td

M

Review

6 Cli

Aggressive Treatment of Primary Tumor inPatients With Non–Small-Cell Lung Cancer

and Exclusively Brain MetastasesCynthia Villarreal-Garza,1 Dolores de la Mata,2 Diego G. Zavala,3

Eleazar O. Macedo-Perez,1 Oscar Arrieta1,3,4

AbstractBetween 30% and 50% of patients with non–small-cell lung cancer (NSCLC) will develop cerebral metastases in thecourse of their illness. As improvements are made in the local brain treatment, the question arises on how to managepatients with NSCLC who have solely stable brain metastatic disease and if treatment should be considered for theprimary lung lesion. The present article will review published series of patients with NSCLC and with brain metastasestreated with aggressive thoracic management, with either lung tumor resection or thoracic radiation with or withoutchemotherapy as definitive treatment. We will also assess which prognostic factors may be useful in the identificationof the subset of patients who could benefit from this more aggressive approach. For patients treated with surgicalresection for the primary lung tumor, median survival ranged from 19 to 27 months, and the 1-, 2-, and 5-year survivalreached 56%-69%, 28%-54%, and 11%-24%, respectively. Patients treated with aggressive radiotherapy with orwithout chemotherapy, achieved a median survival of 15.5-31.8 months, with a 1-year survival of 50%-71%, and a2-year survival of 16%-60%. Well-selected patients with NSCLC and with exclusively oligometastatic cerebraldisease represent a subgroup of patients with stage IV NSCLC that might achieve long-term survival after treatmentdirected to the brain and lung tumor lesions. Patients with N0 or N1 disease may be selected for surgical thoracictreatment, whereas those with N2 or N3 disease may benefit from combined chemoradiotherapy in the absence ofprogression after induction chemotherapy.

Clinical Lung Cancer, Vol. 14, No. 1, 6-13 © 2013 Elsevier Inc. All rights reserved.

Keywords: Cerebral, Chemoradiation, Non–small-cell lung cancer, Radiotherapy, Resection

3

IntroductionLung cancer is the most common malignancy in the world. In

2008, 1.61 million new cases were reported worldwide, which ac-counted for 12.7% of all newly diagnosed malignancies.1,2 It is alsohe leading cause of death from cancer, with 1.38 million annualeaths, which represents 18.2% of the global cancer mortality,1,2

with a high fatality rate (ratio of mortality to incidence) of 0.86.2

1Department of Medical Oncology, Instituto Nacional de Cancerología (INCan)2Department of Radio-Oncology, INCan3Facultad de Medicina, Universidad Nacional Autónoma de México4Experimental Oncology Laboratory, INCan

exico City, Mexico

Submitted: Feb 7, 2012; Revised: Apr 26, 2012; Accepted: May 1, 2012; Epub: June7, 2012

Address for correspondence: Oscar Arrieta, MD, Department of Medical Oncology,Instituto Nacional de Cancerología, Col. Sección XVI, Delegación Tlalpan, 14080,México, Mexico

pE-mail contact: ogar@unam.mx

nical Lung Cancer January 2013

Non–small-cell lung cancer (NSCLC) is the most common type oflung cancer, which accounts for 85% of lung malignancies. Themajority of cases are diagnosed in advanced stages (clinical stages IIIand IV), which explains why the outcome in this group has notchanged to a great extent in the past 3 decades, with a 5-year overallsurvival (OS) of only 16%.3,4

This review will examine published studies on patients withsynchronic metastatic NSCLC cerebral lesions managed with lo-cal brain treatment in addition to radical treatment of the primarypulmonary lesion with surgery or radiotherapy (RT) with or with-out chemotherapy (CT).

Management of Brain Metastasesin NSCLC

Brain metastases are identified upon initial diagnosis in 7.4%-10% of patients with NSCLC.5 Moreover, brain metastases occur in0%-50% of patients during the course of their disease and confers a

oor prognosis and a negative impact on quality of life.6-11 The

1525-7304/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.cllc.2012.05.002

cft

idswailotbt

a4

dbzm

shcdt

rcgwma

waap5mnac(lCt(y

median survival of patients who receive supportive care and aretreated only with corticosteroids is approximately 1-2 months.7 TheRadiation Therapy Oncology Group used a recursive partitioninganalysis (RPA) of patients with brain metastases to define 3 classesaccording to pretreatment characteristics with prognostic signifi-cance to select homogeneously candidates for local interventions.12

RPA class I patients have a Karnofsky performance score (KPS) �70and age �65 years, with the primary tumor controlled and withoutextracranial metastases. RPA class III is defined by a KPS of �70, andRPA class II covers the remaining patients. The median survivaltimes for the 3 RPA classes are 7.1, 2.3, and 4.2 months, respectively.

Brain metastases treatment includes surgery, stereotactic radiosurgery(SRS), whole brain radiation therapy (WBRT), or a combination, whichhave achieved a median survival that ranges from 6.5 to 11 months.13-18

Management with surgery with or without WBRT achieves a medianOS of 10.9 months in patients with 1-3 cerebral lesions.13,18 The trialsonducted have been designed for the enrollment of patients with dif-erent cancer types, without taking into account specific biologic sub-ypes (ie, NSCLC, breast cancer, and/or melanoma).

For patients with one or a limited number of lesions in surgicallynaccessible locations and for those who are not surgical candidates orecline surgery, SRS is effective for the treatment of brain metasta-es.19,20 For patients with favorable prognostic features, treatmentith SRS and WBRT can prolong OS to 11.6 months.17 In the

bsence of a direct comparison, the choice of SRS instead of surgeryn patients with brain metastases is usually based upon the size of aesion, its surgical accessibility, symptoms, and the functional statusf the patient.21 For patients with poor performance status, a rela-ively short life expectancy due to extracranial disease, or extensiverain metastases, WBRT as a sole treatment can improve local con-rol and quality of life.22

