between 25% and 30% of non - small cell lung cancer ( nsclc ) patients will develop metastatic disease in the brain ( brain metastases from non - small cell lung cancer 
frequently they are the first site of recurrence in early - stage nsclc patients treated with definitive therapies [ 15 ] .
the prognosis is poor for untreated patients with bmf - nsclc , with median overall survival ( os ) 12 months [ 1 , 4 , 5 ] .
the combination of neurosurgery with stereotactic radiosurgery ( srs ) and/or whole - brain radiotherapy ( wbrt ) can increase the os up to 36 months , and in selected cases over 12 months [ 1 , 4 , 610 ] .
currently , the role of systemic treatment of bmf - nsclc patients is being widely discussed [ 3 , 4 , 10 ] .
historically , chemotherapy was considered as a poorly effective method of treatment , mainly because of predicted difficulties in penetrating the blood - brain - barrier ( bbb ) . for a long period of time
, patients with bmf - nsclc were excluded from controlled clinical trials for chemotherapy of nsclc [ 1 , 3 , 4 , 11 , 12 ] .
nowadays it seems that even if most of the drugs can not penetrate normal bbb , the integrity of the bbb is significantly altered , e.g. in bmf - nsclc patients , which can be proved by oedema and increased contrast uptake around the metastatic site .
the significant amount of information indicates the possibility of efficient palliative systemic treatment of chosen patients with bmf - nsclc [ 2 , 3 , 10 , 11 , 13 ] .
the role of targeted therapies , besides chemotherapy , is significantly increasing [ 1 , 4 , 10 , 13 , 14 ] .
the purpose of this work is to review , relying on the literature , the actual knowledge on the methods and results of systemic treatment of brain metastases from non - small cell lung cancer .
recent phase ii trials indicate efficacy , however limited , of platinum - based chemotherapy of bmf - nsclc patients [ 1520 ] , which is presented in table 1 .
efficacy of platinum - based chemotherapy of bmf - nsclc patients in phase ii trials phase ii trials demonstrating efficacy of first - line bmf - nsclc chemotherapy . as outlined in table 1 , the response rates after platinum - based chemotherapy range from 23% to 45% ; chaubet - houdu and basse report 2350% .
literature indicates that temozolomide ( tmz ) combined with radiotherapy , in bmf - nsclc , has a slight influence on survival , but it might increase the toxicity of the treatment [ 2 , 11 , 2123 ] .
development of epidermal growth factor receptor tyrosine kinase inhibitors ( egfr - tkis ) : gefitinib or erlotinib , has clearly improved the treatment of advanced nsclc patients [ 3 , 4 , 9 , 10 , 13 , 2445 ] .
egfr mutations are present in 1025% of nsclc , with the highest prevalence found in never - smoking women of east asian descent ( up to 55% ) [ 13 , 24 ] .
pao et al . found egfr mutations to be present in 63% and 50% of bmf - nsclc patients , respectively , which suggests increased risk of developing brain metastases among patients with these mutations [ 25 , 26 ] . in a non - selected group of patients with bmf - nsclc
the overall response rates after gefitinib range from 10% to 38% , and the duration of response ranges from 9 to 13.5 months [ 2730 ] ; erlotinib has similar efficacy [ 3135 ] .
it seems that erlotinib achieves higher central nervous system ( cns ) concentration in comparison to gefitinib [ 10 , 13 ] .
gefitinib and erlotinib are both approved as first - line treatment , palliative treatment ( second- and third - line ) , and in combination with radiotherapy ( wbrt  srs ) , their efficacy was presented in case reports , case series , and nonrandomised phase ii trials [ 2 , 27 , 31 , 38 , 40 , 42 , 45 ] .
two phase ii trials evaluated the efficacy of tki in the first - line setting on patients with bmf - nsclc [ 38 , 40 ] .
both trials did not include data for egfr mutations , whereas the studies included never - smokers .
reported 10 patients ; seven demonstrated an objective response to gefitinib , one had a stable disease , and two had a progressive disease after a median 48-week follow - up period .
