lung cancer is the most common cause of brain metastases ( 4050% ) , and comes before breast cancer ( 1525% ) and melanoma ( 515% ) in this respect [ 16 ] . in patients with non - small cell lung cancer ( nsclc ) , accounting for 8085% of all lung cancers , the risk of development of brain metastases ( bmf - nsclc ) throughout the course of the disease is 3050% ; brain metastases are found in 710% of patients with nsclc at diagnosis [ 718 ] . the risk of bmf - nsclc development is significantly higher in patients with advanced nsclc ( stage iii and iv ) and in patients with adenocarcinoma and large - cell carcinoma , as compared to squamous - cell carcinoma histology [ 1214 , 19 , 20 ] . hsiao et al . , in an analysis of 482 patients with stage iiib  iv nsclc , found that the risk of brain metastasis was statistically significantly higher in women , patients aged less than 60 years and in patients with adenocarcinoma histology . in over 50% of patients bmf - nsclc occur synchronously , and in 4550% of patients multiple focal lesions are found ; 515% patients are asymptomatic and brain metastases are found in them on imaging studies [ 10 , 12 , 14 ] . occurrence of bmf - nsclc is associated with a very poor prognosis : median survival of untreated patients is about 1 month [ 1 , 6 , 8 , 10 , 11 , 15 , 17 , 18 , 21 , 22 ] and of those receiving palliative corticosteroid treatment slightly over 2 months [ 17 , 18 ] . palliative whole brain radiotherapy ( wbrt ) prolongs median survival to 36 months [ 8 , 10 , 17 ] . for many years , these extremely poor treatment results caused exclusion of patients with bmf - nsclc from any controlled clinical studies that investigated e.g. systemic treatment . however , in recent years a positive change has been observed [ 15 , 22 ] . in patients qualified for definitive surgery or stereotactic radiosurgery ( srs ) , with or without wbrt , median survival reaches even more than 10 months ; however , this is true only for selected patients : with good performance status , complete or very good extracranial disease control and 13 bmf - nsclc [ 8 , 15 , 18 , 2327 ] . the following methods are used in the treatment of bmf - nsclc : surgery , srs , wbrt , systemic treatments ( chemotherapy , immunotherapy ) and various combinations of these methods [ 1 , 2 , 46 , 8 , 9 , 11 , 12 , 1719 , 26 , 2835 ] . in general , local ( surgery , srs ) [ 1 , 4 , 6 , 8 , 17 , 18 , 2830 , 35 ] or regional ( wbrt ) [ 1 , 4 , 19 , 2830 , 3335 ] treatment is preferred , including combination of surgery and radiotherapy . there is a growing importance of systemic treatment , in particular of immunotherapy [ 1 , 2 , 4 , 11 , 12 , 3032 ] . three controlled clinical studies have compared the efficacy of surgery combined with wbrt to that of wbrt alone , in patients with single brain metastasis , mainly from nsclc [ 3638 ] . results of controlled clinical studies comparing the efficacy of surgery combined with wbrt to that of wbrt alone in the study of patchell et al . , median survival was 15 weeks in patients treated with radiotherapy alone and 40 weeks in the group of patients treated with surgery ; time to relapse or progression of brain lesions was 21 weeks and 59 weeks , respectively ; both differences were highly statistically significant . has confirmed the statistically significant positive effect of surgery on patients survival , expressed as prolongation of median survival by 12 months . in a study by mintz et al . , no improvement of survival of patients treated with surgery and wbrt was found , as compared to patients treated with wbrt alone . it should be stressed however that in this study , extracranial disease control was achieved in only 21% of patients , whereas in the previous two studies this control was found in over 60% of patients . additionally , patients analysed by patchell et al . had a mri scan before surgery , whereas it was not done in any patient from the group studied by mintz , which puts into question unifocality of brain lesions in the latter group [ 36 , 38 ] . qualification of patients for surgical treatment of bmf - nsclc is based on assessment of three basic factors : patient s performance status , level of extracranial disease control and brain lesion status [ 4 , 6 , 30 ] . patients with single bmf - nsclc , with karnofsky score ( kps ) of 70 or more and controlled extracranial disease are the best candidates for surgery [ 4 , 29 ] . according to mamelak et al . , combination of surgery and wbrt in this group of patients allows 5-year survival to be achieved in 1020% of patients . it is however unquestionable that the level of extracranial disease control has a significant impact on the patient s future and on the decision whether to perform surgical treatment of bmf - nsclc . analysis of the study of mintz et al . clearly shows that the majority of deaths resulted from locoregional nsclc progression or from distant extracranial metastasis and not from the presence of bmf - nsclc themselves . in general , bmf - nsclc surgery is not recommended for patients with life expectancy not exceeding 3 months [ 4 , 6 ] . in some patients