TOPIC REVIEW

Brain metastasis from ovarian cancer: a systematic review

Shabnam Pakneshan • Damoun Safarpour •

Fattaneh Tavassoli • Bahman Jabbari

Received: 27 January 2014 / Accepted: 13 April 2014

� Springer Science+Business Media New York 2014

Abstract To review the existing literature on brain metas-

tasis (BM) from ovarian cancer and to assess the frequency,

anatomical, clinical and paraclinical information and factors

associated with prognosis. Ovarian cancer is a rare cause of

brain metastasis with a recently reported increasing preva-

lence. Progressive neurologic disability and poor prognosis is

common. A comprehensive review on this subject has not

been published previously. This systematic literature search

used the Pubmed and Yale library. A total of 66 publications

were found, 57 of which were used representing 591 patients

with BM from ovarian cancer. The median age of the patients

was 54.3 years (range 20-81). A majority of patients (57.3 %)

had multiple brain lesions. The location of the lesion was

cerebellar (30 %), frontal (20 %), parietal (18 %) and occip-

ital (11 %). Extracranial metastasis was present in 49.8 % of

cases involving liver (20.7 %), lung (20.4 %), lymph nodes

(12.6 %), bones (6.6 %) and pelvic organs (4.3 %). The most

common symptoms were weakness (16 %), seizures (11 %),

altered mentality (11 %) visual disturbances (9 %) and diz-

ziness (8 %). The interval from diagnosis of breast cancer to

BM ranged from 0 to 133 months (median 24 months) and

median survival was 8.2 months. Local radiation, surgical

resection, stereotactic radiosurgery and medical therapy were

used. Factors that significantly increased the survival were

younger age at the time of ovarian cancer diagnosis and brain

metastasis diagnosis, lower grade of the primary tumor, higher

KPS score and multimodality treatment for the brain metas-

tases. Ovarian cancer is a rare cause of brain metastasis.

Development of brain metastasis among older patients and

lower KPS score correlate with less favorable prognosis. The

more prolonged survival after using multimodality treatment

for brain metastasis is important due to potential impact on

management of brain metastasis in future.

Keywords Ovarian cancer � Brain metastasis � Survival �Radiation � Chemotherapy � Multimodality treatment �CA-125 � Serouse cystadenocarcinoma

Introduction

Brain metastasis, although a common and severe complica-

tion in lung and breast cancer [1, 2], is considered a rare and

late event in ovarian cancer [2–4]. A variable incidence of

0.3–12 % [5–11] has been reported in different studies as

well as its association with poor prognosis [12]. The reported

incidence of brain metastasis is higher in more recent studies

[3, 4] possibly reflecting advances in imaging and longer

survival from primary ovarian cancer [13–21]. The rarity and

small number of patients affected, have prevented the

establishment of a consensus for optimal therapy [3]. The

increasing incidence of brain metastasis in ovarian cancer,

however, mandates special attention [22] since the treatment

strategy clearly affects the prognosis [22–25].

We conducted a comprehensive review of the existing

literature on this subject in order to create a database to

recognize and compare different patient characteristics,

treatment modalities and prognostic factors that may

impact the ultimate outcome and survival.

Materials and methods

A total of 66 articles published between 1978 and 2013

were reviewed following a Yale web based search of

S. Pakneshan (&) � D. Safarpour � F. Tavassoli � B. Jabbari

Department of Neurology, Yale University School of Medicine,

15 York Street, LCI Building, New Haven, CT 06520, USA

e-mail: sh.pakneshan@yahoo.com

123

J Neurooncol

DOI 10.1007/s11060-014-1447-9

Medline, PubMed, Ovid and other medical databases. Nine

manuscripts were excluded because either they did not

separate ovarian malignancy from other gynecologic can-

cers or they did not separate brain metastasis from metas-

tasis to other sites. The remaining 57 articles provided a

total of 591 patients with brain metastasis from ovarian

neoplasm. Of these, five were from a single prospective

study [24, 26] and the rest were retrospective observations.