Although data supporting the use of computed tomography forbrain metastasis are limited, the use of systemic therapy is usuallyconsidered in patients with good performance status and multiple,small metastases, especially if the primary tumor is chemosensi-tive.23,24 The CT regimens used are typically platinum based, eithers single agent or combination, with response rates between 20% and5%.25-27 Despite concerns regarding the ability of molecular-tar-

geted agents to pass through the blood-brain barrier, it appears thatthese agents may have therapeutic potential in brain metastases fromNSCLC.28,29 Trials with gefitinib, erlotinib, and other EGFR (epi-

ermal growth factor receptor) inhibitors as single agents or in com-ination with RT are in progress. In addition, studies with bevaci-umab to address its safety and efficacy in patients with treated brainetastasis from NSCLC are underway.As improvements are made in the management of brain metasta-

es, the question arises on how to manage patients with NSCLC whoave solely stable brain metastatic disease and if treatment should beonsidered for the primary lung lesion, because the main cause ofeath, despite metastatic illness, is the poor control of the primaryumor.30,31 Long-term survival has been achieved in some patients

who have undergone local brain therapy and aggressive thoracicmanagement with either lung tumor resection or chemoradio-therapy, clearly superior to previously reported survival in patientstreated with standard palliative CT, as will be discussed. In fact, a

recent review published by Modi et al32 addressed whether surgical t

esection of NSCLC with cerebral metastasis prolongs survival andoncluded that surgical resection may prove beneficial in a selectroup of patients with synchronous brain metastases and lung cancerithout lymph node metastases. However, despite these findings, theajority of patients are only offered CT or RT with palliative intent

fter their brain metastases have been treated.33

The purpose of this article is to update the previous review and toinclude those series in which patients were treated with aggressivethoracic RT with or without CT to identify those who might benefitfrom either of these approaches. Relevant studies related to this topicwere identified through a structured literature search of PubMed byusing the following medical subject headings: “(lung or NSCLC) and(brain or cerebral) and (metastasis or metastases)” and (1) specificallyfor the review of surgical treatment to the primary lung lesion “(sur-gery or surgical or thoracic or primary),” and (2) for the assessment ofRT to the primary lesion “(RT or chemoradiotherapy).” Studies wereselected based on a detailed reading of online abstracts. The referencelists from retrieved articles were reviewed to identify further studies.No randomized studies were found.

Surgical Treatment of PrimaryLung Lesion

Studies that evaluated the surgical treatment of the primary lungtumors in patients with brain metastatic disease are enlisted in Table1. These studies use different treatment alternatives for the brain andlung malignancies. For the brain metastases, the patients were treatedwith either surgery, SRS, and/or WBRT. With regard to the primarythoracic lesion, different surgical approaches were used (pneumonec-tomy, lobectomy, or wedge resection), and, in some cases, thoracicRT and/or systemic CT were used.

The largest series that used these approaches are the following.Wronski et al34 included 231 patients with surgical management ofthe brain metastases, 80% also underwent surgical management forthe primary lung tumor. Median survival reached 11 months, and 1-,2-, and 5-year OS rates were 55%, 31%, and 21%, respectively. Thisstudy included patients with extracranial metastases and identifiedsex (female), absence of extracranial disease, complete primary tumorresection, age (�60 years), and location of the brain metastases (su-pratentorial) as the most significant prognostic factors. Bonnette etal,35 in a retrospective multicenter study that involved 103 patients

ho underwent combined resection of synchronous brain metastasesnd primary lung tumor, concluded that, at least in patients with thedenocarcinoma subtype, proceeding with lung surgery after com-lete resection of a single brain metastasis improves survival. OS was6% at 1 year and 11% at 5 years, and the median survival was 12.4onths. Small lung tumors without enlarged intrathoracic lymph

odes seemed to have the greatest benefit. In their series, Moazami etl36 included 91 patients with locally advanced NSCLC and meta-hronous brain metastatic disease, with single (46%) and multiple53%) brain metastases. Two-thirds of these patients underwentung surgery, and the majority were treated with thoracic RT and/orT after resection. Median survival was 5.2 months. However, pa-

ients with lung resection were identified as having a better prognosisP � .02). Other factors that predicted an improved OS wereounger age, good performance status, absence of extracranial me-

astases, and stage IIIA lung disease.

Clinical Lung Cancer January 2013 7

Lung Treatment in Patients With Non–Small-Cell Lung Cancer and Brain Metastases

8 Cli

Table 1 Surgical Treatment of Primary Lung Lesion

Study, YNo.

PatientsNeurologic Aspects Thoracic Aspects Significant Prognosis Variables Survival

Magilligan et al,50

198641

Synchronous mets, 14;metachronous mets, 27;

craniotomy, 16; craniotomy �WBRT, 25

Lobectomy, 20; pneumonectomy,14; wedge, 4; bilobectomy, 3

Wedge resection: this was associated withimproved survival (P � .01)

Median survival, 1.1 y; OS at 1 y, 55% �7.9%; OS at 2 y, 31% � 7.4%; OS at 3 y,

24% � 6.9%; OS at 4 y, 21% � 6.5%; OS at5 y, 21% � 6.5%; OS at 10 y, 15% � 6.0%

Wronski et al,34

1995231

Synchronous mets, 86;metachronous mets, 145; CR,

218; PR, 13; WBRT, 194

Lung resection, 185; othertreatment, 46

Sex: women had better survival (P � .008);systemic metastases: patients without

extracranial metastases had better prognosis(P � .008); primary tumor resection: completeresection had better prognosis (P � .0002); age:

patients �60 y had a better outcome (P �.0398); location of metastasis: patients withsupratentorial metastasis had a better prognosis

(P � .0497)

Median survival (from first craniotomy), 11mo: OS at 1 y, 46.3%; OS at 2 y, 24.2%;

OS at 3 y, 14.7%; OS at 5 y, 12.5%

Mussi et al,48 1996 45

All single metastases,synchronous mets:

craniotomy, 15; WBRT, 2;metachronous mets:craniotomy 30; WBRT, 6

Synchronous mets: lobectomy,13; pneumonectomy, 2; adjuvantCT, 13; metachronous mets:

lobectomy, 22; pneumonectomy,8; adjuvant CT, 16; chest wall

RT, 3

Lung resection: patients with lobectomy had bettersurvival than those would had pneumonectomy(P � .04); nodal stage: N1-N2 had a negative

impact on survival (P � .009)

Median survival, 11 mo: OS at 5 y, 16%;OS at 5 y SM, 6.6%; OS at 5 y MM, 19%

Chidel et al,30

199933

Synchronous mets: Sx �WBRT, 21; SRS � WBRT, 5;

Sx, 3; SRS, 2; WBRT, 2

Aggressive management: Sx:2; Sx � RT, 3; RT, 8 (50.4-65Gy); palliative management:RT, 13 (15-50 Gy); no treatment, 7

WBRT: patients who received WBRT had bettersurvival (P � .043); aggressive thoracic

management: patients in the aggressive grouphad better survival (P � .02)

Median survival, 6.9 mo; OS at 3 y, 12%

Billing et al,37

200128

Synchronous mets:craniotomy, 28

Pneumonectomy, 4; bilobectomy,4; lobectomy, 18; wedge, 2

Nodal stage: N1-N2 had a negative impact onsurvival (P � .001)

