lung cancer is the leading cause of cancer death in most countries . although much effort has been made over the last few decades to improve the survival of lung cancer patients , overall five - year survival rates remain unsatisfactorily low ( 14% in the u.s.a . )
brain metastasis ( bm ) is a major cause of the low survival rate and poor quality of life of cancer patients .
the prognosis for patients with bm who go untreated is extremely poor ( about one month following diagnosis ) ( 2 ) , whereas patients with non - small cell lung cancer ( nsclc ) who are treated with radiation therapy survive for about 8 months ( 3 ) .
the incidence of bm in patients with locally advanced nsclc is 12 - 28% over the entire course of the disease . in most cases of nsclc , bm
are diagnosed only after the development of symptoms , which is partly responsible for the poor prognosis of patients with nsclc . in patients with small cell lung cancer ( sclc ) ,
the incidence of detectable bm at the time of initial diagnosis is 10 - 14% ; the cumulative incidence at three years for patients that are in complete remission and that have few signs of disease is 59% ( 4 ) . for patients with nsclc ,
the incidence of bm at the time of initial diagnosis is about 6% according to a prospective study in which computerized axial tomography ( ct ) was used ( 5 ) .
the prognoses of patients with symptomatic bm are substantially worse than those in which the metastases are asymptomatic ( 6 - 8 ) .
clearly , improvements in systemic and local therapies can improve the long - term survival of cancer patients , which means that early and accurate diagnosis of bm has become crucial to improving the quality of life and poor survival rates of cancer patients .
the use of imaging to detect extrathoracic metastasis , particularly bm , at the time of initial staging in asymptomatic patients is the subject of debate ( 8 - 10 ) .
imaging is usually recommended in patients who form part of a population in which the overall incidence of bm is particularly high , such as in cases with adenocarcinomas ( 6 , 11 - 13 ) . of the different imaging methods ,
mri is more sensitive than ct and is the method of choice with which to screen for intracranial metastasis ( 12 , 14 - 17 ) .
however , a major drawback to the routine use of brain mri is its high cost .
therefore , we carried out the modified standard mri or limited mri procedure to detect bm at lower cost and without loss of sensitivity ( 18 ) .
in our pilot study limited mri showed no difference with conventional mri for detecting bm ( sensitivity 97.67% , specificity 100% ) ( 18 ) .
the cost of the modified mri was us$ 180 , which is substantially lower than the cost of conventional brain mri ( us$ 480 ) . based on these results
, we conducted the present study to screen for bm at the time of initial staging and validated the clinical significance of the early detection of bm using limited brain mri .
the results have implications for the quality of life and survival of patients with nsclc .
between may , 2001 and april , 2002 , 183 patients were newly diagnosed with primary nsclc at chungnam national university hospital .
all patients underwent the following initial staging procedures : clinical examination ; routine blood tests ; chest radiography ; chest ct ( including liver and adrenal glands ) ; whole - body bone scan ; and limited brain mri .
the limited brain mri was modified from conventional mri by omitting t2-weighted axial , proton density axial , and contrast- enhanced t1-weighted images ( table 1 ) to decrease the cost from us$ 480 to us$ 180 without any decrease in sensitivity ( 18 ) . as a control group , we used 131 patients who were newly diagnosed with nsclc between may , 2000 and april , 2001 .
control patients underwent the initial staging procedures described above , except that a brain mri was carried out only in cases that exhibited neurologic symptoms related to bm ( e.g. headaches , seizures , or unexplained weakness ) at the time of initial diagnosis .
the incidence of bm in the initial staging of patients with primary nsclc and the incidence of metastases to other systemic sites were compared .
we compared the clinically relevant characteristics of both groups ( age , sex , cell type , performance status , clinical stage , and incidence of brain metastasis ) .
patients were followed up until the 30th of april , 2003 ( i.e. , a minimum period of one year ) and we analyzed the clinical significance of early detection of bm and the relationships among the various prognostic factors .
differences between the two groups were evaluated for statistical significance using a chi - squared test .
survival data were calculated using the kaplan - meier method and statistical differences were confirmed by means of the log - rank test .
there were no statistically significant differences between the groups with respect to gender , age , performance status , tumor subtype , or clinical stage ( excluding brain metastasis ) ( table 2 ) .
bm was detected in 38 of 183 ( 20.8% ) and 6 of 131 ( 4.6% ) patients in the study and control groups , respectively ( p<0.001 ) .
twenty - three of 139 ( 16.5% ) males and 15 of 44 ( 34.1% ) females had bm .
patients with non - squamous - type cells ( 32.6% ) had a higher frequency of bm than those with squamous - type cells ( 8.8% ) . during the follow - up period , subsequent bm developed in 3 of study group , and 9 of control group . in these patients , 1 of study group and 5 of control group had synchronous bm ( within 6 months after initial diagnosis ) ( table 3 ) .
eighteen patients ( 47.4% ) had a single focus of metastasis within the brain , 17 patients ( 44.7% ) had multiple intracranial foci , and 3 patients ( 7.9% ) had a leptomeningeal pattern of metastasis ( table 4 ) .
