lung cancer is the most common cause of metastasis to the central nervous system ( 1 ) .
the brain is also one of the most commonly involved organs in metastases from non - small cell lung cancer ( nsclc ) ( 2 ) .
unfortunately , once metastatic brain disease become clinically apparent , the cancer usually has already disseminated widely , which signifies extremely poor prognosis .
the median survival duration of patients with brain metastases from nsclc is approximately 1 month without treatment ( 3 ) , 2 - 3 months when treated with steroids alone ( 4 ) , and 3 - 6 months when treated with whole brain radiotherapy ( wbrt ) ( 5 ) . as the survival of patients with brain metastases tends to be so short , quality of life and alleviation of symptoms
recently , however , aggressive treatment involving either surgical resection or radiosurgery has been applied , with potential curative intentions .
neurosurgical resection of solitary brain metastasis of various origins resulted in a prolongation of median survival to 3.5 - 8 months ( 6 ) .
also , in lung cancer cases , several retrospective reviews have suggested that aggressive therapy , such as resection of the lung and isolated synchronous brain lesions , as well as metachronous brain metastases , may be associated with prolonged survival duration ( 7 - 9 ) . under the presumption
that low - burden metastatic disease can be effectively surgically resolved in certain subsets of patients , we have treated patients exhibiting primary nsclc and isolated synchronous brain metastases aggressively , by the combined control of lung and brain lesions .
this study retrospectively examined our experiences with patients who underwent treatment of isolated synchronous brain metastases coupled with primary nsclc in the last ten years .
from january 1995 to june 2004 , 1,590 patients underwent surgical resection for nsclc at our institution .
twelve ( 0.7% ) of these patients exhibited isolated synchronous brain metastases coupled with primary nsclc .
preoperative workups included computed tomography ( ct ) scanning of the chest and upper abdomen in all patients , bronchoscopy or percutaneous needle aspiration , when applicable , for the histologic evaluation of all patients , brain magnetic resonance imaging ( mri ) in all patients with neurologic symptoms or adenocarcinoma , bone scans , and positron - emission tomography ( pet ) or pet - ct .
pathologic reviews of pulmonary and cerebral or cerebellar neoplastic tissue confirmed identical histological diagnoses for all patients who underwent craniotomies .
synchronous brain metastases were defined as those metastases which were diagnosed less than 60 days from the time at which the primary nsclc was diagnosed .
the medical records of each patient were examined with regard to age , sex , histologic type and grade , pathologic intrathoracic tn stage , surgical procedure , postoperative complications , adjuvant therapy , and survival duration .
cerebral resections were considered complete when all gross evidence of disease was removed . in all patients , pathologic
staging was conducted according to the guidelines of the international staging system for nsclc ( 10 ) .
operative mortality included patients who died within the first 30 days after the thoracic procedure , as well those who died later , but during the same period of hospitalization .
median patient age was 52 yr , in a range of 32 to 75 yr .
median time between the first cerebral treatment or pulmonary resection and the pulmonary resection or cerebral treatment was 15 days , in a range of 10 to 380 days .
pulmonary resection included pneumonectomy in 1 patient , bilobectomy in 4 , lobectomy in 6 , and wedge resection in 1 .
mediastinoscopic lymph node biopsies were conducted in 3 patients , all of which generated negative findings .
complete pulmonary resections ( r0 ) and mediastinal lymph node dissections were performed in all patients , with the exception of one , who underwent wedge resection .
the nsclc histologic type was adenocarcinoma in 7 patients ( 58.3% ) , squamous cell carcinoma in 3 ( 25% ) , and adenosquamous cell carcinoma in 2 .
lymph node metastases were present in 7 patients , and were staged n1 in 3 patients and n2 in 4 .
these included headaches in 4 , visual disturbances in 1 , slurred speech in 1 , motor weakness in 1 , and gait disturbances in 1 .
treatment for brain lesions included 5 craniotomies , 7 stereotactic radiosurgery ( srs ) , and 11 wbrt .
as modality to increase local control , either craniotomy or srs was applied , and the decision on modality selection was made on an individual bases considering the advantages and the disadvantages of each modality .
craniotomy was favored if the lesions were rather superficially located and were causing distressing neurologic symptoms and signs , while srs was favored if the lesions were in deep and eloquent areas .
further local treatment for the brain lesions was not performed in two patients following wbrt , who were with very small sized metastatic lesions .
treatment for brain lesions was carried out prior to that for pulmonary lesions in 7 patients , one of whom underwent craniotomy and wbrt at another hospital .
gross total removal of metastatic tumors was verified in all patients who underwent craniotomy at our institution .
srs was conducted with linear accelerator - based radiosurgery system in 1 patient , and gamma - knife unit in 6 patients .
survival was estimated by the kaplan - meier method , with the date on which treatment on cerebral or pulmonary lesion was initiated as the starting point , and the date of death or last follow - up as the end point .
a p value of less than 0.05 ( p<0.05 ) was considered to be statistically significant .
all analyses were performed using the spss software package ( spss for windows , release 11.0 , standard version ) .
