the first gefitinib exposure .
an initial disease stage of iiib was the only statistically significant factor for longer pfs after initial gefitinib use in both the univariate and multivariate analyses ( table 2 ) .
first - line gefitinib treatment naturally correlated with a longer pps than did - second - line treatment ( table 3 ) . additionally , there was no significant difference in os between the first - line and second - line gefitinib treatment groups ( 24.5 vs 28.5 months ; p = 0.855 ) .
the number of metastatic organs at the time of pd during gefitinib treatment correlated with pps in univariate analysis ( hazard ratio [ hr ] , 0.53 for < 3 metastatic organs ; p = 0.009 ) , but not in multivariate analysis ( hr , 0.62 ; p = 0.061 ) . resuming tki use also significantly influenced longer pps in univariate analysis ( hr , 0.41 ; p = 0.004 ) but not in multivariate analysis ( hr 0.53 ; p = 0.095 ) . the regimens used after the initial gefitinib exposure were compared between the tki - resumed and not - resumed groups to rule out confounding effects of chemotherapies besides resumed tki in multivariate analysis .
pemetrexed and docetaxel were used significantly more frequently in the tki - resumed group than in the not - resumed group . additionally , the proportion of patients who were treated beyond fourth - line chemotherapy was significantly higher in the tki - resumed group .
the chemotherapies used throughout disease progression are summarized in table 4 up to fifth - line treatments , which mostly comprise doublet regimens .
the median tki - free interval time in this study was 13 months ( range , 0.5 - 41.1 months ) and the median number of interim cytotoxic treatments was 2 .
2 shows differences in the kaplan - meier survival curves according to resumed tki use and pemetrexed use after gefitinib failure .
the median pps was 10.3 months ( 95% confidence interval [ ci ] , 7.458 - 13.142 ) .
although pemetrexed use and tki reuse yielded superior pps according to the log - rank test , pemetrexed use was the only significant factor that affected pps in multivariate analysis according to the cox proportional hazards model ( 18.5 vs 8.6 months ; hr , 0.45 ; p = 0.008 ) .
finally , the median pfs for patients who resumed gefitinib treatment was 3.7 months ( 95% ci , 2.843 - 4.557 ) .
although tkis have improved nsclc patient survival , acquired resistance has been an emerging problem even in responsive patients .
thus , various efforts have been made to investigate the clinical outcomes of this acquired resistance group and overcome resistance .
strategies to overcome acquired resistance to egfr tkis include resumed egfr tki use , new - generation irreversible egfr tki use , met inhibitor use for met amplification , and use of pi3k / akt / mtor inhibitor plus mek inhibitor ( 18 - 21 , 26 ) .
the lux - lung1 study included lung adenocarcinoma patients who had received 1 or 2 previous chemotherapy regimens and experienced disease progression after  12 weeks of erlotinib or gefitinib treatment .
the results showed that afatinib could provide for a pfs benefit ( 3.3 vs 1.1 months ; hr , 0.38 ; p < 0.001 ) ( 15 ) .
metastatic organ numbers > 3 at the time of progression suggest a heavy disease burden and are assumed to result in shorter pps . since pps begins at the time of progression during gefitinib treatment , the first - line gefitinib group naturally presents with a longer pps than the second - line group .
( 22 ) suggested that pemetrexed is a suitable third - line treatment option with good efficacy and a tolerable toxicity profile for nsclc .
this retrospective study of 100 patients , 88 of whom had adenocarcinoma , showed that 70% of the patients received pemetrexed as the third- or further - line treatment .
( 23 ) reported good responses to pemetrexed in lung adenocarcinoma patients with egfr mutations . in that study , patients with egfr mutations ( n = 93 ) had a better response rate ( p = 0.016 ) and longer pfs ( p = 0.030 ) than those with wild - type egfr ( n = 63 ) .
in addition , there were no statistical differences in the response rates among patients with classical mutations , exon 19 deletion and l858r mutations , and non - classical mutations .
( 24 ) suggested that reduced thymidylate synthase ( ts ) gene expression in egfr - mutated nsclc could affect pemetrexed efficacy .
pemetrexed appears to be a potential good option for nsclc cases with acquired resistance to egfr tkis .
pemetrexed was administered to 11 of 33 patients who had received first - line gefitinib , and 1 of those 11 patients received second - line pemetrexed immediately after gefitinib . among 48 second - line gefitinib users ,
17 patients were treated with pemetrexed and 14 of these received pemetrexed immediately after gefitinib .
there was no significant difference in pps between 14 patients who received third - line pemetrexed treatment and 3 who received beyond - fourth - line pemetrexed ( median pps , 8.2 vs 8.9 months ; p = 0.864 )
. resumed tki use in nsclc after tki failure might be a treatment option . in this study , resumed tki use did not show statistical significance in multivariate analysis ; however , the small number of patients might act as a limitation .