only 7 of 38 patients ( 18.4% ) in which bm was observed using limited mri also exhibited clinical symptoms related to bm ( table 4 ) . in 15 of 38 patients ( 39.5% )
in which bm was observed using limited mri , the brain was the only site of systemic metastasis , and these 15 patients were upstaged to stage iv based solely on the diagnosis of bm .
this number included 11 of 68 patients ( 15.9% ) that were considered initially to be resectable surgically in the absence of bm .
two stage i , three stage ii , six stage iiia , and four stage iiib patients were upstaged to stage iv ( table 5 ) .
for the survival analysis , 10 of 183 patients in the study group were excluded due to insufficient follow - up data .
the survival analysis was carried out on 173 patients . the overall median survival time and
one - year survival rate of patients with bm were 43 weeks and 39.5% and 31 weeks and 16.7% for the study and control groups , respectively .
the number of patients in the control group was too small to determine whether there were any statistically significant differences between the two groups .
the one - year survival rate and median survival time of patients who had bm ( 46.7% and 49 weeks , respectively ) was greater only than patients who had multiple systemic metastases that included the brain ( 34.8% and 27 weeks , respectively ) .
eighteen patients had between one and three metastatic nodules in the brain that could be accessed for stereotactic radiosurgery and 20 patients ( including three with leptomeningeal involvement ) had multiple ( > 3 nodules ) foci within the brain .
the one - year survival rate and median survival time for the former and latter type of patient was 44.4% and 45 weeks and 35.0% and 24 weeks , respectively .
of the 38 patients who had bm and were strongly recommended to receive radiation therapy to the brain with systemic chemotherapy , 14 were treated with whole brain irradiation only and 23 were treated with both radiation and chemotherapy .
the one - year survival rate and median survival time of irradiation- treated patients was 21.4% and 21 weeks , respectively , and the one - year survival rate and median survival time of those treated with both radiation and chemotherapy was 52.2% and 49 weeks , respectively .
the one - year survival rate and median survival time for symptomatic vs. asymptomatic patients was 42.9% and 45 weeks and 38.7% and 43 weeks , respectively ( table 6 ) .
the one - year survival rate and median survival time overall for stage iv patients were 36.1% and 37 weeks , respectively .
the median survival of 12 patients in whom bm was diagnosed during the follow - up treatment period was 8 weeks .
even though locoregional control rates of 50% and higher have been achieved after neoadjuvant chemoradiotherapy and definitive resection ( multimodal therapy ) in patients with locally advanced nsclc , the brain is the most frequent site of initial treatment failure and is the site of approximately one third of all relapses that occur ( 11 , 13 , 19 , 20 ) .
therefore , treatment strategies that reduce the risk of bm are needed to optimize the efficacy of multimodal therapy and to improve survival . between 25 and 30% of all patients with lung cancer
develop bm at some stage , and this incidence is likely to increase if survival is prolonged by means of aggressive multi - modal treatment . the increasing frequency of treatment failure , the development of new imaging techniques and treatments , as well as the reports of prolonged survival of patients that have received aggressive treatment , suggest that approaches to treating patients who have bm should be reassessed .
specifically , novel treatment paradigms should be developed to ensure that such patients receive optimal therapeutic intervention . to this end ,
prophylactic cranial irradiation in nsclc and sclc patients has been introduced and has led to several reports of positive outcomes , although a large - scale study is needed to confirm this ( 11 , 13 , 21 ) .
an alternative means to the same end is the introduction of brain imaging when the initial workup is carried out .
this approach would facilitate the early detection of bm and promote the timely application of appropriate treatments , which would improve the survival rates of cancer patients .
however , such early imaging should be considered only if it is practicable and available at a reasonable cost .
considering each of the aforementioned factors , we designed the present study to assess the clinical effectiveness of using limited brain imaging at the time of initial screening of lung cancer patients .
the rate of bm in patients with locally advanced nsclc has been estimated previously to be between 17 and 32% ( median : 22% ) with a median time - to - brain recurrence of 7.5 - 9.3 months ( 8 , 11 , 13 ) .
it has been shown previously that most recurrences of metastases within the central nervous system occur within 2 yr of the initial diagnosis ( 13 ) .
furthermore , bm is a direct cause of death in between one third and one half of affected patients ( 12 ) .
the incidence of bm in the initial screening of patients with primary lung cancer has been reported to be between 12 and 18% ( 22 , 23 ) . in the present study ,
we suspect that this slightly higher incidence was the result of using the limited brain mri procedure , which is more sensitive than brain ct ( 5 , 17 ) .
there are several risk factors that are related to bm , including non - squamous histological characteristics ( particularly adenocarcinomas ) , bulky lymph nodes in the mediastinum , younger age , stage iiib , etc .
our data supported the same trend and , in addition , suggested that the incidence of such risk factors is greater in females than in males .
specifically , in the present study , the incidence of bm and non - squamous tumors in females was 30.6 and 26.2% , respectively , which was statistically higher than in males ( 15.5 and 8.8% , respectively ) .