kim et al .   presented a group of 23 patients with synchronous bmf - nsclc with a response rate to gefitinib or erlotinib of 69% and median overall survival of 18.8 months .
the rate of cns progression was lower among egrf - mutant patients treated with gefitinib or erlotinib compared with upfront chemotherapy ( patients without egfr mutation ) 
33% vs. 48% , respectively , at a median follow - up of 25 months .
two phase ii trials assessed the role of gefitinib in the palliative setting in non - selected patients with bmf - nsclc [ 27 , 31 ] .
reported 41 patients with a 10% response rate and median overall survival of five months , wu et al .   reported 40 patients ( adenocarcinoma , never - smokers ) with a 32% response rate and median overall survival of 15 months .
+ gefitinib vs. wbrt + tmz , failed to show an advantage of gefitinib in a non - selected group of patients with bmf - nsclc ; os 6.3 months in the gefitinib arm and 4.9 months in the tmz arm , the difference was statistically irrelevant .
.   showed that tmz or erlotinib combined with wbrt + srs in a non - selected group of patients with 13 bmp - nsclc did not improve the os ; however , it increased the toxicity of the treatment .
study   evaluated the efficacy of erlotinib in combination with wbrt in 40 patients with bmf - nsclc .
patients negative for egfr mutations had a median overall survival of 9.3 months , whereas patients positive for egfr mutations had 19.1 months .
it is also undoubted that either gefitinib or erlotinib can be safely combined with wbrt [ 43 , 44 ] . some authors suggest that in selected groups of patients with bmf - nsclc , commencing treatment with gefitinib or erlotinib , with delayed wbrt , is acceptable .
it relates to women with adenocarcinoma , never - smokers , and patients positive for egfr mutations .
iuchi et al . presented good efficacy of gefitinib alone ( without radiotherapy ) in patients with adenocarcinoma bmf - nsclc , positive for egfr mutation 
the phase ii aprage trial , comparing wbrt + gefitinib with gefitinib alone in bmf - nsclc patients , is ongoing [ 3 , 12 ] . in conclusion ,
tki ( gefitinib , erlotinib ) overall response rate depends essentially on the presence of egfr gene activating mutation [ 10 , 12 , 13 , 36 , 37 ] ; if mutation is present , orr reaches more than 50% . in non - selected groups of patients ( adenocarcinoma , asian descents , never - smokers , asymptomatic bmf - nsclc ) after tkis therapy , it is possible to reach 70% orr [ 13 , 38 ] .
tkis improve survival of bmf - nsclc patients with egfr mutations in comparison to patients without these mutations [ 10 , 12 , 13 , 39 ] .
in approximately 35% of patients with nsclc , an alk ( anaplastic lymphoma kinase ) rearrangement occurs .
it results in forming an eml4-alk fusion gene ; it relates to mostly young , male , never - smokers , with adenocarcinoma [ 10 , 1214 , 46 ] . in this group , administration of crizotinib ,
an anti - eml4-alk ( echinoderm microtubule - associated protein - like 4-anaplastic lymphoma kinase ) drug , is reasonable and effective [ 10 , 14 , 4648 ] .
reported a 57% response rate , and a randomised phase iii trial presented by shaw et al .  
indicated statistically relevant improvement of progression - free survival of subjects treated with crizotinib , compared to patients treated with a second - line chemotherapy ( pemetrexed or docetaxel ) .
unfortunately , crizotinib has a poor bbb penetration , so its efficacy in bmf - nsclc patients is doubtful [ 10 , 13 , 14 , 46 , 4951 ] .
the available literature provides poor corresponding data [ 12 , 49 , 50 , 52 ] .
presented a case of bmf - nsclc progression during crizotinib treatment , despite regression of the disease outside cns .