Among retrospective cases, 62 were from 28 articles

reflecting a single case or small case series, 524 were from

37 manuscripts of larger and mixed case series with little

detail of individual cases.

Data from all the 57 studies regarding patient characteris-

tics, initial approach to ovarian cancer management, interval

between primary diagnosis to brain metastasis, treatment

modalities, signs, symptoms and location of brain metastases,

different serum markers of the tumor and tumor cell receptors

as well as survival outcomes were reviewed and compared.

The mean time interval between primary ovarian cancer

diagnosis and brain metastasis, and the survival time after the

appearance of brain metastasis were compared in different

groups using student T test. P value was calculated.

Results

The reported incidence of brain metastases among these

studies varies from 0.49 to 11.54 % with an average of

2.55 % (Table 1). The median age of patients at the time of

primary ovarian malignancy diagnosis was 52 years (range

13–92) and at the time of brain metastasis was 54.3 years

(range 20–81). The median time interval between initial

ovarian malignancy diagnosis and development of brain

metastasis was 24 months (0–133). In three cases, the brain

metastasis was found before the diagnosis of ovarian

cancer.

A majority of patients with brain metastasis had

advanced stage ovarian cancer-using The International

Federation of Gynecology and Obstetrics (FIGO) staging

system (83 % FIGO stage III/IV vs. 17 % FIGO stage I/II).

Serous cyst-adenocarcinoma was the predominant histo-

logic subtype (54.5 %). The histologic grade of the primary

ovarian tumor was reported in 26 studies for 436 patients

with brain metastasis, the majority of patients who devel-

oped brain metastasis had high grade initial tumors (14.2 %

G1, 17 % G2, 66.5 % G3, 2.3 % unreported grade),the

presence of higher grade primary ovarian tumor signifi-

cantly increased the likelihood of brain metastasis (P value

\0.0001). Presence of regional lymph node involvement at

the time of initial diagnosis of ovarian cancer, mentioned in

17 studies for 68 cases was 73.8 %. A majority of patients

had multiple brain lesions (57.3 %). Among 582 patients

with brain metastasis, extra-cranial metastasis was present

in 292 cases (49.8 %), extra cranial lesions were noted in

the liver (20.7 %), lung (20.4 %), lymph nodes (12.6 %),

bone (6.6 %) and pelvic organs (4.3 %). The most common

Table 1 Incidence of brain

metastasis in different studiesAuthor Published in Years included OVC cases BM cases Incidence

Sekine et al. 2013 1983–2007 340 7 2.1

Matsuo et al. 2011 1995–2009 302 5 1.66

Sehouli et al. 2010 1981–2008 4,077 74 1.82

Ratner et al. 2009 1983–2007 2,097 23 1.1

Chen et al. 2009 2000–2007 539 10 1.86

Yang et al. 2008 1986–2007 1,055 7 0.66

KIM et al. 2007 1996–2005 490 13 2.65

Gadducci et al. 2007 1995–2005 195 12 6.15

Kastritis et al. 2006 1995–2004 150 8 5.33

Tay et al. 2005 1993–2003 605 4 0.66

Cohen et al. 2004 1975–2001 8,225 72 0.88

Kumar et al. 2003 1991–2001 658 18 2.74

Anupol et al. 2002 1986–2000 1,042 15 1.44

Kolomainen et al. 2002 1980–2000 3,690 18 0.49

Sanderson et al. 2001 1995–2000 1,222 13 1.06

Geisler et al. 1995 1979–1992 479 16 3.34

Bruzzone et al. 1993 1981–1989 413 9 2.18

Rodriguez et al. 1992 1977–1990 795 15 1.89

Hardy et al. 1989 1981–1984 52 6 11.54

Barker et al. 1981 1969–1979 430 4 0.93

J Neurooncol

123

symptoms in patients with brain metastasis were: sensory

and motor disturbances, ataxia, seizure and alteration of

consciousness (Fig. 1). Among anatomic sites, cerebellum

was the most common site of intracranial cerebral metas-

tasis (Fig. 2).