Median survival, 24 mo; OS at 1 y, 64.3%;OS at 2 y, 54%; OS at 5 y, 21%

Abrahams et al,49

200170

Synchronous andmetachronous mets:

supportive care, 3; Sx, 6; Sx �WBRT or SRS, 44; WBRT or

SRS, 17

Thoracotomy (� CT/RT), 26; noSx (� CT/RT), 44

KPS: score of 100 had better survival than thosewith 90 or lower (P � .05); metachronous brain

mets: better prognosis (P � .05)

Median survival, 12.9 mo; OS at 1 y,52.2%; OS at 2 y, 30.7%; OS at 5 y,

18.1%

Bonnette et al,35

2001103

Synchronous mets:complete resection, 97;incomplete resection, 6;WBRT, 75 (20-50 Gy)

Complete pulmonary resection,95; incomplete pulmonary

resection, 8; RT, 33 (45-55 Gy)

Histology: adenocarcinoma had better prognosisthan squamous cell carcinoma (P � .019); tumor

stage: decrease in survival from stage T1 tostages T2 and T3; not significant (P � .068);nodal stage: N0 tumors vs. N� tumors: not

significant (P � .069)

Median survival, 12.4 mo; OS at 1 y, 56%;OS at 2 y, 28%; OS at 3 y, 13%; OS at

5 y, 11%

Granone et al,39

200130

Group 1: synchronous mets,20; craniotomy, 20; WBRT, 15(4000 cGy: 250 cGy/d); and

group 2: metachronous mets,10; craniotomy, 10; WBRT, 10

Group 1: lobectomy, 14;bilobectomy, 2; segmentectomy,

4; postoperative therapy:WBRT � CT, 11; CT, 3; WBRT, 4;

and group 2: lobectomy, 7;pneumonectomy, 3; postoperativetherapy: WBRT � CT, 6; WBRT, 4

(Univariate analysis): nodal stage: N0 showedbetter survival (P � .027); histology:

adenocarcinoma achieved better survival thanother histologic types (P � .0006); synchronous

vs. metachronous: not significant (P � .33)

Median survival: 23 mo in group 1 and 11mo in group 2; mean survival: 30.3 mo ingroup 1 and 22.8 mo in group 2; OS at

1 y: 95% in group 1 and 50% in group 2;OS at 2 y: 47% in group 1 and 30% ingroup 2; OS at 3 y: 14% in group 1 and

20% in group 2

Moazami et al,36

200291

WBRT, 43; Sx (� WBRT), 23;SRS (� WBRT), 24; no

treatment, 1

CT � RT, 29; Sx, 11; Sx � CT,22; Sx � CT � RT, 26; no

treatment, 1

Stage IIIA: better prognosis than IIIB (P � .001);age: younger age at diagnosis results in betterprognosis (P � .009); ECOG: 0-1 had better

survival than 2-3 (P � .0001); lung resection:better than not performing lung Sx (P � .02);

extracranial metastases: not havingextracranial metastases represents betterprognosis (P � .04); metastasectomy

(P � .0001); SRS (P � .003)

Median survival, 5.2 mo; OS at 1 y, 22%;OS at 2 y, 10%

Getman et al,51

200432

Group 1: synchronous mets,16; Sx, 9; SRS, 3; SRS � Sx,4; WBRT, 12 (20-50 Gy); andgroup 2: metachronous mets,

16; Sx � WBRT, 4; SRS �WBRT, 9; SRS, 1; WBRT, 2

Group 1: wedge, 2; lobectomy, 8;bilobectomy, 1; pneumonectomy,5; induction CT, 2; adjuvant CT, 3;

and group 2: wedge, 1;lobectomy, 11; bilobectomy, 2;

pneumonectomy, 2; induction �adjuvant CT, 1; adjuvant CT, 4

Univariate and multivariate analysis did not revealany risk factor that significantly predicted survival

Median survival after cerebral procedures,9.3 mo in group 1 and 6.2 mo in group 2;median survival after lung surgery: 8.5 moin group 1 and 16.4 mo in group 2; aftercerebral procedures: OS at 1 y, 37.5% ingroup 1, and 31.3% in group 2; OS at 2 y:25.0% in group 1, and 15.6% in group 2;OS at 5 y: 18.8% in group 1, and 0% ingroup 2; after lung surgery, OS at 1 y,

37.5% in group 1, and 62.5% in group 2;OS at 2 y, 25.0% in group 1, and 43.8%in group 2; OS at 5 y, 18.8% in group 1,

18.8% in group 2

(continued on next page)

nical Lung Cancer January 2013

art2N

out brais meta

Cynthia Villarreal-Garza et al

The series reported by Billing et al37 evaluated these combinedggressive modalities. All 28 included patients underwent surgicalesection with complete clearance of both synchronous brain metas-ases and primary NSCLC. Median survival was 24 months, with 1-,-, and 5-year survival being 64.3%, 54%, and 21.4%, respectively.odal disease (N1-N2) was associated with poor prognosis.Iwasaki et al38 included 70 patients with synchronous and meta-

chronous brain metastases and divided them into 2 groups: lung andbrain resection (LBR) and lung resection without brain surgery (LR).Group LBR had a 1- and 3-year survival of 66.4% and 22.9%,respectively, compared with 33.2% and 6.6%, respectively, for theLR group (P � .034). Nodal stage N0, adenocarcinoma histology,and low serum carcinoembryonic antigen were the only significant

Table 1 (Continued)

Study, YNo.

PatientsNeurologic Aspects Thoracic Aspects

Iwasaki et al,38

200470

Synchronous mets, 28;metachronous mets, 42; LBR:lung and brain; resection, 41;Sx, 25; Sx � GKS, 4; Sx �

WBRT, 8; Sx � GKS � WBRT,4; LR: lung resection only, 29;

GKS, 28

LBR: lobectomy, 29; bilobeor pneumonectomy, 12;

lobectomy, 26; bilobectompneumonectomy, 3

Furak et al,52 2005 65

Synchronous mets, 19;craniotomy, 18; WBRT (30 Gy),

18 metachronous mets, 46;craniotomy, 44; craniotomy �

SRS, 2; WBRT (30 Gy), 46

Synchronous mets, 1pneumonectomy, 2; lobec

11; wedge, 6; adjuvamediastinal RT and CT, 10

RT (10 Gy), 18; metachromets, 46; pneumonectom

lobectomy, 21; wedge,exploration, 2; induction C

tumor RT (10 Gy), 46

Girard et al,24

200651

Synchronous mets, 51; singlemets, 43; multiple mets, 8;

curative intent: brainmetastasectomy, 29;

palliative intent: brainmetastasectomy, 22; adjuvantRT, 36 (10-50 Gy) (group not

specified)

Curative intent:pneumonectomy, 5; lobec

19; bilobectomy, 1;segmentectomy, 1; inducti13; induction CT � thorac3; palliative intent: indu

CT, 12; thoracic RT,

Khan et al,44 2006 23Sx, 1; Sx � RT, 6; RT or SRS,

15; CT, 1CT � RT, 12 (26-61.2 Gy)RT � Sx, 7 (39-43.2 Gy);

Flannery et al,33

200842

Synchronous single mets:GKS � SRS, 9; GKS � SRS �

WBRT, 33

Definitive management:RT, 9; Sx, 12; CT � RT �nondefinitive managemCT, 6; RT, 4; RT � CT, 3

therapy, 3

Yang et al,67 2008 16 Synchronous mets: SRS, 16 Sx, 16

Louie et al,43 2009 35Synchronous mets: Sx �

WBRT, 35Sx, 8; CT, 24; RT, 14

Lo et al,40 2010 17Synchronous mets:

craniotomy, 14; SRS, 3Pneumonectomy, 1; lobec

15; wedge, 1

Abbreviations: CEA � carcinoembryonic antigen; CI � curative intent; CR � complete resection;KPS � Karnofsky performance score; LBR � lung and brain resection; LR � lung resection withodds ratio; PI � palliative intent; PR � partial resection; RT � radiotherapy; SM � synchronou

prognostic factors identified in the multivariate analysis.

Girard et al24 proposed a treatment algorithm in which brainmetastasectomy is followed by CT and further primary lung tumortreatment only in responders to CT. In their report, 51 patients withsynchronous brain metastases were divided into curative and pallia-tive intent groups. Median survival was 13.2 months. Prognosismainly depended on the treatment of the lung tumor, with a markedsurvival advantage in the 29 patients who received a focal treatment(thoracic surgery or RT) vs. the 22 other patients treated with palli-ative intent; median, 1-, and 2-year survival were 22.5 months, 69%,and 42%, respectively, vs. 7.1 months, 33%, and 5%, respectively(P � .001). Response to preoperative CT before focal treatment wasthe main favorable prognostic factor (P � .023) and further identi-fied patients who had benefit from resection of the lung tumor, with

Significant Prognosis Variables Survival

Histology: adenocarcinoma had better prognosisthan nonadenocarcinoma types (P � .0035);

nodal stage: N0 had better prognosis than N�(P � .0366); serum CEA: better prognosis withlower serum CEA (P � .0103); metachronous

vs. synchronous: no significant difference (P �.0987)

OS at 1 y: 66.4% in LBR, and 33.2% inLR; OS at 3 y: 22.9 in LBR, and 6.6% inLR; LBR group had better prognosis (P �

.0342)

Clinical status: patients without lung cancer–related symptoms after brain surgery had betterprognosis than those with symptoms (P � .05)

Median survival after brainmetastasectomy: 19 mo in SM; 12 mo inMM median survival after lung resection:18 mo in SM; 30 mo in MM after brain

metastasectomy, OS at 5 y; 24% in SM;16% in MM; after lung resection: OS at

5 y, 23.5% in SM; 19.9% in MM

KPS: � 70% showed better prognosis (P � .005);histology: adenocarcinoma had better prognosis(P � .009); primary tumor treatment: betterprognosis for surgical resected primary tumor

(P � .001); age: �60 y favors response to CT(P � .024)

Median survival after metastasectomy,13.2 mo; median survival, 22.5 mo in CI,7.1 mo in PI OS at 1 y, 69% in CI; 33% in

PI; OS at 2 y, 42% in CI; 5% in PI

Not includedMedian survival, 20 mo; OS at 1 y: 71.3%;

OS at 2 y: 34.1%; OS at 5 y: 21.0%

Primary tumor treatment: better prognosis forsurgical resected lung tumor (P � .02); KPS:�90% showed better prognosis (P � .001)

Median survival, 18 mo; OS at 1 y, 71.3%;OS at 2 y, 34.1%; OS at 5 y, 21.0%

Primary lung resection: pulmonary resectionresult in better survival (OR 78.4)

Median survival, 64.9 mo; local braintumor control rate at 1 y, 97.1%; 5 y,

93.5%

Chest surgery: better survival for patients withsurgically resection (P �.0033); stage I or II:

disease stage I/2 (excluding brain metastases) hadbetter prognosis (P � .0467); time to thoracicintervention: patients who received a thoracictreatment 8 wk after their initial brain treatment

had better survival (P � .0128)

Median survival, 7.8 mo; OS at 1 y, 30%;OS at 2 y, 23%; OS at 3 y, 20%

Univariate analysis did not reveal any risk factorthat significantly predicted survival

Median survival, 52 mo; OS at 1 y, 63%;OS at 2 y, 54%; OS at 5 y, 27%

hemotherapy; ECOG � Eastern Cooperative Oncology Group; GKS � gamma knife radiosurgery;n surgery; mets � metastases; MM � metachronous metastases; OS � overall survival; OR �stases; SRS � stereotactic radiosurgery; Sx � surgery; WBRT � whole brain radiotherapy.

ctomyLR:y or

9;tomy,nt; tumornousy, 18;5;

T, 11;

tomy,

on CT,ic RT,ction

1

; CT �Sx, 4

CT �Sx, 5;ent:; no

tomy,

CT � c

a significantly better outcome. KPS (�70%), histology of adenocar-

Clinical Lung Cancer January 2013 9

atmw26mmtmw

dttm7

swtcd5di1vt

diosurgp Tx � tr

Lung Treatment in Patients With Non–Small-Cell Lung Cancer and Brain Metastases

10 C

cinoma, and age (�60 years) were significant prognostic factors.Interestingly, some studies that used the combined aggressive ap-proach have reported extraordinary long median survivals thatreached 23-52 months.37,39,40 This effect was more importantly seenin patients with synchronous brain metastases and limited extensionof the primary pulmonary lesions.