. reported on crizotinib in 38 alk ( + ) patients ; 28 demonstrated progressive disease , and in 46% the first site of recurrence was bmf - nsclc . among patients with isolated recurrence in bmf - nsclc , treated with radiotherapy ( wbrt or srs ) followed by crizotinib , progression - free survival of 7.1 months
single cases of bmf - nsclc responsive to crizotinib were reported by kaneda et al .   and kinoshita et al . .
kinoshita suggest that administering ionising radiotherapy before crizotinib treatment may play an important role in both cases [ 43 , 48 ] . in 2006 yuan
et al . indicated in a murine model that cns radiotherapy increases penetrability of the bbb .
mehra et al . , in a phase i trial , demonstrated responses in bmf - nsclc patients treated with one of the new generation of alk inhibitors  ldk 378 .
bevacizumab is a humanised monoclonal antibody that binds selectively to vegf  vascular endothelial growth factor .
eventually , cancer cells should not develop their own blood supply , causing a lack of oxygen and nutrients , helping to slow down the growth of the tumour .
treatment of advanced nsclc with bevacizumab remains controversial [ 1 , 12 , 13 ] . results of two randomised phase iii trials , ecog 4599 and avail , reported that bevacizumab combined with chemotherapy improved the response rate and progression - free survival compared to chemotherapy alone in nsclc .
ecog 4599 also reported a significantly longer os ( 12.3 vs. 10.3 months ) [ 5658 ] .
hypertension , massive haemoptysis , disorders in blood coagulation , and bmf - nsclc were also qualified as exclusion criteria .
the restriction of the patient population to non - squamous histology was based on the research of johnson et al . , which indicated the occurrence of life - threatening haemoptysis in this group ( 4/13 patients ) .
exclusion of bmf - nsclc patients was based on the current opinion that bevacizumab significantly increase the risk of intracranial bleeding in this group [ 1 , 12 , 13 ] . in both trials ,
the incidence of cns haemorrhages among patients receiving bevacizumab was similar to the incidence of those reported in patients who did not receive bevacizumab .
based on the results of these trials , bevacizumab is currently licensed for use ase first - line therapy in combination with chemotherapy ( carboplatin + paclitaxel ) in the usa , or in addition to platinum - based chemotherapy in europe in patients with advanced non - squamous nsclc .
however , it does not mean it is commonly used ; this is because of absent or poor benefit compared to chemotherapy alone , with a slightly increased toxicity .
it is obvious that there are no reasons to exclude patients with brain metastases from clinical trials on antiangiogenic agents , as took place in the recent past [ 1 , 13 , 56 ] . despite antiangiogenic therapy ,
patients with or without brain metastases have similar risk of intracranial bleeding ( 90.83.3% ) [ 6064 ] .
several retro- and prospective clinical trials conducted in the past few years indicate that the combination of bevacizumab with chemotherapy or erlotinib is safe in the treatment of bmf - nsclc , with a slight risk of intracranial bleeding [ 60 , 6268 ] .
a prospective phase iv study aries evaluated the safety and efficacy of the first - line setting in patients with non - squamous nsclc treated with bevacizumab combined with chemotherapy .
a total of 150 patients with bmf - nsclc were enrolled , median pfs and os were 6.0 and 11.7 months , respectively , and no grade 3 to 5 cns haemorrhage occurred .
the phase ii study passport enrolled 115 nsclc patients with previously treated bmf - nsclc with wbrt and/or surgery .
patients received as a first - line bevacizumab , with platinum - based doublet chemotherapy or erlotinib , and as a second - line , bevacizumab with single - agent chemotherapy or erlotinib ; no grades 1 to 5 cns haemorrhage , among patients who received bevacizumab - based therapy were reported .
the phase iii atlas study was designed to evaluate the combination of bevacizumab / erlotinib versus bevacizumab / placebo as maintenance therapy after four cycles of induction platinum - containing chemotherapy plus bevacizumab as first - line treatment in advanced nsclc patients . among 25 evaluable patients with a history of cns metastases pretreated with wbrt and/or neurosurgery , one grade 2 cns bleeding
was observed in a patient on post - progression therapy after 14 cycles of bevacizumab [ 66 , 67 ] .
the sail study assessed the safety and efficacy of the addition of bevacizumab to first - line chemotherapy .
this study proved that bevacizumab - based therapy resulted in median os of 14.6 months , with a median time to disease progression of 7.8 months .