surgical treatment may be justified irrespective of the level of extracranial disease control ; the following patients are included : patients with large ( > 3 cm ) tumours , causing significant neurological deficit and/or high intracranial hypertension ( mass effect ) , patients with tumours located in the posterior cranial fossa , with a risk of secondary hydrocephalus or brainstem compression , patients with haemorrhagic , necrotic or cystic tumours , with a surrounding oedema zone . nowadays , presence of more than one bmf - nsclc is not a contraindication for surgical treatment of brain metastases ; even if resection of all bmf - nsclc is impossible , removal of one or more metastases that are particularly burdensome to the patient may be justified [ 6 , 3941 ] . surgery may also be indicated in case of uncertain nature of brain lesions or if there is a need to determine biological features of bmf - nsclc that may affect selection of e.g. targeted therapy [ 4 , 6 , 29 ] . appropriate qualification of patients for surgical treatment of bmf - nsclc ensures good tolerance and lack of complications . improvement of local efficacy of bmf - nsclc surgery may be expected along with progress of surgical technique , including in particular en bloc resections and resections with clear microscopic margins [ 29 , 42 , 43 ] . stereotactic radiosurgery may be performed with three types of radiation : high energy photons obtained from linear accelerators , gamma rays from a cobalt unit ( gamma - knife ) and relatively rarely , due to limited availability , with a proton beam from a cyclotron . according to protocol rtog 90 - 05 , the maximum tolerated single dose of radiation for a tumour of a diameter of 3140 mm is 15 gy , of 2130 mm  18 gy and below 20 mm  24 gy [ 30 , 35 , 44 ] . slightly lower doses are suggested for bmf - nsclc located in or near the brain stem , optic nerves and optic chiasm . stereotactic radiosurgery is used as : the only treatment method for selected patients with bmf - nsclc , the primary treatment method , followed by wbrt , a method of local dose escalation ( boost ) after wbrt , a method of treatment of bmf - nsclc relapses , after both wbrt and srs ( re - srs ) . the best candidates for srs treatment are patients : with single ( 13 ) bmf - nsclc , of a diameter not exceeding 33.5 cm , with bmf - nsclc located in all brain regions including those not accessible to surgery , with no or only minor neurological symptoms , with controlled extracranial disease [ 4 , 30 , 35 ] . stereotactic radiosurgery efficacy in the treatment of bmf - nsclc has been confirmed unequivocally in numerous retrospective and prospective studies [ 4 , 8 , 17 , 18 , 28 , 30 , 35 , 4459 ] . a response to srs ( decreased size of the metastasis or its growth inhibition ) is found in 8093% of patients , 1-year local control in 6186% of patients ; median survival ranges from 7 to 14 months [ 4 , 8 , 18 , 35 , 49 , 50 ] . acute toxicity develops in 518% of patients undergoing srs , and includes headache , nausea , exacerbation of existing neurological symptoms , epilepsy ; a late complication may be radiation - induced brain necrosis that is found in 26% of patients , with a clear association with srs dose and with the size of the target volume [ 4 , 35 , 44 ] . in 2004 , hu et al . reported that in a group of patients with stage i nsclc according to the ajcc , patients with single bmf - nsclc had similar survival as patients with disease of the same stage without bmf - nsclc , provided that an aggressive treatment ( chemo - radiotherapy ) of chest lesion and surgery or srs of the brain metastasis were performed . in 2008 , flannery et al . analysed a group of patients treated with curative intent for nsclc , with a single synchronous bmf - nsclc treated with srs ; median survival of patients was 18 months , and 5-year overall survival was 21% . in 2010 , mariya et al . described a group of 84 patients treated initially with srs ; in 44 ( 52.4% ) patients 1 metastasis was found , in 27 ( 32.1% )  2 , in 8 ( 9.5% )  3 , and in 5 ( 6.0% ) more than 4 bmf - nsclc . one- and 5-year overall survival was 38% and 11% , respectively , and median survival was 9 months . fifteen patients survived over two years , of whom 97% ( 13/15 ) had 1 bmf - nsclc at presentation , and brain metastases outside the irradiated ( srs ) volume appeared only in 3/15 ( 20% ) patients . in 2011 , marko et al . presented an analysis of 26 patients with asymptomatic bmf - nsclc , treated with srs alone . in this group , kps was 90100 , and the mean number of brain metastases was 1.6 ; 40 bmf - nsclc were irradiated in total . the investigated group of patients was compared with groups of patients subject to wbrt alone ( mean survival  12.3 months ) , wbrt + srs ( mean survival 12.7 months ) and wbrt + surgery ( mean survival  20.2 months ) , matched with respect to clinical characteristics . . there are numerous controversies in the literature about the role of wbrt as a treatment adjuvant to srs [ 8 , 35 , 4548 , 5456 ] . in retrospective studies and hu et al . did not find any positive effect of adjuvant wbrt