In three patients, brain metastases were diagnosed prior

to the discovery of the ovarian cancer. They were 36, 39

and 56 years of age. Two of the three women had endo-

metrioid carcinoma and the third one had undifferentiated

carcinoma. Two of these three patients did not have any

pelvic lymph node involvement.

The CA-125 measurement at the time of initial diagnosis

of ovarian cancer was mentioned in 17 studies for 52

patients; it was positive in 78.8 %. In 82 patients with brain

metastasis, CA-125 measurement was available, and was

positive in 58.5 %. The quantitative CA-125 analysis was

available in 12 patients with brain metastasis. The median

value was 107 and the average was 170.67 (range: 4–4,428,

normal values \35). Other markers including CA 72-4,

LDH, EMA, Chromogranin, CD-56, pan-CK along with

serum levels of HCG, and AFP have been rarely reported.

A documented BRCA gene mutation status was only

reported in 4 studies, with 5 of 15 patients showing

mutation. The Karnowsky performance score was reported

in 10 studies for 217 patients, 107 of whom had scores\70

and 111 cases had [70.

The reported treatment options for primary ovarian

cancer consist of: surgery (51.6 %), chemotherapy

(28.8 %) and combination of chemotherapy and surgery

(16.6 %). Of 218 patients in whom type of surgery was

described, 39.9 % had optimal (\1 cm residual tumor)

cytoreduction and 60.1 % had suboptimal cytoreduction

([1 cm residual tumor). Second look surgery status was

reported for 193 patients with 22.3 % positive, 39.9 %

negative and 37.8 % not performed. Response to treatment

of primary malignancy was mentioned in 148 patients

(66.9 % complete and 33.1 % incomplete).

Treatment options for brain metastasis included whole

brain radiotherapy(WBRT: 30 %), WBRT and surgery

(15.4 %), WBRT and chemotherapy (13 %), all three

modalities (11.1 %), systemic chemotherapy (9.1 %),

steroids (6.5 %), palliative care or no treatment (6.5 %),

surgery (5.3 %), intrathecal (IT) chemotherapy (0.5 %),

surgery and chemotherapy (1.9 %) and WBRT and IT

chemotherapy (0.4 %).

Patients with primary serous cystadenocarcinoma had

significantly longer interval between the primary diagnosis

and development of metastasis (25.6 vs. 18.6 months,

P value = 0.031) compared to other subtypes. Patients

who had extra cranial metastasis at the time of initial

diagnosis of ovarian cancer had a shorter time interval

between diagnosis of ovarian cancer and brain metas-

tasis (24.6 vs. 61.7 months, P value = 0.040). Different

treatment options for primary ovarian cancer did not sig-

nificantly impact this interval. Patients age at the time of

diagnosis of ovarian cancer, positive or negative CA-125 did

not influence the time interval between primary ovarian

cancer and diagnosis of brain metastasis significantly either.

The median survival of patients after confirmation of

brain metastasis was 8.2 months (average of 16 months).

A total of 26 studies compared the presence of multiple brain

lesions with solitary metastasis. The average survival was

9.2 months for multiple lesions compared to 21.4 months

for single lesions (P value = 0.17). Patients who were

\50 years of age at the time of diagnosis of the primary

ovarian cancer, had a better survival than older patients

(38.9 months vs. 13 months respectively, P value = 0.002).

Likewise, in patients with brain metastasis, survival was

Fig. 1 Signs and symptoms of brain lesion in patients with brain

metastasis from ovarian cancer Miscellaneous symptoms include:

Memory loss, Personality changes, Jerky movements of extremities,

Neuropathy, Cerebrovascular accidents and etc

Fig. 2 Location of brain metastasis in patients with primary ovarian

cancer Miscellaneous locations include: Basal ganglia, cerebral

aqueducts and suprasellar regions

J Neurooncol

123

longer for these younger patients (30.6 vs. 8.1 months, P

value = 0.01). A Karnowsky performance scale (KPS) of

[70 increased survival rates compared to lower KPS

(28 months vs. 11.7 respectively. P value = 0.031). Com-

bination of surgery, WBRT and chemotherapy was associ-

ated with longer survival compared to WBRT alone

(20.5 months vs. 9.1 months, P value = 0.04); palliative

therapy alone, compared to the combination of surgery,

chemotherapy and WBRT significantly reduces the survival

rate (9.6 months, P value = 0.045).