the specific safety of bevacizumab was assessed in patients who either developed bmf - nsclc during treatment or had occult bmf - nsclc at study entry .
of the 281 patients evaluated , five ( 2% ) had cns bleeding . the phase iii betalung study evaluated the addition of bevacizumab to erlotinib for the second - line treatment of advanced nsclc patients .
a total of 636 patients were randomised to receive bevacizumab in combination with either erlotinib or erlotinib alone .
the addition of bevacizumab to erlotinib increased pfs compared to erlotinib alone ( 3.4 vs. 1.7 months , respectively ) .
this trial included patients with bmf - nsclc , previously treated with wbrt and neurosurgery or wbrt + srs .
among 68 bmf - nsclc patients , 37 received erlotinib + bevacizumab and 31 erlotinib alone .
besse et al . presented an analysis including more than 12,000 advanced / metastatic breast cancer , nsclc , renal , and colorectal cancer patients , with previously treated cns metastases , from 13 phase ii / iii randomised controlled trials , two open - label , single - arm safety studies , and two prospective studies .
the rate of cerebral haemorrhage in the bevacizumab - treated group was 3.3% , compared to 1% in the group not treated with bevacizumab .
this study suggests that the administration of bevacizumab should no longer be contraindicated based solely on the presence of cns metastases .
several clinical trials have been launched to determine the safety and efficacy of various other antiangiogenic agents in the treatment of new or progressive brain metastases from solid tumours : sunitinib , cediranib , and vatalanib .
chemotherapy is generally effective in bmf - nsclc , and platinum - based provides response rates ranging from 23% to 45% .
epidermal growth factor receptor tyrosine kinase inhibitors ( egfr  tkis )  gefitinib and erlotinib  have a definite activity in bmf - nsclc with activating egfr mutation , or in selected groups of patients ( woman of east asian descent , never - smokers , those with adenocarcinoma ) ; the response rate ranges from 38% to 70% .
both egfr - tkis have been investigated in first - line , palliative , and in combination with radiotherapy .
patients with bmf - nsclc - egfr - mutant have improved overall survival compared with egfr wild - type tumours , when receiving an egfr inhibitor .
there is no data on the activity of the agent ani - eml4-alk - crizotinib in patients with bmf - nsclc .
data from a clinical trial enrolling patients with pretreated or occult bmf - nsclc showed that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment , associated with a low incidence of cns haemorrhage . however , bevacizumab should be used with caution in patients with active bmf - nsclc .
 in the systemic treatment of brain metastases from non - small cell lung cancer ( bmf - nsclc ) chemo- and targeted therapy are used . 
 response rates after platinum - based chemotherapy , range from 23% to 45% . 
 development of epidermal growth factor receptor tyrosine kinase inhibitors ( egfr - tkis ) : gefitinib or erlotinib , was an improvement in treatment of advanced nsclc patients . 
 egfr mutations are present in 1025% of nsclc ( mostly adenocarcinoma ) , and up to 55% in never - smoking women of east asian descent . in the non - selected group of patients with bmf - nsclc , the overall response rates after gefitinib or erlotinib treatment range from 10% to 38% , and the duration of response ranges from 9 to 13.5 months . in the case of present activating egfr mutation , the response rate after egrf - tkis is greater than 50% , and in selected groups ( adenocarcinoma , patients of asian descent , never - smokers , asymptomatic bmf - nsclc ) even 70% . 
 gefitinib or erlotinib treatment improves survival of bmf - nsclc patients with egfr mutation in comparison to cases without the presence of this mutation . 
 there is no data on the activity of the anti - eml4-alk agent crizotinib . 
 bevacizumab , recombinant humanised monoclonal antibody anti - vegf , in the treatment of advanced non - squamous nsclc patients is a subject of intense research . 
 data from a clinical trial enrolling patients with pretreated or occult bmf - nsclc proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment , associated with a low incidence of csn haemorrhages . 
 however , the efficacy and safety of bevacizumab used for therapeutic intent , regarding active brain metastases is unknown . 
Introduction
Chemotherapy
Tyrosine kinase inhibitors
Crizotinib
Bevacizumab