( 18 ) reported in a pooled analysis that erlotinib , when used after gefitinib failure , could produce clinical benefits in patients with long sd during prior gefitinib treatment , with a pfs range from 1.7 to 5.9 months
. in our study , one - third of the tki - resumed group resumed erlotinib treatment after gefitinib failure .
the longer pfs for initial gefitinib treatment and pfs for resumed tki use was not correlated , and a median pfs of 2.8 months ( range , 0.6 - 3.7 months ) for resumed tki use was determined .
three of 5 patients ( 60% ) showed a better than sd response , which was comparable to the results of other trials that reported disease control rates of up to 63% and a median progression - free survival range of 1.7 to 6.2 months ( 25 ) .
( 26 ) reported a relatively high response rate of 25% and a disease control rate of 65% for gefitinib reuse initial gefitinib responders .
the authors stated that a sufficient egfr tki - free interval ( median , 217 days ) that included some cytotoxic treatments ( 1 - 3 regimens ) affected the response rate , which was higher than that of other reports regarding erlotinib after resistance to initial gefitinib .
the median tki - free interval time of the current study was 13 months ( range , 0.5 - 41.1 months ) and the median number of interim cytotoxic treatments was 2 .
the response rate was 27% ( 3/11 ) , and the disease control rate was 73% ( 8/11 ) for those who resumed gefitinib use ( table 5 ) .
the disease control rate of 73% is also comparable with the results of other reported re - administration trials , which ranged from of 44%-89% ( 25 ) .
( 25 ) suggested tumor heterogeneity as an explanation for different responses to the same egfr - tki regimen after a drug holiday .
the authors proposed that tumor volume is the sum of the egfr - tki sensitive clones and resistant clones , regardless of molecular mechanisms .
there have been some suggestions to the effect that this acquired resistance group possesses a distinct indolent biology .
( 27 ) reported that patients with acquired resistance to egfr tkis had a median pps of 16 months . in this study ,
pps > 10.3 months was assumed to be due to differences in the proportion of tki use as the first - line therapy ( 77% vs 40% ) .
hayashi et al . ( 28 ) reported that the average pps for advanced nsclc patients after first - line chemotherapy was longer in recent trials than in older trials ( 6.5 vs 4.4 months ; p < 0.001 ) . in future studies
, the possibility of relatively indolent nsclc biology with acquired resistance to tkis should be better clarified and considered when investigating this subgroup and interpreting the results .
first , this retrospective study lacks data for a molecular egfr mutation study because very few patients had been tested .
however , the definition of acquired resistance to tkis usually includes a clinical definition that covers patients who showed objective clinical benefits from egfr tki treatment before progression ( 13 ) .
the clinical definition of acquired resistance to tkis is reasonable , especially with regard to tumor heterogeneity and the quantities of biopsied stage iiib and iv disease .
further , pemetrexed administration after gefitinib failure was administered in all cases beyond third - line chemotherapy ( 68% in the third - line and 28% in the beyond - fourth - line groups ) .
we adjusted for the number of total chemotherapies as a potential confounding factor in the multivariate analysis , but statistical significance persisted ( p < 0.001 ; table 3 ) .
( 29 ) reported that both sequences , either non - platinum - based first - line therapy followed by platinum - based second - line chemotherapy or the reverse , yielded similar efficacies in terms of os , although that was a retrospective study of 390 nsclc patients .
( 30 ) conducted a randomized phase 2 study of irinotecan plus cisplatin vs gemcitabine plus vinorelbine as first - line chemotherapy regimens with a second - line crossover phase and showed similar survival rates for both sequences .
there is no assumption regarding established evidence for the effects of chemotherapy sequence on os .
( 28 ) identified 69 trials that showed a strong association between os and pps . in conclusion , resumed tki use or pemetrexed use in nsclc patients with acquired resistance to gefitinib is associated with longer pps and thus merits further evaluation .
these regimens might be good treatment options for patients who develop acquired resistance to gefitinib .
 most patients with tyrosine kinase inhibitor ( tki)-sensitive non - small cell lung cancer ( nsclc ) eventually develop acquired resistance to tkis . 
 factors that affect tki - sensitive patient survival after progression during tki treatment remain unknown . 
 we attempted to identify factors that affected post - progression survival . 
 we retrospectively reviewed 81 advanced nsclc patients with disease progression following tumor response and durable (  6 months ) disease stabilization with first - line or second - line gefitinib . 
 post - progression survival ( pps ) and characteristics were investigated and compared in patients who did ( n = 16 ) and did not ( n = 65 ) resume tkis . most patients were female never - smokers with adenocarcinoma . 
 median overall pps was 10.3 months ( 95% confidence interval [ ci ] , 7.458 - 13.142 ) . 
 age , gender , smoking history , histology , eastern cooperative oncology group performance status at gefitinib initiation , initial stage , and platinum - based chemotherapy after gefitinib were not significant predictors of pps . 
 pemetrexed use after gefitinib significantly improved pps ( 18.5 vs 8.6 months ; hazard ratio [ hr ] , 0.45 ; p = 0.008 ) . 
 gefitinib reuse tended to lengthen pps but was insignificant in multivariate analysis ( 27.4 vs 8.8 months ; hr , 0.53 ; p = 0.095 ) . 
 nsclc patients assumed to have clinically acquired resistance to tkis had relatively long pps . 
 tkis reuse or pemetrexed use after progression with gefitinib may improve pps . 
INTRODUCTION
MATERIALS AND METHODS
Ethics statement
RESULTS
DISCUSSION