Treatment and Prognosis of Brain Metastases From Gynecological Cancers

Abstract

Brain metastases from gynecological cancers were retrospectively investigated in 18 patients who were treated between 1985 and 2006. Six patients received surgical resection followed by radiotherapy, and 12 patients received only radiotherapy. The median survival for all patients was 4.1 months (range 0.7-48.2 months), and the actuarial survival rates were 11% at both 12 months and 24 months. Univariate analysis showed that treatment modality, extracranial disease status, total radiation dose, number of brain metastases, and Karnofsky performance status (KPS) all had statistically significant impacts on survival. Two patients survived for more than 2 years, and both had single brain metastasis, inactive extracranial disease, 90-100% KPS, and were treated with surgical resection followed by radiotherapy. Improvements in neurological symptoms were observed in 10 of the 12 patients treated with palliative radiotherapy, with median duration of 3.1 months (range 1.5-4.5 months). The prognoses for patients with brain metastases from gynecological cancers were generally poor, although selected patients may survive longer with intensive brain tumor treatment. Palliative radiotherapy was effective in improving the quality of the remaining life for patients with unfavorable prognoses.

Full text

57
Received July 30, 2007; Accepted December 3, 2007
57
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¿
63, 2008
Treatment and Prognosis of Brain Metastases From
Gynecological Cancers
Kazuhiko O
GAWA
, Yoshihiko Y
OSHII
*
,YoichiA
OKI
**
,YutakaN
AGAI
**
,
Yukihiro T
SUCHID A
*
, Takafumi T
OITA
, Yasum as a K
AKINOHANA
,
Wakana T
AMAKI
, Shiro I
RAHA
,GenkiA
DACH I
,MakotoH
IRAKAWA
**
,
Kazuya K
AMIYAMA
**
, Morihiko I
NAMINE
**
,
Akio H
YODO
*
, and Sadayuki M
URAYAMA
Departments of Radiology,
*
Neurosurgery, and
**
Obstetrics and Gynecology,
University of the Ryukyus School of Medicine, Okinawa
Abstract
Brain m etastases from g ynecological cancers were retrospectively investigated in 18 patients who were
treated betwe en 1985 and 2006. Six patients received surgical resection followed by r adiotherapy, and
12 patients received only radiotherapy. The median survival for all patients w as 4.1 mon ths (range
0.7–48.2 months), and the actuarial survival rates were 11% at both 12 months and 24 months. Univari-
ate analysis showed that treatment modality, extracranial disease status, total radiation dose, number
of brain metastases, and Karnofsky performance status (KPS) all had statistically significant impacts
on survival. Two patients survived for more than 2 years, and both had single brain metastasis, inactive
extracranial disease, 90–100% KPS, and were treated with surgical r esection followed by radiotherapy.
Improvements in neurological symptoms were observed in 10 of the 12 patients treated with palliative
radiotherapy, with median duration of 3.1 months (range 1.5–4.5 months). The prognoses for patien ts
with brain metastases from gynecological cancers were generally poor, although selected patients may
survive longer with intensive brain tumor treatment. Palliative radiotherapy was effective in improv-
ing the quality of the remaining life for patients with unfavorable prognoses.
Key words: radiation therapy, brain metastasis, gynecological neoplasm, uterine cervical cancer,
endometrial can cer, ovarian cancer
Introduction
Brain metastases develop in approximately 10–30%
of cancer patients and the pr ogno ses of these
patients have historically been po or. The most co m -
mon primary tumors responsible for brain
metastases are lung, breast, and u nknow n primary
tumors, and melanoma.
41)
In contrast, brain
metastases originating from gynecological malig-
nancies are extremely rare, with the exception of
choriocarcinoma, and the incidence of brain
metastases in clinical series for all gynecological
cancers is approximately 1%.
36,41)
Recently, advances in neuroimaging, such as com-
puted tomo g raphy (CT) and m ag netic resonance
(MR) imaging, have allowed careful monitoring of
cancer patients, which together with the increased
survival of patients, has led to more frequent and
earlier detection of brain metastases. Therefore,
clinical reports of brain m etastases from gynecologi -
cal cancers have i n creased gradually .
19,32)
The present study evaluated o ur experience with
brain metastases from gyneco lo gical cancers to
identify the treatments and factors th at influence the
prognosis of these patients.
Materials and Methods
A retrospective review of the medical records of
2729 patients with gynecological cancer treated at
the University of the Ryukyus Hospital between
1985 and 2006 identified 18 patients (0.7%) with
documented brain metastases from gynecological
cancers. The brain me tastase s were diagnosed by
CT with cont rast medium or, more rec ent ly, CT
and/or MR imaging . Six of the 18 patien ts had histo-

58
Table 1 Incide nces and median survival of patients w ith brain metastases (BM ) from gynecological cance rs
Primary site
Previous repor ts Current study
Reference
No.
Incidences
of BM (%)
Median
survivals
(mos)
Patients with
BM/total
patients
Incidence
of BM (%)
Median survival
(range) (mos)
Ovary 4, 10–19 0.3–2.2 1.3–19.5 7/335 2.1 7.3 (0.9–48 .2)
Uterine cerv ix 20–24 0.4–1.2 3.0–7.8 7/1716 0.4 2.8 (0.7–28 .4)
Uterine corpu s 25–30 0.3–0.9 1.0–5.3 4/556 0.7 4.3 (3.1–4.9)
All sites included
*
31 1.8 7.3 18/2729 0.7 4.1 (0 .7–48.2)
*
Other sites include vagina, vulva, and fallopian tube.
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logical co nf irm ati on o f the diagno si s aft e r under-
going surgical resection of the brain lesion. All
patients underwent prim a ry medica l evaluation in-
cluding detailed history, revie w of symp t oms, and
physical examination before a treatment plan was
formulated, and follow-up information wa s obtained
from the patients' records or from communications
with the patients or their physicians.
Six of the 18 p atients w ere treated with surgical
resection followed by radiotherapy (S
＋
RT group),
and the remaining 12 p atients were treated with
radiothera py (RT gr ou p). Radiotherapy used a 4-MV,
6-MV, or 10-MV linear accelerator to administer dai-
ly frac tions of 2–3 Gy 5 days pe r week . Stereotactic
radiosurgery was not applied. Fifteen patients
received whole brain radiotherapy (WBRT) of 5–50
Gy (median dose 30 Gy), and three patients received
WBRT(40Gyin20fractions)followedbylocalboost
using the appropriate technique (dose range 50–60
Gy). The d oses were 30–60 Gy (median 50 Gy) for the
S
＋
RT group and 5–50 Gy (median 30 G y) for the
RT group. Corticosteroids in individualized doses
were given during radiotherapy. Three p atients th en
received systemic chemotherapy using cisplatin
with or without 5-fluorouracil or a combination of
adriamycin and cyc lo phospham ide.
In this study, statistical analysis examined the fol-
lowing potential prognostic factors affecting sur-
vival: age (
º
65 years or
Æ
65 years), Karnofsky per-
formance status (KPS;
Æ
70% or
º
70%), primary
histology (squam o us cell carcinoma or othe rs), ini-
tial International Feder ation of Gynecolo gy and Ob-
stetrics (FIGO) stage, extracranial diseas e status (ac-
tive or inactive), num ber of b rain m etastases (single
or multiple), greatest dimension of brain metastases
(
º
4cmor
Æ
4 cm), i nterval between diagnosis of
primary tumor and brain metastases (
º
2yearsor
Æ
2 years), treatment modality for brain metastases
(S
＋
RT or RT), total r ad iation dose (
º
50 Gy or
Æ
50
Gy), primary tumor site (ovary or others), and use of
chem othera py (y es or no ). Pat ients were considered
to have no evidence of active extracran ial disease if
there were no m etastases ou tside the brain and the
primary tumor was controlled. The term
controlled
primary tumor
referred to a primary tumor in com-
plete remission after surgical resection, radical
radiotherapy /radio che motherapy, or a combination
of these treatments.
A recur sive partition ing analysis (RPA) of three
Radiation T he rapy Onco logy Group (RTOG) studies
used the following cla ssification: Class 1, patients
with KPS
Æ
70, age
º
65yearswithcontrolledpri-
mary disease and no evidence of ex tra cran ial
metastases; Class 3, patients with KPS
º
70; and
Class 2, all remaining patients who did not fit into
Class 1 or 3.
14)
To ascertain whether this scoring
system is also applicable to patients with brain
metastases from gynecological cancers, our patients
were grouped into these three c lasses for analysis.
All data were updated to December 2006. Overall
survival rate was ca lculated ac cordin g to the
Kaplan-Meier method
18)
and sur vi val was measured
from the date of diagnosis of brain metasta ses until
thedateoflastfollowuporuntildeath.Differences
between g roup s were estimate d using the log-rank
test.
27)
A probability level of 0.05 was chosen for
statistical significance. Statistical analys is was per-
formed using the SPSS software package (version
11.0; SPSS Inc., Chicago, Ill., U.S.A.).
Results
Table 1 indicates the incidence rates of brain
metastases fro m gynecological cancers according to
the primary tumor site. In total, 0.7% of th e patients
with gynecological malignancies treated in our insti-
tutions developed brain metastases. Th e incidence
of brain metastases from ovarian cancer (2.1%) was
higher than those from other primaries (0.4–0.7%).
The patients were aged 38–74 years (median 53