The type of ovarian cancer, presence or absence of extra

cranial metastasis, and positive or higher positive levels

of CA-125 did not correlate with survival after brain

metastasis.

Discussion

The reported incidence for brain metastasis from ovarian

cancer ranges widely from less than 1–12 % (Table 1). The

average figure of 2.55 % found in our literature review is

consistent with the most recent post mortem review with

the incidence of 2.1 % (7 out of 340 cases) [12]. However,

since most reports are from clinical studies and very few

postmortem studies have been performed, it is possible that

the actual incidence of brain metastasis from ovarian

cancer is higher since brain imaging is not a routine

component of follow up for patients with ovarian cancer to

detect asymptomatic lesions.

From an anatomical point of view, this review found

cerebellum to be the most common site of intracranial

metastasis for ovarian cancer (Fig. 1). This may be due to

the rich blood supply of the cerebellum. Rostami et al. [27]

reported a similar observation for brain metastasis from

breast cancer.

From a histological standpoint, high grade primary

ovarian cancer (G3) as well as advanced stage at presen-

tation of the primary malignancy at the time of diagnosis

significantly increases the likelihood of development of

brain metastasis (P value\0.0001). The finding that serous

cystadenocarcinoma (SCAC) is associated with longer

interval (Table 1) is surprising since many CACs reflect a

high grade, aggressive form of ovarian carcinoma. Possibly

most cases of the studied cohorts were of low grade SCAC

variant. It is also worth mentioning that none of the three

patients in whom brain metastases preceded detection of

the ovarian cancer, had serous cystadenocarcinoma.

Factors that correlated with better survival after devel-

opment of cerebral metastasis were young age both at the

time of initial diagnosis and at the time of brain metasta-

sis detection (30.6 months for age \50 vs. 8.1 for [50,

P value = 0.002), and a high KPS score. Correlation with

high KPS scores is in agreement with previous observations

(6, 22, 25, and 26). The type of ovarian pathology, grade and

stage of tumor, interval between diagnosis of ovarian cancer

and diagnosis of brain metastasis, high CA-125 titers (ini-

tially or later) and concurrent presence of motor or sensory

symptoms did not correlate with prognosis. Presence of

extracranial metastasis, although significantly influencing

the interval between ovarian cancer and brain metastasis, is

not a predictor of survival after central nervous system

involvement. The presence of multiple brain lesions showed

a considerably reduced survival (9.2 months for multiple

lesions vs. 21.4 months for single lesions), however, the

statistical analysis failed to reveal a significant difference,

possibly due to the small sample size. The impact of initial

pelvic lymph node involvement on interval to brain metas-

tasis and overall survival was not evaluated due to the few

number of studies in which, the detailed information about

lymph node involvement and survival of the patients were

included (Table 3).

Previous studies have shown inconsistent results regard-

ing the impact of extra cranial metastasis on outcome;