the incidence of bm in all patients with adenocarcinomas was 33.3% , whereas the incidence in females with adenocarcinomas was 50% . in clinical stage iv patients , the brain was the second most common site of metastasis ( 38/87 patients or 43.7% ) , following bone ( 39/87 , 44.8% ) , and was a more common site of metastasis than lung , liver , and the adrenal glands .
although neurological symptoms have been reported to be associated with a poor prognosis ( 7 , 8 , 14 ) , the survival rates in the present study were unrelated to the presence of clinical symptoms .
we found that patients who had a single focus of bm , and isolated bm , and who were treated with chemotherapy had better survival , as reported by others .
the survival rate of patients who had bm was equivalent to those who did not have any clinical symptoms of bm ; this was due to early treatment using whole brain radiotherapy , stereotactic radiosurgery , and chemotherapy .
reported that the use of chemotherapy to control not only bm but also extracranial lesions prolonged the survival of patients with bm due to nsclc ( 26 ) . in the present study , the survival rates of patients who had bm and who received both chemotherapy and radiotherapy were similar to those of patients in stage iiib ( data not shown ) , which would appear to support our hypothesis that early detection of bm and subsequent application of appropriate treatment may improve overall survival . in the present study ,
15 patients ( 15/111 , 13.5% ) were upstaged from clinical stage i ( n=2 ) , ii ( n=3 ) , iiia ( n=6 ) , or iiib ( n=4 ) to stage iv , because of the presence of bm , including 11 patients ( 11/68 , 15.9% ) who had been considered initially to be suitable for surgical resection in the absence of evidence for the presence of bm . all of the aforementioned patients were treated with either radiotherapy alone ( n=7 ) or both radiotherapy and chemotherapy ( n=8 ) . the median survival time and
one - year survival rate of the former and latter patients was 43 weeks and 28.6% and 72 weeks and 66.7% , respectively .
that was greater than the survival rate of all patients with bm ( median survival time and one - year survival rate for radiotherapy only and radiotherapy plus chemotherapy for all patients with bm were 21 weeks and 21.4% , and 49 weeks and 52.2% , respectively ) ( table 6 ) . during a follow up period of at least one year , 12 patients ( 3 of study group and 5 of control group ) subsequently developed bm .
all of these patients ( except one ) were treated with chemotherapy after the diagnosis of bm .
initially , these patients responded to chemotherapy such that four exhibited partial responses , five exhibited a stable disease state , and three exhibited progression of the disease . the median time to relapse in treated patients ( n=11 ) was 38 weeks , which is similar to the time reported by ceresoli et al .
these 11 patients were treated with radiation only without any further chemotherapy ; their median survival time after the diagnosis of bm was 8 weeks , which was shorter than that of patients in whom metastasis was detected during the initial screening and who were treated with radiation therapy alone ( 21 weeks ) .
their overall median survival time and one - year survival rate ( after the diagnosis of lung cancer ) was 38 weeks and 27.3% , respectively , worse than the study group that had bm at the time of the initial screening ( 43 weeks and 39.5% ) and worse than patients who received whole - brain radiation and chemotherapy ( 49 weeks and 52.2% ) following the initial screening .
nevertheless , these outcomes were slightly better than those of the control patients , who were diagnosed and treated for brain metastasis only upon the development of symptoms ( 31 weeks and 16.7% ) . in conclusion
, limited brain mri appears to be a useful and cost - effective means by which to detect bm at the time of initial staging of lung cancer patients
. such early detection of bm enabled patients to be treated immediately with radiotherapy and chemotherapy and led to improved rates of survival .
consequently , we recommend that limited brain mri should be used as an initial screening procedure for the early detection of bm .
this will allow lung cancer patients to receive the appropriate treatment in a timely manner , which should improve both the survival and quality of life of such patients .
 the purpose of this prospective study was to determine whether using magnetic resonance imaging ( mri ) for early screening for brain metastases ( bm ) can improve quality of life , survival in patients with non - small cell lung cancer ( nsclc ) . 
 the study group comprised 183 patients newly diagnosed with nsclc . 
 all patients underwent limited brain mri and routine workups . 
 the control group comprised 131 patients with nsclc who underwent limited brain mri only if they had neurologic symptoms . 
 the incidence of bm was 20.8% ( 38/183 ) in the study group and 4.6% ( 6/131 ) in the control group . 
 the rate of upstaging based on the mri data was 13.5% ( 15/111 ) overall and 15.9% ( 11/69 ) in patients that had been considered initially to be resectable surgically . 
 there was no significant difference in survival outcome between the groups . 
 patients who had bm alone had a greater overall survival time ( 49 weeks ) than those who had multiple systemic metastases ( 27 weeks ; p=0.0307 ) . in conclusions 
 , limited brain mri appears to be a useful , cost - effective method to screen for bm at the time of initial staging . and 
 it may facilitate timely treatment of patients with nsclc and improve their survival and quality of life . 
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION