The efficacy of = gamma knife radiosurgery for advanced gastric cancer with brain = metastases

From: Subject: The efficacy of gamma knife radiosurgery for advanced gastric cancer with brain metastases Date: Wed, 3 Nov 2010 10:22:09 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CB7B40.F93D0400" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5994 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CB7B40.F93D0400 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/gh06540693326841/fulltext.html The efficacy of = gamma knife radiosurgery for advanced gastric cancer with brain = metastases

Journal of Neuro-Oncology

=A9 Springer Science+Business Media, = LLC. 2010

10.1007/s11060-010-0405-4

Clinical Study =96 Patient Study

The efficacy of = gamma knife=20 radiosurgery for advanced gastric cancer with brain metastases

Young Seok Park¹,=20 Jong Hee Chang¹, = Jin Woo Chang¹ and=20 Yong Gou Park¹

(1)	Department of Neurosurgery, Gamma = Knife=20 Clinic, Severance Hospital, Brain Research Institute, Yonsei = University=20 College of Medicine, 134, Shinchon-dong, Seodaemoon-gu, Seoul, = 120-752,=20 Republic of Korea

Received:=20 28 January 2010 Accepted:=20 6 September 2010 Published online: = 19 October 2010

Abstract

The aim of this study was to retrospectively = investigate the=20 efficacy of gamma knife radiosurgery for brain metastases from advanced = gastric=20 cancer (AGC) comparing whole brain radiotherapy (WBRT). Between January = 1991 and=20 May 2008, 56 patients with brain metastases from AGC, treated with GKR = or WBRT,=20 were reviewed to assess prognostic factors affecting survival. Most = brain=20 metastases were diagnosed based on MRI, both metachronous and = synchronous brain=20 metastases, adenocarcinoma and signet ring carcinoma were included, but = excluded=20 cases of gastric lymphoma. Fifteen patients with a median age of = 54.0 years=20 (range, 42=9667 years) were treated with GKR: 11 were treated with = GKR only,=20 2 with surgery plus GKR, 1 with repeated GKR, 1 with GKR plus WBRT, and = the=20 other 1 with WBRT plus GKR. Forty-one were treated with WBRT only. The = median=20 number of metastatic brain lesions was 3 (range, 1=9615), and treatment = involved=20 17.0 Gy (range 14=9623.6 Gy), or 30 Gy with fractionated=20 radiotherapy. The median survival after brain metastases for GKR = treatment was=20 40.0 weeks [95% confidence interval (CI) 44.9=96132.1 weeks] = and WBRT=20 was 9.0 weeks 95% CI, 8.8=9621.9 weeks). The progression free = survival=20 of 15 GKR treated patients was 56.5 weeks (95% CI = 33.4=9679.5 weeks).=20 The recursive partitioning analysis (RPA) (class 2 vs. class 3) and use = of GKR=20 were correlated with prolonged survival in univariate and multivariate = analyses.=20 Age, sex, pathology, leptomeningeal seeding, tumor size = (≥3 cm),=20 extracranial metastases, single metastasis, chemotherapy, and = synchronous=20 metastases were not correlated with a good prognosis in both univariate = and=20 multivariate analysis. Based on our study, the use of GKR and RPA class = 2=20 resulted in more favorable clinical outcomes in patients with brain = metastases=20 from AGC.

Keywords Gastric=20 cancer - Metastasis - Radio=20 surgery - Radiotherapy - Survival

Introduction

Gastric cancer is the fourth most common type of = cancer in the=20 world [1],=20 the second most common cause of cancer-related death [2],=20 and the most common cause of cancer-related death in Korea [3].=20 However, metastasis of gastric carcinomas to the brain is very rare, = generally=20 occurring in only 0.16=960.69% of gastric cancer patients, and resulting = in a poor=20 prognosis [4=966].=20 Patients with brain metastases from advanced gastric cancer (AGC) = usually=20 develop severe cachexia at the end stage of disease progression, and = have a poor=20 median survival time of only 1.3=962.4 months [2,=20 4,=20 5,=20 7].=20

Advances in surgery and chemotherapy have led to = better clinical=20 outcomes for gastric cancer patients, but these increased survival rates = may=20 lead to an increased incidence of metastases [6].=20 The treatments of brain metastases arising from other forms of = gastrointestinal=20 tumors have been described [4,=20 8=9610].=20 These studies were typically presented as case reports, and with small = study=20 samples [11,=20 12].=20 Gamma knife radiosurgery (GKR) for these brain tumors has not been well=20 described, and the role of whole-brain radiotherapy (WBRT) or GKR for = brain=20 metastases from AGC has not been thoroughly studied. The aim of this = study was=20 to retrospectively investigate the efficacy of gamma knife radiosurgery = for=20 brain metastases from AGC comparing WBRT.

Patients and methods

Patients

We retrospectively analyzed all patients who underwent = GKR or=20 WBRT for brain metastases from AGC between January 1991 and May 2008. A = total of=20 56 patients with a mean age of 55.5 years (range, = 30=9677 years) were=20 treated with WBRT or GKR at the same medical facility. We performed GKR = in 15=20 patients. Of these 15 patients treated with GKR, 11 were treated with = GKR only,=20 2 were treated with surgery plus GKR, 1 was treated with WBRT followed = by GKR as=20 a booster, and 1 was treated with GKR followed by WBRT for = leptomeningeal=20 seeding. GKR was performed repeatedly in 1 patient, and 41 patients = (73.2%) with=20 brain metastases underwent WBRT only. We reviewed the medical records, = pathology=20 reports, magnetic resonance imaging (MRI) and our GKR registry.

Most brain metastases were diagnosed based on MRI, = with the=20 exception of 2 patients that were diagnosed based on biopsy. Both = metachronous=20 and synchronous brain metastases were also included in this study. All = patients=20 included in this study were diagnosed with AGC based upon pathology = reports. We=20 included adenocarcinomas and signet ring carcinomas, but excluded cases = of=20 gastric lymphoma. Fifty patients (89.3%) were diagnosed with = adenocarcinoma and=20 6 patients (10.7%) were diagnosed with signet ring carcinomas. Thirty = patients=20 (53.6%) underwent subtotal or total gastrectomy, and 26 patients (46.4%) = underwent a lymph node biopsy or open biopsy without surgical resection = of the=20 primary disease. Fifty patients (89.3%) were diagnosed with brain = lesions after=20 the primary diagnosis of metachronous carcinoma, and 6 patients (10.7%) = were=20 diagnosed simultaneously with synchronous carcinoma. Extracranial = diseases were=20 diagnosed through a systemic work up [13].=20

All but 6 of the patients were treated with various = chemotherapy=20 regimens. We could not analyze the impact of chemotherapy on survival = because=20 many different chemotherapy regimens with various cycles had been used. = None of=20 the patients in this study underwent intrathecal chemotherapy. We = classified the=20 causes of death as neurological or systemic.

Methods of GKR

GKR were performed using the Leksell Gamma Knife = (Elekta,=20 Stockholm, Sweden) model B or C. We obtained brain MRI image using=20 image-compatible Leksell stereotactic coordinate frame (Elekta) in the = morning=20 of the day of operation with local anesthesia combined with or without=20 intravenous sedation. MR image acquisition covered the entire brain with = 2-mm-thick slices including T1, T2, and double-dose gadolinium-enhanced = MR=20 images. Then, computerized imaging data were transferred to the = Gammaplan=20 Software (Elekta). After three-dimensional image reconstruction with a = Gamma=20 plan (Elekta), the neurosurgeon identified the tumor and its near = critical=20 structures. All patients underwent brain MRI before WBRT or GKR. The = tumors=20 eligible for GKR had a diameter of less than 3 cm and a number of=20 metastasis less than 10 using preoperative contrast-enhanced MRI. = Patients with=20 multifocal over 10 brain metastasis and leptomeningeal metastases were = treated=20 with 10 fractions of WBRT at 30 Gy. We performed WBRT in several = single=20 brain metastases in our early experience. Two patients (patients #1 and = #14 in=20 Table 1)=20 that had less than 10 lesions on the preoperative contrast-MRI, but = found to=20 have greater than 10 lesions on the planning MRI, were included in this = study.=20 Patients with single or multiple metastases were treated with a marginal = dose of=20 17.0 Gy (range 14.0=9623.6 Gy). The median number of = parenchymal=20 metastases was 3 (range, 1=9618), and GKR treatment was carried out in = one=20 session, with the exception of one patient who was treated three times = for new=20 lesions.

Table 1 Clinical=20 results of GKR after brain metastases

Yong Gou Park
Email:=20 ygpark@yuhs.ac

Patient no.	Age/sex	PATH	No. of metastases	Treatment modality	Median marginal dose (Gy)	Median tumor volume (cm³)	Survival after brain metastasis = (months)	Outcome^a
1	53/F	A	6	Surgery + GKR	17.0 (9.8=9621)	1.95 (0.17=966.24)	3	Systemic death
2^b	52/M	A	1,2,15	GKR + GKR + GKR	18.9 (15.1=9628)	0.70 (0.11=9612.70)	46	Alive
3	54/F	S	3	Surgery + GKR	16 (16=9627)	0.41 (0.16=960.61)	3	Systemic death
4	51/M	S	2	GKR	18.1 (17=9619.2)	7.38 (4.00=9610.76)	16	Systemic death
5	45/M	A	1	GKR	14	1.10	7	Systemic death
6	66/M	A	3	GKR	18 (17=9619.8)	12.39 (0.63=9617.8)	7	Systemic death
7	54/M	A	1	GKR	16	14.90	25	Alive
8	67/M	S	2	GKR	16	0.39 (0.33=960.44)	11	Alive
9	42/F	A	7	GKR	14.3 (13.1=9615.4)	0.24 (0.02=960.59)	12	Alive
10	63/M	A	8	GKR + WBRT^c (30 Gy) =	18.9 (15=9619.5)	0.13 (0.01=9610.3)	10	Neurogenic death
11	51/M	S	3	GKR	15.9 (15=9617.99)	0.08 (0.03=963.30)	9	Systemic death
12	65/F	A	5	GKR	16 (15=9628)	0.11 (0.01=960.42)	3	Alive
13	60/F	A	3	GKR	17 (17=9619)	0.45 (0.41=963.40)	3	Alive
14	61/M	A	15	WBRT^d (30 Gy) + GKR =	23.6 (14.9=9627.1)	0.26 (0.01=964.00)	31	Alive
15	57/M	A	1	GKR	18.0	3.00	4	Systemic death

A adenocarcinoma, GKR gamma knife = radiosurgery,=20 S signet ring carcinoma, WBRT whole brain radiotherapy=20

^aSurvival data were updated to August = 2008=20

^bThe median marginal doses and median = tumor volumes=20 of the three GKR treatments were calculated for patient #2

^cThe patient underwent WBRT 3 months = after GKR=20 due to leptomenineal metastasis

^dThe patient underwent WBRT over 10 = lesions with=20 30 Gy, the tumors were decreasing but refractory after = 6 months, GKR=20 was performed as booster treatment

Follow-up

The patients were followed-up for clinical and = neurological=20 exams 1 month after treatment, and every 3 months after the = initial=20 follow-up. An image follow-up was usually carried out at 2- or 3-month = intervals=20 after radiosurgery or WBRT using double-dose gadolinium-enhanced MRI. In = the=20 case of neurological aggravation, we performed additional brain imaging = using=20 brain computed tomography (CT) or contrast-enhanced brain MRI. We took = at least=20 one follow-up brain MRI or CT scan for 15 GKR patients, but only 14 = patients=20 were available in WBRT patients in this study. The recursive = partitioning=20 analysis (RPA) classification and Karnofsky performance status (KPS) = were used=20 to compare the prognosis. Patients were classified as RPA class 1 (KPS = ≥70%, age=20 <65 years, controlled primary, no extracranial metastasis, RPA = class 2=20 (KPS ≥70%, age ≥65 years, and/or uncontrolled = primary, and/or=20 extracranial metastases), or RPA class 3 (all patients with = KPS <70%)=20 [14].=20 All patients were assessed for KPS and RPA before radiotherapy or GKR. = Local=20 control was defined by as the reappearance of a metastasis as the = original=20 treated lesion and was detected using a brain CT image or MRI. Tumor = progression=20 was defined as more than a 25% increase in size of the tumor volume. We = took at=20 least one follow-up brain MRI or CT scan for all of patients with GKR, = but only=20 14 patients were available to compare tumor progression in patients with = WBRT in=20 this study. It was probably caused by rapid systemic disease aggravation = and=20 retrospective data acquisition. This is a limitation in comparing PFS = between=20 WBRT and GKR in this study.

Statistical analysis

Independent sample t test and Fisher=92s exact = test were=20 used to compare the GKR and radiotherapy groups. Survival data were = updated to=20 August 2008. Comparative overall survival was calculated using the = Kaplan=96Meier=20 method. Comparisons of overall survival according to clinical factors = were=20 calculated with a log-rank test. A Cox proportional hazard model with = the=20 forward stepwise method was used in multivariate analysis to determine = the=20 clinical factors affecting survival.

The mean =B1 standard deviation, median and = range of=20 each clinical characteristic were calculated. We used SPSS 15.0 software = for=20 statistical analyses.

Results

Clinical characteristics

Patient characteristics are summarized in = Tables 1=20 and 2.=20 Patients with a mean age of 55.5 years (range, 30=9677 years) = were=20 treated with GKR or radiotherapy. There were 12 female patients (21.4%) = and 44=20 male patients (78.6%). The median interval from gastric cancer to brain=20 metastasis was 6 months (0=9678 months) in the GKR group and=20 11 months (0=96119 months) in the WBRT group. There was no = difference in=20 the time interval changes between the two groups. Nine patients in the=20 radiotherapy group had leptomeningeal seeding.

Table 2 Patient=20 characteristics in the GKR only versus WBRT only groups

Patient characteristic	No. of patients	P value*
GKR, n =3D 11	WBRT, n =3D 41 =
Age	54 (42=9667)	57 (30=9677)	0.969⁼⁸⁶
Sex			0.424
Female	3	7
Male	8	34
Pathology			0.283
Adenocarcinoma	9	38
Signet ring carcinoma	2	3
KPS at GKR			1.000
≥70	9	31
<70	2	10
RPA class			1.000
2	9	31
3	2	10
Pattern of metastasis			0.177
Parenchymal	11	32
Leptomeningeal	0	9
No. of metastases
1	4	21	0.503
2=963	5	5
4=966	1	1
>6	1	14
Tumor size			0.571
<3 cm	11	36
≥3 cm	0	5
Cause of death			0.566
Neurolocal	0	9
Systemic	5	29
Extracranial disease			1.000
Yes	10	37
No	1	4
Interval from gastric cancer to brain = metastasis	6 months (0=9678)	11 months (0=96119)	0.769⁼⁸⁶ =

GKR gamma knife radiosurgery, RPA = recursive=20 partitioning analysis, WBRT whole brain radiotherapy

* P value obtained using Fisher=92s = exact test=20

⁼⁸⁶ P value obtained using = independent=20 t test

Fifty-one patients (91.1%) had extracranial metastasis = to the=20 lung, liver, bone, distant lymph node, or adrenal gland. A systemic = work-up had=20 not uncovered a brain metastasis at the time of diagnosis in 5 of the = patients=20 (0.9%). The GKR and WBRT groups showed no differences in extracranial = disease,=20 and local control at 3 months was better in the GKR group. =

GKR

The characteristics and clinical demographics of the = patients=20 that underwent GKR are described in Table 1=20 . The median number of lesions was three (range, 1=9618), and = they were=20 treated with marginal doses of 17.0 Gy (range, 14=9623.6 Gy). = We=20 decreased the radiation doses from the typical dose for patient #1 = (brain stem=20 lesion) and for patient #5 (cavernous sinus invading lesion near the = optic=20 nerve).

Patients #1 and #3 underwent GKR after tumor = removal, while=20 patient #2 underwent repeated GKR for new lesions. Patient #10 underwent = GKR for=20 a cerebella surface lesion (Fig. 1a).=20 We initially diagnosed patient #10 with a parenchymal lesion, but the = lesion=20 progressed into a leptomeningeal metastasis after 3 months, and the = patient=20 underwent WBRT (Fig. 1b).=20 Patient #14 also underwent WBRT for multiple lesions, but after = 6 months,=20 the metastatic lesions were refractory to WBRT and were subsequently = treated=20 using GKR as a booster. An MRI performed 12 months after the GKR = treatment=20 of patient #14 showed good local control for each of the multiple = lesions=20 (Fig. 2).=20 Crude local control was 93.3% at 3 months for 15 GKR-treated = patients. The=20 progression-free survival of 15 GKR-treated patients was 56.5 weeks = (95%=20 CI, 33.4=9679.5 weeks). The median survival after brain metastases = for GKR=20 was 40.0 weeks (95% confidence interval [CI] = 44.9=96132.1 weeks) and=20 WBRT was 9.0 weeks (95% CI, 8.8=9621.9 weeks).=20

Fig. 1 Gamma knife=20 stereotactic radiosurgery was performed on a 64-year-old male patient = (patient=20 #10 in Table 1)=20 for cerebellar metastases. a A T1 gadolinium-enhanced magnetic = resonance=20 image (MRI) shows cerebellar surface metastasis prior to GKR. b = This=20 tumor showed leptomeningeal metastasis after 3 months, at which = time WBRT=20 was performed

Fig. 2 Whole-brain=20 radiotherapy (WBRT) was performed on a 61-year-old male patient (patient = #14 in=20 Table 1)=20 with multiple metastases. a A T1-weighted gadolinium-enhanced = coronal=20 image shows multiple lesions prior to WBRT. b Three months after = WBRT,=20 there was decrease in the enhanced lesions. c Six months after = WBRT, MRI=20 showed an increased size and number on the right temporal and left = insular=20 areas, prior to GKR. d The post-GKR 12-month follow-up MRI showed = a=20 decreased size and number of tumors

GKR only versus WBRT only: univariate and = multivariate=20 analyses

The median age of the GKR only group = (n =3D 11)=20 was 54.0 years (range, 42=9667 years), and the median age of = the WBRT=20 only group (n =3D 41) was 57.0 years (range,=20 30=9677 years). There were no significant differences between the = GKR only=20 group and the WBRT only group with regard to age, sex, pathology, = pattern of=20 metastasis, RPA class, tumor size (≥3 cm), or the number of = metastases.=20 There was no difference in the number of neurological deaths between the = two=20 groups. Single metastasis was higher in the WBRT group with 21 patients = (51.2%)=20 compared to only 4 patients (36.3%) in the GKR only group; however, this = difference was not significant. Multiple metastases (>6 lesions) were = found=20 in 1 patient in the GKR only group, but in 14 patients (34.1%) in the = WBRT only=20 group. The clinical characteristics of patients in the GKR only and WBRT = only=20 groups are shown in Table 2.=20

Univariate and multivariate analyses showed that = survival=20 outcome was not affected by age (<60), gender, pathology, = metachronous=20 lesions, tumor size (≥3 cm), single metastasis, extracranial = metastases, or=20 leptomeningeal metastases (Table 3).=20 A tumor size greater than 3 cm in diameter did not affect survival = in=20 univariate and multivariate analyses. Patients with extracranial = metastasis at=20 the time of brain metastasis from AGC had a poor median survival, but = the=20 difference compared to that of patients without extracranial metastasis = was not=20 significant. Chemotherapy was used to treat 50 patients (89.3%) and was = shown to=20 have affected survival in univariate but not in multivariate analyses. = However,=20 these data may have been affected by selection bias since only patients = with a=20 good prognosis underwent chemotherapy. In addition, the use of a variety = of=20 chemotherapy regimens may also have affected these results.

Table 3 Univariate=20 and multivariate analyses for survival in 56 patients with brain = metastases from=20 advanced gastric cancer

Variable	No. of patients	MST =B1 SE weeks (95% CI)	Univariate Analysis^a	Multivariate analysis^b	Hazard ratio (95% CI)
Age (years)			0.694	0.969
<60	33	14 =B1 2.2 (9.6=9618.4)			1
≥60	23	13 =B1 7.1 (0.0=9627.0)			0.98 (0.43=962.26)
Sex			0.881	0.209
Male	44	14 =B1 2.7 (8.6=9619.4)			1
Female	12	13 =B1 2.6 (8.0=9618.1)			0.56 (0.23=961.39)
Pathology			0.866	0.023
Adenocarcinoma	50	14 =B1 1.6 (10.8=9617.2)			1
Signet ring carcinoma	6	9 =B1 15.3 (0.0=9639.0)			3.40 (1.18=969.81)
Pattern of metastasis			0.615	0.104
Leptomeningeal	9	9 =B1 1.5 (5.9=9612.1)			1
Parenchymal	47	14 =B1 1.0 (12.0=9616.0)			0.34 (0.09=961.25)
Synchronous			0.698	0.762
Metachronous	50	13 =B1 1.5 (10.0=9616.0)			1
Synchronous	6	11 =B1 2.4 (6.2=9615.8)			1.24 (0.31=964.89)
RPA class			<0.001	<0.001
2	43	14 =B1 1.5 (11.0=9617.0)			1
3	13	5 =B1 0.3 (4.5=965.5)			15.8 (4.58=9654.80)
Single metastases			0.139	0.146
1	25	13 =B1 2.0 (9.1=9616.9)			1
>1	31	14 =B1 2.5 (9.0=9619.0)			0.46 (0.16=961.31)
Tumor size (cm)			0.145	0.464
<3	51	14 =B1 2.7 (8.6=9619.4)			1
≥3	5	12 =B1 4.3 (3.4=9620.6)			1.70 (0.41=967.00)
Extracranial metastasis			0.152	0.065
None	5	14 =B1 2.0 (10.0=9617.9)			1
Yes	51	13 =B1 2.0 (9.2=9616.8)			9.03 (0.88=9693.25)
Chemotherapy			0.009	0.165
None	6	8 =B1 2.7 (2.6=9613.4)			1
Yes	50	14 =B1 1.1 (11.8=9616.1)			0.37 (0.09=961.50)
Treatment			<0.001	<0.001
GKR	15	40.0 =B1 19.3 (44.9=96132.1)			1
WBRT	41	9.0 =B1 0.4 (8.8=9621.9)			7.96 = (3.10=9620.41)

RPA recursive partitioning analysis, = MST median=20 survival time, SE standard error, WBRT whole brain = radiotherapy,=20 CI confidence interval

^aLog-rank test for univariate analysis = dependent=20 variables

^bForward stepwise cox proportional hazard = model for=20 multivariate analyses

GKR was the only form of treatment for 11 of the = patients=20 (19.6%), and WBRT was used to treat 41 patients (73.2%). Patients in the = GKR=20 only group had better overall survival than those in the WBRT group=20 (Fig. 3a).=20 Due to the small patient population, we could not compare the surgery = and GKR=20 combination treatment with the WBRT only treatment. RPA class 2, as = opposed to=20 RPA class 3 (cox, P < 0.001), and GKR (cox,=20 P < 0.001) showed better prognoses in univariate and = multivariate analyses (Table 3;=20 Fig. 3a,=20 b).=20

Fig. 3 a A=20 Kaplan=96Meier curve illustrating the overall survivals of patients who = had=20 undergone GKR (n =3D 11) as opposed to those who had = undergone=20 WBRT (n =3D 41). Patients who underwent GKR had better = overall=20 survival (log rank, P < 0.001). b Patients = with RPA=20 class 2 had a better prognosis in Kaplan=96Meier curve analysis (log = rank,=20 P < 0.001)

Complications

In the GKR group, one patient had severe brain = swelling due to=20 radionecrosis which was controlled with intravenous corticosteroids = medication.=20 One patient had cavernous sinus invasion with diplopia, her diplopia = aggravated=20 temporary and improved after GKR. One had developed uncontrolled seizure = at=20 3 months after GKR. It might be related with peritumoral edema. It = improved=20 after intravenous corticosteroid medication and anticonvulant = medication. There=20 were no intracranial tumor bleeding after GKR or radiotherapy. One = patient=20 presented with intracranial tumor bleeding; she underwent GKR for the = previous=20 tumor bleeding area and the other lesion after craniotomy. There were no = mortalities related to radionecrosis. As of August 2008, 43 patients = (76.8%) had=20 died, including 9 neurological deaths (20.9%) and 34 (79.1%) systemic = deaths.=20 There was no difference in the number of neurological deaths between the = GKR and=20 WBRT groups.

Discussion

In this study, we found that RPA class 2 as opposed to = RPA class=20 3 and GKR were good prognostic factors in patients diagnosed with brain=20 metastases from AGC. Although WBRT is the most common type of treatment = for=20 multiple metastases, surgical resection of metastases and stereotactic=20 radiosurgery (SRS) are important options if the patient has a limited = number of=20 metastases [15,=20 16].=20 The prognosis for patients with one to three brain metastases appears to = be=20 better than that for patients who have more than three lesions [17,=20 18].=20 Although WBRT is effective for brain metastasis, SRS could be as = effective as=20 WBRT. Patients can undergo WBRT multiple times to combat disease = progression,=20 but this may increase the patients=92 risks for the delayed effects of = radiation=20 [19=9623].=20 IF SRS delivered in higher doses at a single fraction, it increases the = risk of=20 radionecrosis as high-dose irradiation. Therefore, both WBRT and SRS = have its=20 optimum radiation dose and limitation due to radiation adverse effect. =

Currently, there are no available treatments for brain = metastases from AGC that are likely to produce long-term survival, and = the use=20 of WBRT, regardless of steroid use, has not been shown to increase = survival=20 [4].=20 York et al. reported 24 brain metastases patients from AGC and they = showed=20 better survival with surgical resection plus WBRT relative to the other = groups=20 among the steroid use only, WBRT, and surgical resection plus WBRT group = [4].=20 Several reports have dealt with the radiosurgery for brain metastasis = from AGC=20 as a case report or mixed with other gastrointestinal cancers [10,=20 24,=20 25].=20 Han et al. report 11 cases with radiosurgery for brain metastases from = AGC and=20 they advocated that radiosurgery plus WBRT seem to be a good alternative = to=20 surgical resection for these patients [8].=20

Leptomeningeal seeding is a relatively common and = devastating=20 neurological complication of cancer [2,=20 6].=20 Occurring in 3=968% of all cancer patients, it is associated with major = neurologic=20 disability and high mortality rates [2,=20 26,=20 27].=20 Although leptomeningeal metastases may occur with virtually any = malignancy,=20 leptomeningeal seeding is most commonly seen in patients with leukemia, = breast=20 cancer, lymphoma, and lung cancer [28].=20 Although leptomeningeal metastasis is relatively rare in patients with = gastric=20 cancer, intracranial metastases in AGC patients usually occur in the = form of=20 leptomeningeal or parenchymal lesions [6,=20 27].=20 Our study shows that there is no significant difference in the survival = rates=20 for patients with leptomeningeal metastases.

Non-small cell lung cancer (NSCLC) and breast cancer = are=20 considered to be chemo-responsive tumors. Although several chemotherapy = regimens=20 have been used to treat brain metastases from AGC, no standard = chemotherapy=20 regimen has been developed. For example, paclitaxel or irinotecan, = cisplatin=20 along with irradiation, and 5-fluorouracic and cisplantin have been used = for=20 brain metastases from AGC [29,=20 30].=20

There was no significant difference in the number of=20 neurological or systemic deaths between the GKR and WBRT groups. We = investigated=20 the local control rate at the 3-month follow-up only because a brain = metastasis=20 from AGC is usually accompanied by cancer cachexia and a dismal survival = outcome.

To our knowledge, no large-scale study on the = prognosis of=20 patients with brain metastases from gastric cancer has been conducted. = One study=20 showed that KPS and the number of metastases were independent prognostic = factors=20 in brain metastases from gastrointestinal tumors in 10 patients (17.5%) = with=20 gastrointestinal tumors [9].=20 They used 50 or 30 Gy in their study, with fractions, but no = significance=20 for overall survival [9].=20

RPA class is one of the most predictive factors for = patients=20 with brain metastases arising from other tumors [14,=20 18,=20 31].=20 We confirmed that those patients with RPA class 2 rather than RPA class = 3 have a=20 better prognosis for brain metastases from AGC.

Our study was limitated by its retrospective design = and small=20 sample size. The patient population was heterogeneous, including both = primary=20 surgery and a non-surgical group. Not all brain metastases were = confirmed by=20 pathologic diagnosis, since some were diagnosed on MRI. In addition, we = used=20 various chemotherapy regimens and frequencies. The two treatments were = not=20 independent rather used in complementary [32,=20 33];=20 however, we could not assess and compare combined treatment such as WBRT = plus=20 GKR or GKR plus WBRT because of the limitation of our cases.

However, our study is valuable despite this = retrospective design=20 and the small number of cases because brain metastasis from AGC is very = rare and=20 large clinical studies have not been reported. Further investigation is = needed=20 in a large-scale study with a prospective controlled design.

Conclusion

We found that GKR treatment and RPA class 2 rather = than class 3=20 are favorable clinical outcomes for patients with brain metastases from = AGC.=20 Age, sex, pathology, leptomeningeal seeding, tumor size = (≥3 cm),=20 extracranial metastases, single metastasis, chemotherapy, and = synchronous=20 metastases were not correlated with a good prognosis in either = univariate or=20 multivariate analysis.

Despite its retrospective design and the small number = of cases,=20 our study is meaningful because brain metastasis from AGC is very rare = and large=20 clinical studies have not been reported. Further investigation is = required in a=20 large scale study with a prospective controlled design. Even though the=20 prognosis was very poor in brain metastases from AGC rather than other=20 metastatic brain tumors, this study highlights the efficacy of GKR for = optimum=20 brain metastases from AGC in RPA 1 or RPA 2.

Acknowledgments The authors thank Mi Kyung Eom (RN), Hana Kang (RN), and = Gi Hong=20 Kim (Radiology technician, BS) for data acquisition and assistance with = this=20 manuscript.

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