on survival [ 5456 ] . in three controlled clinical studies , the efficiency of srs versus srs + wbrt was evaluated . did not show any difference in patients survival , but addition of wbrt statistically significantly improved local and distant ( brain areas outside the srs volume ) control . the effectiveness of wbrt combined with an srs boost used in the treatment of 13 brain metastases was compared with that of wbrt alone [ 35 , 45 , 5153 ] . in a study of andrews et al . ( rtog 9508 ) , in a group of patients with single , inoperable brain metastasis , statistically significant improvement of median survival was achieved , from 4.9 to 6.9 months , after combined treatment with wbrt + srs . in patients with 2 or 3 metastases , local control improvement , without overall survival improvement after wbrt + srs treatment , was also found by sanghavi et al . many authors have reported the feasibility and efficacy of repeated srs , as a salvage therapy , in the treatment of local recurrences of bmf - nsclc after previous irradiation , in a highly selected group of patients [ 17 , 35 , 44 , 58 , 60 , 61 ] . to conclude , srs alone may be used in selected patients with single bmf - nsclc , without neurological symptoms , having a good performance status ( kps  90100 ) , with controlled extracranial disease . these patients need regular follow - up with frequent visits , as according to the literature 2050% of them develop new bmf - nsclc in regions outside the srs volume , and they sometimes experience local recurrences that are amenable to further treatment ( e.g. repeated radiotherapy or surgery ) [ 8 , 28 , 30 , 62 ] . literature data show clearly that wbrt following srs reduces the risk both of local relapse and of development of metastases in parts of the brain outside the srs volume . in patients with single metastasis , addition of srs to initial wbrt improves patients survival , and in patients with multiple metastases it improves local control without any effect on survival . for several decades , wbrt combined with corticosteroid treatment has been a basic method of treatment of patients with bm - nsclc . whole brain radiotherapy alone is indicated primarily in patients : with multiple bm - nsclc , not qualifying for surgery or srs , with poor performance status , with uncontrolled extracranial disease . whole brain radiotherapy is also used as an adjuvant to surgery , and similarly as in the case of combination with srs it allows for reduction of the number of brain metastasis relapses [ 1 , 4 , 15 , 19 , 29 , 30 , 3537 ] . radiotherapy doses used in wbrt range from 20 to 40 gy , given in 520 fractions ; the most common is the regimen administering 30 gy in 10 fractions , and the majority of authors avoid administration of fraction doses higher than 3 gy [ 30 , 33 , 35 ] . suggest a possibility of improvement of wbrt efficacy , in patients with single bmf - nsclc , disqualified from surgery or srs , by escalation of the dose to the metastatic lesion with photons from a linear accelerator . whole brain radiotherapy has a modest effect on survival of patients with bmf - nsclc ; median survival after this treatment ranges from 3 to 6 months [ 4 , 5 , 19 , 28 , 30 , 63 ] , and half of patients die due to progression of brain metastases . however , wbrt allows for : reduction of the dose of corticosteroids , improvement of neurological symptoms , improvement of quality of life , and survival prolongation in comparison to corticosteroid treatment alone [ 4 , 19 ] . there is no doubt that there is a group of patients with bmf - nsclc who do not benefit from wbrt and should receive only best supportive care ( bsc ) ; however , precise selection of these patients remains difficult [ 5 , 6466 ] . in a prospective study by bezjak et al . , 55% of patients with brain metastases had obvious progression or died during the first month after wbrt . in a retrospective study conducted by sundaresan et al . ( 2010 ) , 23% of analysed patients with brain metastases from lung cancer died during the first 6 weeks ; the authors tried to develop a prognostic index for these patients with multiple brain metastases that would allow for selection of patients who would not benefit from wbrt because of a too short life expectancy . ecog ( eastern cooperative oncology group ) performance status was the sole statistically significant prognostic factor . in 2012 , craighead and chan defined benefit from wbrt as survival of over 3 months after diagnosis of brain metastases . the results of their study suggest that patients from category 2 and 3 according to rpa - rtog ( recursive partitioning analysis  radiation therapy oncology group ) , with more than 3 metastases , do not benefit from wbrt , due to a short life expectancy ( median survival 3.9 and 2.8 months , respectively ) . rpa - rtog criteria are presented in table 2 , and recist 1.1 ( response evaluation criteria in solid tumours ) response criteria for primary and metastases of the brain are presented in table 3 . recist 1.1 ( response evaluation criteria in solid tumours )  response criteria for primary and metastases of brain in 2013 , windsor et al . presented a group of 3459 patients subject to wbrt due to brain metastases from various cancers . after wbrt , 312 ( 17% ) out of 1800 patients with lung cancer survived 6 months or less , and 1498 ( 83% ) survived more than 6 months . the results showed that older patients ( median age  64 vs. 61 years ) and patients with a shorter interval between lung cancer diagnosis and wbrt ( 31 vs. 35 weeks ) had worse survival ; these differences were statistically significant . concluding their study , definition of the group of patients for whom bsc is a better solution remains a challenge for investigators . in 2013 , preliminary results of a controlled clinical study of the medical research council , quartz , were published . the study compared the results of wbrt with bsc in patients with bmf - nsclc ; 85% of patients in the wbrt group and 99% in the bsc group were in category 2 and 3 according to rpa - rtog criteria . preliminary results of this study showed that using bsc alone did not worsen patients survival or their quality of life ( median survival 1.6 vs. 1.7 months ) . in the same year ( 2013 ) a study by nieder et al . was published , which was similar to the quartz study . in 41 patients bsc alone was used , in 41 wbrt with a dose of 30 gy/10 fr . , and in 31 wbrt with a dose of 20 gy/5 fr . ; median survival of all patients was 2.0 months , and in the groups listed above it was 1.7 , 2.2 and 2.2 months respectively ; the authors confirm in general the conclusions of the quartz study . tolerance of wbrt is usually good , and early reactions are usually mild and resolve within several weeks after irradiation ; they include mainly headache , fatigue , nausea and hair loss . other early complications (  6 months ) , in the form of a syndrome including somnolence , short - lasting memory disturbances and mild leukoencephalopathy , are also transient in nature . however , a serious problem is late complications ( > 6 months after radiotherapy ) that are in general irreversible , usually progressive and even life - threatening . the risk of developing the most serious of them , i.e. radiation - induced necrosis , is lower than 1% with appropriately dosed wbrt ; encephalopathy occurs in 218% of patients , usually after 2 years following radiotherapy . demyelination lesions and vascular damage may lead to memory , concentration and attention disturbances , mood swings , neurocognitive function ( ncf ) disorders and even dementia [ 19 , 29 , 35 , 69 ] . it should be however kept in mind that many of these complications may be related to causes other than wbrt , e.g. disease progression , previous treatment ( surgery , systemic treatment ) , anticonvulsants , patient s age , concomitant diseases ( atherosclerosis , diabetes ) , etc . prevention of late wbrt complications includes mainly : avoidance of exceeding fraction doses of 3 gy , hippocampal sparing radiotherapy , and use of neuroprotective agents ( memantine , donepezil , lithium , renin - angiotensin system blockers , etc . ) . to conclude , wbrt , due to its efficacy and lack of good alternative treatment options , remains a basic treatment for patients with multiple bmf - nsclc and poor performance status . in summary , surgical treatment is recommended in patients with single bmf - nsclc , with good performance status ( kps of 70 or more ) and controlled extracranial disease . patients with single ( 13 ) bmf - nsclc of diameter below 33.5 cm , with no or only minor neurological symptoms , located in different regions of the brain , including those not accessible to metastasectomy , with controlled extracranial disease , are the best candidates for srs . whole brain radiotherapy following srs reduces the risk of local relapse and progression of brain metastases outside the srs volume . whole brain radiotherapy alone , due to its efficacy and lack of good alternative treatment options , remains a basic treatment for patients with multiple bmf - nsclc , poor performance status , with uncontrolled extracranial disease , disqualified from surgery or srs .
this article presents methods and results of surgery and radiotherapy of brain metastases from non - small cell lung cancer ( bmf - nsclc ) . 
 patients with single bmf - nsclc , with karnofsky score  70 and controlled extracranial disease are the best candidates for surgery . 
 stereotactic radiosurgery ( srs ) is recommended in patients with 13 bmf - nsclc below 33.5 cm , with minor neurological symptoms , located in parts of the brain not accessible to surgery , with controlled extracranial disease . 
 whole brain radiotherapy ( wbrt ) following srs reduces the risk of local relapse ; in selected patients median survival reaches more than 10 months . 
 whole brain radiotherapy alone is a treatment in patients with multiple metastases , poor performance status , uncontrolled extracranial disease , disqualified from surgery or srs with median survival 3 to 6 months . 
 there is no doubt that there are patients with bmf - nsclc who should receive only the best supportive care . 
 there is a debate in the literature on how to select these patients .