pulmonary resection included pneumonectomy in 1 patient , bilobectomy in 4 , lobectomy in 6 , and wedge resection in 1 .
mediastinoscopic lymph node biopsies were conducted in 3 patients , all of which generated negative findings .
complete pulmonary resections ( r0 ) and mediastinal lymph node dissections were performed in all patients , with the exception of one , who underwent wedge resection .
the nsclc histologic type was adenocarcinoma in 7 patients ( 58.3% ) , squamous cell carcinoma in 3 ( 25% ) , and adenosquamous cell carcinoma in 2 .
lymph node metastases were present in 7 patients , and were staged n1 in 3 patients and n2 in 4 .
six out of 12 patients exhibited neurological symptoms . these included headaches in 4 , visual disturbances in 1 , slurred speech in 1 , motor weakness in 1 , and gait disturbances in 1 .
treatment for brain lesions included 5 craniotomies , 7 stereotactic radiosurgery ( srs ) , and 11 wbrt .
as modality to increase local control , either craniotomy or srs was applied , and the decision on modality selection was made on an individual bases considering the advantages and the disadvantages of each modality .
craniotomy was favored if the lesions were rather superficially located and were causing distressing neurologic symptoms and signs , while srs was favored if the lesions were in deep and eloquent areas .
further local treatment for the brain lesions was not performed in two patients following wbrt , who were with very small sized metastatic lesions .
treatment for brain lesions was carried out prior to that for pulmonary lesions in 7 patients , one of whom underwent craniotomy and wbrt at another hospital .
gross total removal of metastatic tumors was verified in all patients who underwent craniotomy at our institution . the radiation dose for wbrt was 30 gy in 10 fractions in every patient .
srs was conducted with linear accelerator - based radiosurgery system in 1 patient , and gamma - knife unit in 6 patients .
survival was estimated by the kaplan - meier method , with the date on which treatment on cerebral or pulmonary lesion was initiated as the starting point , and the date of death or last follow - up as the end point .
cox 's proportional hazard model was used for multivariate analyses . a p value of less than 0.05 ( p<0.05 )
all analyses were performed using the spss software package ( spss for windows , release 11.0 , standard version ) .
follow - up was completed for all 12 patients for a median of 10.6 months and a range of 2 to 55.8 months .
recurrence occurred in the brain in 2 , distant organ in 2 ( pelvic bone / ovary , adrenal gland / rib ) , and both the brain and distant organ in 3 ( brain / extremity , brain / liver / pleura , brain / spine ) .
the pathologic tn stages of patients developing recurrences were t2n0 in 3 , t1n2 in 1 , t2n2 in 2 , and t3n1 in 1 .
the median interval from initiation of treatment to recurrence was 4.5 months ( 2.8 - 6.5 months ) .
treatment of recurrence included 2 wbrt and 4 srs for cerebral lesions , radiotherapy for spine , extremities , ribs , and pelvic bones , adrenalectomy , and salphingooophrectomy .
currently , 8 patients remain alive , and 4 of them have exhibited no signs of recurrence at 8.5 , 12.9 , 34.5 , and 55.8 months after the initial treatment .
the median survival duration for pathologic n2 was 6.2 months ( 95% ci , 4.8 - 7.5 months ) ( fig .
the difference between survival rates according to pathologic n stage evidenced a trend toward statistical significance ( n0 vs. n2 , p=0.0586 ) .
the 1-yr survival rates for locoregional pathologic stages i and iii were 75% and 53.3% , respectively ( p=0.2492 ) .
the 1-yr survival rates for solitary and multiple brain metastases were 75% and 44.4% , respectively ( p=0.1442 ) .
the 1-yr survival rate for the 9 patients with brain metastases involving less than 4 lesions was 70% .
the 1-yr survival rate for the 4 patients with 2 or 3 cranial metastases was 66.7% , which was not significantly different from that for patients with solitary brain metastases ( p=0.5 ) .
currently , 3 patients of them remain alive , at 5.6 , 8.5 , and 12.8 months after the initial treatment .
survival was not found to vary significantly with histologic type ( adenocarcinoma vs. non - adenocarcinoma , p=0.9859 ) .
approximately 25% of patients with stage iv nsclc exhibit brain metastases , as well as other incidences of metastatic disease ( 11 ) .
the natural course of untreated brain metastases included progressive neurological deterioration , with a median survival time of 1 - 2 months ( 6 ) .
the prognoses of brain metastasis patients tend to be poor , with a median survival of 2 months when treated with steroids alone , and 3 to 6 months when treated with wbrt .
aggressive treatment of brain metastases may involve either the surgical resection of the metastases , or the ablation of the metastases by srs .
removal of brain metastases has been determined to prolong survival and improve quality of life ( 12 ) .
the effect of treatment of brain metastases without treatment of the primary site , however , may be quite limited .
retrospective series suggest that some patients with stage iv lung cancer , coupled with a solitary synchronous site of extrathoracic metastatic disease , can be effectively treated by the resection of both the primary tumor and the metastasis ( 7 - 9 , 13 ) . among patients with lung cancer that has metastasized to the brain ,
the most favorable prognoses are associated with complete resection of the primary lung tumor ( 14 ) .