association with lower survival (after detection of brain

metastasis) was suggested by Cormio et al. [23] and Anupol

et al. [25], while Sehouli et al. [26], like us, did not find such

Table 2 Different factors involved in the time interval between

primary ovarian cancer and appearance of brain metastasis

Factor OVC to BM

time interval

P value

Age at BM diagnosis

\50 49.6 0.139

[50 23.4

Primary pathology

SCAC 25.6 0.031

Others 18.6

LN involvement

Positive 20.3 0.462

Negative 14.3

Number of brain lesions

Multiple lesions 23.13 0.352

Single lesions 47

CA 125 status

Positive 6.8 0.594

Negative 23.3

CA 125 level

\100 15 0.997

[101 28.6

Extracranial metastasis

Present 61.7 0.04

Absent 24.5

BM breast metastasis, SCAC serous cystadenocarcinoma, LN lymph

node

Statistically significant difference considered as P value \ 0.05

J Neurooncol

123

association. This may be due to the smaller size of the pop-

ulation studied in the former studies. Cormio et al. [28] also

reported longer interval between diagnosis of brain metas-

tasis and death in patients with longer interval between the

diagnosis of the primary ovarian cancer and the subsequent

brain metastasis (Table 2). Our review which encompasses

the literature to date and a similar study by Pietzner et al. [2]

found no such correlation.

Brain metastasis from ovarian cancer was treated differ-

ently by different groups using a range of palliative and no

treatment to multi modal treatment strategy using surgery,

radiation and chemotherapy [15–18, 23, 25]. Among dif-

ferent therapeutic choices, combination of surgery, radiation

and chemotherapy produced a more effective response and

was associated with better survival (Table 3). The relation-

ship between KPS score, and treatment options and survival

is of practical value and can be used effectively in tailoring

the management plan for patients with brain metastasis from

ovarian cancer based on their performance status.

In conclusion, brain metastasis is an uncommon com-

plication of ovarian cancer but its true incidence is not well

established. Cerebellum was the most common site of

cerebral metastasis from ovarian cancer. Absence of distant

metastasis at the time of diagnosis of ovarian cancer cor-

relate with delayed manifestation of brain metastasis.

Survival following the detection of brain metastasis is

influenced by patients’ age, absence of multiple metastasis

and performance status (KPS score), but presence of extra

cranial metastasis, and increased serum CA-125 titers do

not have prognostic significance. Since the therapeutic

options have significant impact on survival after appear-

ance of brain metastasis, it is reasonable to use multi-

modality therapy when feasible, depending on patients’

condition.

At present, neither a standard screening method to

diagnose brain metastasis in ovarian cancer patients, nor a

standardized therapeutic guideline is available. The rarity

of brain metastasis precludes performance of large scale

studies; therefore, establishment of multicenter collabora-

tive studies to configure standard management approaches

is warranted.

Conclusion

Brain metastasis is a rare and fatal outcome of ovarian

cancer that is accompanied by a very poor survival.

However, based on the data presented in this review, there

are factors that are associated with more favorable out-

comes. These factors- patient age, histologic subtype of the

cancer, primary KPS score indicating the performance

status, existing extra cranial metastasis—constitute

important elements that should be considered in selection

of optimal therapy for each patient.

The association between multimodal therapy and

better survival is important information that suggests

more personalized decision making in terms of thera-

peutic choice based on patients’ health status and che-

motherapy side effects versus the overall benefit of this

approach.

The inconclusive data regarding the role of other factors

in the overall disease progression may be due to the paucity

of available data and therefore, the potential role of these

factors (i.e.; multiplicity of metastatic lesions, CA 125

level, primary location of tumor, etc.) on overall disease

progression should be investigated in larger, multicenter

studies in the future.

Conflict of interests The authors have no conflicts of interest to

disclose.

Table 3 Different Prognostic factors involved in survival for patients

with brain metastasis due to ovarian cancer

Factor Survival (months) P value

Age at BM diagnosis

\50 38.9 0.001

[50 13.0

Age when ovarian cancer was diagnosed

Age \50 30.6 0.002

Age [50 8.1

Primary pathology

SCAC 16.7 0.715

Other 14.3

Number of brain lesions

Multiple lesions 9.2

Single lesions 21.4 0.17

CA 125 status

Positive 23.2 0.118

Negative 28.9

CA 125 level

\100 6.7 0.674

[101 1.7

KPS score

\70 11.7 0.031

[70 28

Treatment option

No treatment 10.8 0.045

WBRT ? Chemo ? SX 20.5

BM breast metastasis, SCAC serous cystadenocarcinoma, LN lymph

node

Statistically significant considered as P value \ 0.05

J Neurooncol

123

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