In a recent review of the literature, Modi et al32 identified 11rticles that addressed the issue of surgical resection of the primaryumor in the context of metastatic brain lesions. They found that theedian survival for curative intent groups (combined therapy with orithout adjuvant treatment) ranged from 19 to 27 months (mean3.12 � 3.3 months), and the 1-, 2-, and 5-year OS reached 56%-9%, 28%-54%, and 11%-24%, respectively. In comparison, theedian survival for the palliative groups varied from 7.1 to 12.9onths (mean 10.3 � 2.9 months), and 1-year survival was limited

o 33%-39.7%. The researchers concluded that, in the absence ofediastinal lymph node involvement, surgical resection of NSCLCith aggressive brain treatment improves prognosis.

Radical RT of PrimaryThoracic Tumor

In patients with locally advanced pulmonary illness (N2-N3), pri-mary surgical therapy as opposed to RT has not shown a benefit indisease-free survival or OS, although additional major morbidity hasbeen encountered.41,42 By extrapolating these results to patients witholigometastatic cerebral lesions that had undergone brain manage-

Table 2 Radical RT of Primary Thoracic Tumor

Study, YNo.

PatientsNeurologic Aspects Thoracic A

Chidel et al,30

199933

Synchronous mets: Sx � WBRT:21; SRS � WBRT, 5; Sx, 3; SRS, 2;

WBRT, 2

Aggressive manaSx � RT, 3; RT, 8

palliative manag(15-50 Gy); no

Moazami et al,36

200291

Synchronous mets: single, 42;multiple, 49; WBRT, 43; Sx � WBRT,

23; SRS � WBRT, 24

CT � RT, 29; Sadjuvant CT, 22; i

Sx, 26; n

Hu et al,45 2006 84Synchronous mets: Sx � WBRT,

53; SRS � WBRT, 31RT, 8 (12-65 Gy); C

13; no the

Khan et al,44

200623

Sx, 1; Sx � RT, 6; RT or SRS, 15;CT, 1

CT � RT, 12 (26-RT � Sx, 7 (39-4

Flannery et al,33

200842

Synchronous single mets: GKS �SRS, 9; GKS � SRS � WBRT, 33

Definitive managRT, 9 (45-68.4 Gy

CT � RT, 5; nomanagement: CT

CT, 3; no th

Louie et al,43

200935 Synchronous mets: Sx � WBRT, 35 Sx, 8; CT, 2

Arrieta et al,47

201130

Synchronous mets: WBRT, 30 (30Gy/10 fx)

Induction(paclitaxel/cisplatinRT, 30 (60 Gy)/(p

Abbreviations: carbo � carboplatin; CT � chemotherapy, fx � fractions; GKS: gamma knife rarogression-free survival; RT � radiotherapy; SRS � stereotactic radiosurgery; Sx � surgery;

ment, a benefit may be observed from primary tumor treatment with I

linical Lung Cancer January 2013

RT with or without CT in the setting of advanced local disease,which allows for less morbidity and increased local control.

Several reports of an aggressive RT approach have been published(Table 2). Seven different studies have reported results in patientswith NSCLC and with brain metastatic disease treated with RTand/or CT to the primary tumor, but some of them also includedpatients treated with other modalities, such as surgical resection ofthe thoracic lesion or solely CT.30,33,36,43,44 The brain management

iffered significantly among these series and included surgical resec-ion of brain metastases, WBRT, stereotactic surgery, or a combina-ion of the former. Median OS times varied between 5.2 and 18onths, with 1- and 2-year survival rates that ranged between 22%-

1.3% and 10%-34.1%, respectively.In their series, Hu et al45 reported the outcome of 84 patients with

ynchronous, solitary brain metastatic lesions who were treated eitherith resection or SRS with or without WBRT. Of those, 48% of pa-

ients did not receive definitive thoracic management, and, in 52% ofases, their primary lung cancer was treated with thoracic RT (medianose, 45 Gy; n � 8), CT (n � 23), or both (n � 13). The 1-, 3-, and-year OS rates were 49.8%, 12.7%, and 7.6%, respectively. The me-ian survival durations for patients who had received treatment (includ-

ng RT and CT) for their primary cancers and those who had not were5.5 and 5.9 months, respectively (P � .046). According to nodal in-olvement, patients with limited thoracic disease had better outcomeshan those with locally advanced lung lesions (stage I, 25.6 months; stage

Significant Prognosis Variables Survival

t: Sx, 2;65 Gy);RT, 13

nt, 7

WBRT: patients who received WBRT had bettersurvival (P � .043); aggressive thoracic

management: patients in the aggressive grouphad better survival (P � .02)

Median survival: 6.9 mo; OS at 3 y,12%

x �CT � *Table 1

Median survival: 5.2 mo; OS at 1 y,22%; OS at 2 y, 10%

T � RT, Univariate analysis did not reveal any risk factorthat significantly predicted survival

Median survival, 9.7 mo; mediansurvival with thoracic treatment,

15.5 mo; median survival withoutthoracic treatment, 5.9 mo; OS at1 y, 49.8%; OS at 2 y, 16.3%; OS

at 3 y, 12.7%; OS at 5 y, 7.6%

); CT �; Sx, 4

Not includedMedian survival, 20 mo; OS at 1 y,71.3%; OS at 2 y, 34.1%; OS at

5 y, 21.0%

: CT �; Sx �

itive4; RT �

Primary tumor treatment: better prognosisfor surgical resected lung tumor (P � .02);

KPS: � 90% showed better prognosis(P � .001)

Median survival, 18 mo; OS at 1 y,71.3%; OS at 2 y, 34.1%; OS at

5 y, 21.0%

4 *Table 1Median survival, 7.8 mo; OS at1 y, 30%; OS at 2 y, 23%; OS at

3 y, 20%

s) CT �/carbo)

Nodal stage: N0-N1 had better survival thanN2-N3 (P � .038)

Median survival, 31.8 mo; OS at1 y, 71.1%; OS at 2 y, 60.2%;

PFS at 1 y, 39.5%; PFS at 2 y,24.7%

ery; KPS � Karnofsky performance score; mets � metastases; OS � overall survival; PFS �eatment; WBRT � whole brain radiotherapy.

spects

gemen(50.4-

ement:treatme

x, 11; Snductiono Tx, 3

T, 23; Crapy, 40

61.2 Gy3.2 Gy)

ement); Sx, 12ndefin

, 6; RT,erapy, 3

4; RT, 1

CT, 25;/2 cycleaclitaxel

I, 9.5 months; and stage III, 9.9 months; P � .006).

Npn

oaWrdMm6

n

s2rms

g

bcHpssv

bibbarrci

tm

ft2

Cynthia Villarreal-Garza et al

Jabbour et al46 reported their experience with 9 patients withSCLC and a single extrathoracic site of disease, bone (n � 3),

ericardial fluid (n � 2), lymph nodes (retroauricular lymph node� 1, axilla n � 1), brain (n � 1), and adrenal gland (n � 1), that

were treated with combined modality therapy. Initial treatment con-sisted of induction CT, except for brain metastases that were man-aged first (n � 1). If patients experienced a response to CT withoutnew metastases, then the extrathoracic site was treated for a totalcontrol with curative dose chemoradiotherapy to the primary site.Median survival was 28 months, with median time to progression of15 months.

Recently, our group reported their experience in 30 patientstreated with radical chemoradiotherapy.47 Unlike other studies, inur report, the treatment delivered to the brain as well as the systemicnd local therapy was homogeneous among all the included patients.

e reported a median survival of 31.8 months, the longest survivaleported until now in patients with synchronous brain metastaticisease treated with definitive chemoradiation to the primary tumor.edian progression-free survival and OS were 8.43 and 31.8onths, respectively. The 1- and 2-year OS rates reached 71.1% and

0.2%, respectively.

Prognostic FactorsPrognostic factors associated with better outcomes with lung radical

treatment after brain management are younger age,24,34 early-stageodal disease,37-39,47,48 good performance status,24,36,49 adenocarci-

noma subtype,24,35,38,39 absence of extracranial metastases,34,36 loca-tion of primary tumor,35 site of brain metastases,34 and low carcinoem-bryonic antigen levels.38

By applying the American Joint Committee on Cancer staging toonly the primary site, Hu et al45 reported that patients with thoracictage I had a more favorable outcome, with a median survival time of5.6 months (compared with 9.5 and 9.9 months for stage II and III,espectively) and concluded that aggressive treatment to the lungay be justified for newly diagnosed thoracic stage I NSCLC with a

olitary brain metastasis. Also, Louie et al43 reported a longer OS forstage I/II disease of 14.7 months compared with 7 months for pa-tients with stage III NSCLC with synchronous solitary brain metas-tasis treated with craniotomy and WBRT. In a previous study, ourgroup reported that patients with N0-N1 disease had a significantlybetter 3-year survival rate compared with those with N2-N3 dis-ease.47 Similar findings have been reported in studies that used sur-ery, RT, or both for the management of the primary tumor.37,38,48

Several series regarding surgical management of lung disease in-cluded patients with either synchronous or metachronous brain me-tastases.34,38,39,48-52 In the case of the latter, brain lesions were diag-nosed at least 2 months after a NSCLC diagnosis, and the primarylung tumor was resected before brain metastases were diagnosed andtreated. Abrahams et al49 stated that patients with metachronousrain metastases have longer survival compared with those with syn-hronous brain disease (5-year survival, 28.9 vs. 0%, respectively).owever, OS was determined from NSCLC diagnosis, which ex-

lains why those patients without metastatic brain disease at diagno-is had a longer survival than those diagnosed with cerebral metasta-es at first. Other studies that evaluated the presence of synchronous

s. metachronous brain disease did not find a significant difference

etween these 2 groups.39,48,38,51,52 Regarding the specific issue thats being discussed in this and previous reviews, only synchronousrain metastases can be considered for primary lung management,ecause, in the case of metachronous disease, the primary tumor haslready been treated. A special consideration could be patients whoeceive induction CT and then brain metastases are diagnosed beforeadical thoracic treatment is delivered. In that case, patients can beonsidered for aggressive thoracic treatment after brain managements administered.

In those series that evaluated surgery as the local treatment for thehoracic disease, several series included patients with multiple brainetastases.24,36,38,49,50,53 In none of these studies was the number of

brain lesions described as a factor that conferred poor prognosis. Inour series, we also included patients with multiple synchronous brainmetastases treated with WBRT that showed a long OS.47

ConclusionsThe traditional management of metastatic NSCLC consists of

palliative CT, which led to an improved quality of life and a pro-longed median OS.54-57 Even so, reported 5-year survival is �3%.32

Moreover, brain metastatic disease confers a worse prognosis, with amedian survival time that ranges from 6.5 to 11 months in patientstreated for cerebral disease if metastatic brain lesions are treated.However, trials that evaluated brain management enrolled patientswith different cancer histologies. Greater attention should be paid topatients with NSCLC and with brain metastases to improve theiroutcome because, in recent years, a prolonged survival has beenachieved with emerging treatments and advances in neuroimaging.Moreover, particular subgroups have been identified as having a bet-ter prognosis, eg, those with specific clinicopathologic characteristics(adenocarcinoma histology, Asian ethnicity, female sex, and non-smoker history) or those harboring EGFR-activating mutations,which can further benefit from brain management.

Evidence derived from the treatment of other neoplasms, such asbreast cancer, melanoma, and renal cancer, shows that oligometa-static disease may be associated with a good prognosis, reaching a 5-yearOS of 20%-30%.58-62 Lung cancer with a solitary, brain metastasis isclassified as M1 in stage IV, but the prognosis and OS in the vast ma-jority of these patients is much closer to that indicated in stage IIIA.52

Although there is a general dogma that metastatic spread precludesfocal treatment of the primary tumor, there is evidence that patientswith lung cancer and with treated synchronous brain metastases arean exception to this rule.24 In patients with NSCLC and with oligo-metastatic disease, treatment should be considered for the primarylung lesion, because, after resection of brain metastases, the majorfactor that influences patients’ survival is the extracranial tumor ac-tivity and progression.13,24,63,64 The same applies for other oligo-metastatic sites. For example, patients with metastasis solely to theadrenal glands, in which surgical resection of both sites was per-formed, a 5-year OS of 20%-25% was achieved, similar to patientswith locally advanced disease without metastatic lesions.65,66 Also,or patients with NSCLC and a single extrathoracic site of diseasereated with combined modality therapy, a median survival time of8 months was reported.46

In this review, series of patients with NSCLC and with oligometa-

static brain disease who received aggressive treatment to the brain

Clinical Lung Cancer January 2013 11

1

1

1

1

1

1

2

2

2

2

2

2

2

Lung Treatment in Patients With Non–Small-Cell Lung Cancer and Brain Metastases

12 C

with surgery and SRS, with or without WBRT, and primary thoracictreatment were reviewed. The level of evidence is C, because all ofthese reports comprised case series or descriptive studies. For patientstreated with surgical resection for the primary lung tumor, mediansurvival ranged from 19 to 27 months, and the 1- and 2-year survivalreached 56% -69% and 28%-54, respectively. Patients treated withaggressive RT with or without CT, achieved a median survival of15.5-31.8 months, with 1-year survival of 50%-71% and a 2-yearOS of 16%-60%.

Patients with NSCLC and with sole brain metastases represent asubgroup of stage IV with better prognosis when the metastatic dis-ease and also the primary tumor are treated in well-selected cases.Even though the majority of patients with brain metastases also haveregional nodal involvement at the time of diagnosis, those with N0 orN1 may be selected for surgical thoracic treatment. In contrast, thosewith N2 or N3 may benefit from combined chemoradiotherapy inthe absence of progression after induction CT. These recommenda-tions are categorized as level 2B, because there is at least fair evidenceto suggest that the intervention might be appropriate, when takinginto account individual considerations. Randomized controlled trialsmight be difficult to perform due to the inclusion of patients withvery particular characteristics, and recruitment can be complicated.However, prospective clinical trials should be done to confirm thebenefits of this treatment.

DisclosureThe authors have stated that they have no conflicts of interest.

References1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;

61:69-90.2. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:

GLOBOCAN 2008. Int J Cancer 2010; 127:2893-917.3. Hayat MJ, Howlader N, Reichman ME, et al. Cancer statistics, trends, and multiple

primary cancer analyses from the Surveillance, Epidemiology, and End Results(SEER) Program. Oncologist 2007; 12:20-37.

4. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2012; 62:10-29.

5. Schuette W. Treatment of brain metastases from lung cancer: chemotherapy. LungCancer 2004; 45;(suppl 2):S253-7.

6. Knights EM Jr. Metastatic tumors of the brain and their relation to primary andsecondary pulmonary cancer. Cancer 1954; 7:259-65.

7. Galluzzi S, Payne PM. Brain metastases from primary bronchial carcinoma: a sta-tistical study of 741 necropsies. Br J Cancer 1956; 10:408-14.

8. Newman SJ, Hansen HH. Proceedings: frequency, diagnosis, and treatment ofbrain metastases in 247 consecutive patients with bronchogenic carcinoma. Cancer1974;33:492-6.

9. Sørensen JB, Hansen HH, Hansen M, et al. Brain metastases in adenocarcinoma ofthe lung: frequency, risk groups, and prognosis. J Clin Oncol 1988; 6:1474-80.

0. Lagerwaard FJ, Levendag PC, Nowak PJ, et al. Identification of prognostic factors inpatients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys1999; 43:795-803.

1. Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of brain metastases in acohort of patients with carcinoma of the breast, colon, kidney, and lung and mela-noma. Cancer 2002; 94:2698-705.

2. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) ofprognostic factors in three radiation therapy Oncology Group (RTOG) brain me-tastases trials. Int J Radiat Oncol Biol Phys 1997; 37:745-51.

3. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in thetreatment of single metastases to the brain. N Engl J Med 1990; 322:494-500.

4. Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al. The choice of treatment of singlebrain metastasis should be based on extracranial tumor activity and age. Int J RadiatOncol Biol Phys 1994; 29:711-7.

15. Alexander E III, Moriarty TM, Davis RB, et al. Stereotactic radiosurgery for thedefinitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995; 87:34-40.

16. Kondziolka D, Patel A, Lunsford LD, et al. Stereotactic radiosurgery plus whole

brain radiotherapy versus radiotherapy alone for patients with multiple brain me-tastases. Int J Radiat Oncol Biol Phys 1999; 45:427-34.

linical Lung Cancer January 2013

17. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapywith or without stereotactic radiosurgery boost for patients with one to threebrain metastases: phase III results of the RTOG 9508 randomised trial. Lancet2004; 363:1665-72.

18. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versusobservation after radiosurgery or surgical resection of one to three cerebral metasta-ses: results of the EORTC 22952-26001 study. J Clin Oncol 2011; 29:134-41.

9. Hussain A, Brown PD, Stafford SL, et al. Stereotactic radiosurgery for brainstemmetastases: survival, tumor control, and patient outcomes. Int J Radiat Oncol BiolPhys 2007; 67:521-4.

0. Mehta M, Noyes W, Craig B, et al. A cost-effectiveness and cost-utility analysis ofradiosurgery vs. resection for single-brain metastases. Int J Radiat Oncol Biol Phys1997; 39:445-54.

1. Brem SS, Bierman PJ, Brem H, et al. Central nervous system cancers. J Natl ComprCancer Netw 2011; 9:352-400.

2. Sejpal SV, Bhate A, Small W. Palliative radiation therapy in the management ofbrain metastases, spinal cord compression, and bone metastases. Semin InterventRadiol 2007; 24:363-74.

3. Grimm SA. Treatment of brain metastases: chemotherapy. Curr Oncol Rep 2012;14:85-90.

4. Girard N, Cottin V, Tronc F, et al. Chemotherapy is the cornerstone of the com-bined surgical treatment of lung cancer with synchronous brain metastases. LungCancer 2006; 53:51-8.

5. Cortes J, Rodriguez J, Aramendia JM, et al. Front-line paclitaxel/cisplatin-basedchemotherapy in brain metastases from non-small-cell lung cancer. Oncology 2003;64:28-35.

6. Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatinand etoposide for patients with brain metastases from breast carcinoma, nonsmallcell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999;85:1599-605.

27. Bernardo G, Cuzzoni Q, Strada MR, et al. First-line chemotherapy with vinorel-bine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Invest 2002; 20:293-302.

28. Drappatz J, Wen PY. Chemotherapy and targeted molecular therapies for brainmetastases. Expert Rev Neurother 2006; 6:1465-79.

29. Ceresoli GL. Role of EGFR inhibitors in the treatment of central nervous systemmetastases from non-small cell lung cancer. Curr Cancer Drug Targets 2012; 12:237-46.

30. Chidel MA, Suh JH, Greskovich JF, et al. Treatment outcome for patients withprimary nonsmall-cell lung cancer and synchronous brain metastasis. Radiat OncolInvestig 1999; 7:313-9.

31. Salvati M, Cervoni L, Tarantino R, et al. Solitary cerebral metastasis as first symp-tom of lung cancer. Neurochirurgie 1994; 40:256-8.

32. Modi A, Vohra HA, Weeden DF. Does surgery for primary non-small cell lungcancer and cerebral metastasis have any impact on survival? Interact CardiovascThorac Surg 2009; 8:467-73.

33. Flannery TW, Suntharalingam M, Regine WF, et al. Long-term survival in patientswith synchronous, solitary brain metastasis from non-small-cell lung cancer treatedwith radiosurgery. Int J Radiat Oncol Biol Phys 2008; 72:19-23.

34. Wronski M, Arbit E, Burt M, et al. Survival after surgical treatment of brain me-tastases from lung cancer: a follow-up study of 231 patients treated between 1976and 1991. J Neurosurg 1995; 83:605-16.

35. Bonnette P, Puyo P, Gabriel C, et al. Surgical management of non-small cell lungcancer with synchronous brain metastases. Chest 2001; 119:1469-75.

36. Moazami N, Rice TW, Rybicki LA, et al. Stage III non-small cell lung cancer andmetachronous brain metastases. J Thorac Cardiovasc Surg 2002; 124:113-22.

37. Billing PS, Miller DL, Allen MS, et al. Surgical treatment of primary lung cancerwith synchronous brain metastases. J Thorac Cardiovasc Surg 2001; 122:548-53.

38. Iwasaki A, Shirakusa T, Yoshinaga Y, et al. Evaluation of the treatment of non-smallcell lung cancer with brain metastasis and the role of risk score as a survival predictor.Eur J Cardiothorac Surg 2004; 26:488-93.

39. Granone P, Margaritora S, D’Andrilli A, et al. Non-small cell lung cancer withsingle brain metastasis: the role of surgical treatment. Eur J Cardiothorac Surg 2001;20:361-6.

40. Lo CK, Yu CH, Ko KM, et al. Surgical management of primary non-small-cellcarcinoma of lung with synchronous solitary brain metastasis: local experience.Hong Kong Med J 2010; 16:186-91.

41. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with orwithout surgical resection for stage III non-small-cell lung cancer: a phase III ran-domised controlled trial. Lancet 2009; 374:379-86.

42. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial ofresection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007; 99:442-50.

43. Louie AV, Rodrigues G, Yaremko B, et al. Management and prognosis in synchro-nous solitary resected brain metastasis from non-small-cell lung cancer. Clin LungCancer 2009; 10:174-9.

44. Khan AJ, Mehta PS, Zusag TW, et al. Long term disease-free survival resulting fromcombined modality management of patients presenting with oligometastatic, non-small cell lung carcinoma (NSCLC). Radiother Oncol 2006; 81:163-7.

45. Hu C, Chang EL, Hassenbusch SJ III, et al. Nonsmall cell lung cancer presentingwith synchronous solitary brain metastasis. Cancer 2006; 106:1998-2004.

46. Jabbour SK, Daroui P, Moore D, et al. A novel paradigm in the treatment ofoligometastatic non-small cell lung cancer. J Thorac Dis 2011; 3:4-9.

4

5

5

5

5

5

5

5

5

5

5

6

6

6

6

6

6

6

6

Cynthia Villarreal-Garza et al

47. Arrieta O, Villarreal-Garza C, Zamora J, et al. Long-term survival in patients with

non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation. Radiat Oncol 2011; 6:166.

48. Mussi A, Pistolesi M, Lucchi M, et al. Resection of single brain metastasis innon-small-cell lung cancer: prognostic factors. J Thorac Cardiovasc Surg 1996;112:146-53.

9. Abrahams JM, Torchia M, Putt M, et al. Risk factors affecting survival after brainmetastases from non-small cell lung carcinoma: a follow-up study of 70 patients.J Neurosurg 2001; 95:595-600.

0. Magilligan DJ Jr, Duvernoy C, Malik G, et al. Surgical approach to lung cancer withsolitary cerebral metastasis: twenty-five years’ experience. Ann Thorac Surg 1986;42:360-4.

1. Getman V, Devyatko E, Dunkler D, et al. Prognosis of patients with non-small celllung cancer with isolated brain metastases undergoing combined surgical treatment.Eur J Cardiothorac Surg 2004; 25:1107-13.

2. Furák J, Troján I, Szöke T, et al. Lung cancer and its operable brain metastasis:survival rate and staging problems. Ann Thorac Surg 2005; 79:241-7; discussion:41-7.

3. Wronski M, Burt M. Results and prognostic factors of surgery in the managementof non-small cell lung cancer with solitary brain metastasis. Cancer 1992; 70:2021-3.

4. EB. H. Treatment of advanced non-small-cell lung cancer: a review of currentrandomized clinical trials and an examination of emerging therapies. Cancer Control2001;8:326.

5. Shanafelt TD, Loprinzi C, Marks R, et al. Are chemotherapy response rates relatedto treatment-induced survival prolongations in patients with advanced cancer?J Clin Oncol 2004; 22:1966-74.

6. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapyregimens for advanced Non–Small-cell lung cancer. N Engl J Med 2002; 346:92-8.

7. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plusgemcitabine with cisplatin plus pemetrexed in chemotherapy-Naive patients withadvanced-stage Non–small-cell lung cancer. J Clinical Oncology 2008;26:3543-51.

8. Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients withcolorectal cancer. Cancer 1993; 71(suppl):4252-66.

9. Andres A, Majno PE, Morel P, et al. Improved long-term outcome of surgery foradvanced colorectal liver metastases: reasons and implications for management onthe basis of a severity score. Ann Surg Oncol 2008; 15:134-43.

0. Rotolo N, De Monte L, Imperatori A, et al. Pulmonary resections of single metas-tases from colorectal cancer. Surg Oncol 2007; 16;(suppl 1):S141-4.

1. Fourquier P, Regnard JF, Rea S, et al. Lung metastases of renal cell carcinoma:results of surgical resection. Eur J Cardiothorac Surg 1997; 11:17-21.

2. Hofmann HS, Neef H, Krohe K, et al. Prognostic factors and survival after pulmo-nary resection of metastatic renal cell carcinoma. Eur Urol 2005; 48:77-81; discus-sion: 81-2.

3. Kaal EC, Niël CG, Vecht CJ. Therapeutic management of brain metastasis. LancetNeurol 2005; 4:289-98.

4. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain me-tastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993;33:583-90.

5. Mercier O, Fadel E, de Perrot M, et al. Surgical treatment of solitary adrenalmetastasis from non-small cell lung cancer. J Thorac Cardiovasc Surg 2005; 130:136-40.

6. Tanvetyanon T, Robinson LA, Schell MJ, et al. Outcomes of adrenalectomy forisolated synchronous versus metachronous adrenal metastases in non-small-cell lungcancer: a systematic review and pooled analysis. J Clin Oncol 2008; 26:1142-7.

7. Yang SY, Kim DG, Lee SH, et al. Pulmonary resection in patients with nonsmall-

cell lung cancer treated with gamma-knife radiosurgery for synchronous brain me-tastases. Cancer 2008; 112:1780-6.

Clinical Lung Cancer January 2013 13