solitary metastases are associated with better prognoses than are multiple metastases ( 9 ) . whether brain metastases are metachronous or synchronous has not generally been found to influence survival .
it remains unclear as to whether or not the lymph node status of the primary tumor is of prognostic significance in patients who undergo resection of a solitary brain metastasis ( 7 ) .
suggested that it seemed legitimate to proceed with lung resection after the complete resection of a single brain metastasis , at least in patients with an adenocarcinoma and a small lung tumor and without abnormal mediastinal lymph nodes , as seen on the ct scans or during mediastinoscopic lymph node biopsies ( 15 ) .
the overall 1-yr survival rate of our patients was 61.7% , which is consistent with the findings of other reviews .
one was a patient who was discovered to have leptomeningeal seeding 48 days after pulmonary resections .
the other was a patient whose multiple brain lesions had regarded as ischemic change , and thus the treatment of this patient 's brain lesion was delayed . excluding these cases from the survival analysis , the overall 1-yr survival rate was 70% .
although no evident statistical differences were detected , the difference between survival rates according to pathologic n status tended toward statistical significance ( p=0.0586 ) .
in addition , the survival of patients with pathologic n1 was not different from that of those with pathologic n0 ( p=0.5316 ) .
when deciding upon the most appropriate treatment option for an individual patient , the following factors should be taken into consideration : symptoms ; general condition of the patient ; extent and status of cerebral disease ; and extent and status of extracranial disease .
craniotomy is the preferred treatment modality for solitary lesions associated with significant edema , large lesions ( greater than 3 cm at maximal diameter ) , superficial lesions , lesions causing symptoms requiring immediate relief , and lesions associated with hemorrhage .
srs is recommended in cases in which the lesion is deep , but is less than 3 cm at maximal diameter , when there are medical contraindications to craniotomy , or in some cases , when the tumor recurs ( 16 ) .
the decision to operate on lesions of intermediate size ( which typically range from 1 to 3 cm in maximal diameter ) is particularly challenging , as in many cases , surgery and srs may be considered to be equally appropriate treatment methods ( 17 ) .
the advantages of craniotomy include the immediate resolution of mass effects , the acquisition of tissue for pathologic diagnosis , and no risk of radiation necrosis ( 18 ) .
the advantages of srs include decreased risks of hemorrhage and infection , less invasiveness , and no risk of tumor seeding .
the disadvantages of srs include the potential exacerbation of peritumoral edema , the necessity for long - term steroid administration , and radiation necrosis ( 19 ) .
tumors in eloquent cortex , or deep - seated tumors , are usually considered unresectable . in these cases
it remains unclear as to whether srs or craniotomy provides better survival benefits , even for patients manifesting single brain metastases ( 18 ) . in our reviewed cases
, we included patients with multiple cerebral metastatic lesions as well as patients with single lesions ( table 2 ) .
the survival rate associated with 2 or 3 cranial metastases was not significantly different from that associated with solitary brain metastases .
a patient with t2n0 stage and 2 cranial metastases was successfully treated via a combination of srs for the smaller lesion , craniotomy for the larger lesion , wbrt , and bilobectomy .
, we could speculate that aggressive management of primary nsclc and isolated synchronous brain metastases was beneficial in a selected group of patients , as long as the brain lesions and pulmonary lesions were limited or resectable .
admitting the positive role of surgery in the management of isolated synchronous brain metastases coupled with primary nsclc , we are planning to design a prospective phase ii study regarding the surgical treatment of nsclc with isolated synchronous brain metastases .
 this study is a retrospective examination of our experiences with patients who underwent treatment of isolated synchronous brain metastases coupled with primary non - small cell lung cancer . from january 1995 to june 2004 , 12 patients presented with isolated synchronous brain metastases coupled with primary non - small cell lung cancer . 
 the patient was comprised of 8 men and 4 women . 
 the median age was 52 yr , in a range of 32 to 75 yr . 
 median follow - up duration was 10.6 months , in a range of 2 to 55.8 months . 
 recurrence developed in 7 patients , and the median interval from 1st treatment to recurrence was 4.5 months ( 2.8 - 6.5 months ) . 
 the overall 1-yr survival rate was 61.7% . 
 the 1-yr survival rates for pathologic n0 and n1 cases were 75% and 66.7% , respectively . 
 the median survival duration for pathologic n2 was 6.2 months ( 95% ci , 4.8 - 7.5 months ) . 
 the 1-yr survival rate for cases of single brain metastasis was 75% . based on our current observations 
 , we could speculate that aggressive management of primary non - small cell lung cancer and isolated synchronous brain metastases was beneficial in a selected group of patients , as long as the brain lesions and pulmonary lesions were limited or resectable . 
INTRODUCTION
MATERIALS AND METHODS
Initial pulmonary manifestation and treatments
Initial cranial manifestation and treatments
Statistical analysis
RESULTS
DISCUSSION