59
Fig. 1 Actuarial overall survival curves for the 18
patients with brain metastases from gyneco-
logical cancers.
Table 2 Univariate an alysis of various potential
prognostic factors for survival in patients
with br ain metastases (BM) from gyneco-
logical cancers
Variable
No. of
patients
Overall
survival
at 1 yr
pValue
Treatment modality
S+RT 6 33 0.0005
RT 12 0
Extracranial disease
active 14 0 0.0011
inactive 4 25
Total radiation dose
º
50 Gy 14 0 0.013
Æ
50 Gy 4 50
No. of BM
single 5 40 0.019
multiple 13 0
KPS
º
70% 10 0 0.021
Æ
70% 8 25
Primary tumor site
ovary 7 14 0.065
others 11 9
Primary tumor histology
squamous cell carcinoma 7 14 0.25
adenocarcinoma 11 9
Age
º
65 yrs 12 17 0.29
Æ
65 yrs 6 0
Use of chemotherapy
yes 3 27 0.40
no 15 7
Initial FIGO stage
stages I–II 11 9 0.42
stages III–IV 7 14
Interval from primary Dx to BM Dx
º
2yrs 12 8 0.60
Æ
2yrs 6 17
Greatest dimension of B M
º
4cm 12 8 0.83
Æ
4cm 6 17
Dx: diagnosis, FIGO: International Federation of Gy-
necology and Obstetrics, KPS: Kar nofsky perfor-
mance status, RT: radiothe rapy, S: surgery.
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Brain Metastases From Gynecological Cancers
years) at the time of initial diagnosis of gyneco logi-
cal cancers. All patients had histologic confirmation
of their primary lesion. Seven patients had squa-
mous cell carcinoma, and 11 had adenocar cinoma.
At the time of initial primary treatment, 11 patients
had clinical FIGO stage I–II tumors, and seven had
stage III–IV tumors.
The patients were aged 42–74 years (median 55
years) at the time brain metastases appeared, and
KPS was 30–100% (median 60%). Th e signs and
symptoms were headache in eight patients, motor
weakness in seven, seizu res in two, and cerebellar
dysfunction, disorientation, speech disturbance, and
diplopia in one each. All patients underwe nt chest
radiography, chest CT, and abdominal CT. Sixteen
of the 18 patients underwent radionucleotid e b one
scintigraphy. Extracranial disease status was acti ve
in 14 patients; three had recurrent extracranial
metastases, and 11 had both uncontrolled primary
tumor and extracranial m e tastase s . The interval be -
tween the diagnoses of prima ry tumor a nd appear-
ance of brain metastases was 0– 78 mo n ths (m edian
16 months). Five patients had single brain metasta-
sis, a nd six had brain metastases with largest dimen-
sion
Æ
4cm.
The median survival was 4.1 months (range
0.7–48.2 months). The actuarial overall survival
rates were 11% at both 12 m o nths and 24 m onths
(Fig. 1). The median survival was 9.3 months (range
4.9–48.2 m onths) for patients in the S
＋
RT group
and 2.9 months (range 0.7–6.2 months) for patients
in the RT group. Univariate analysis showed that
treatme nt modality, KP S, e xtr acranial disease sta -
tus, number of brain metastase s, a nd total radiation
dose a ll had statistically significant imp acts on sur-
vival (Table 2). No significant differences in survival
were seen with respect to other factors.
Two patients survived for more than 2 years. Both
patients had single b rain m etastasis, inactive ex-
tracranial disease, 90–100% KPS, and were treated
with S
＋
RT.Nolatecomplications,suchasmental
deterioration, were observed during follow up in
either patient. O ne patient died of recu rrent brain
metastasis after 48.2 m onths, a nd the other patient
died of recurrent extracranial metastasis after 28.4
months.

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The median survival was 22.4 months for the three
patients in RPA class I, 4.9 m onths for the six
patients in RPA class II, and 2 .8 mo nths for the nine
patients in RPA c lass III. There were statistically sig-
nificant di f ferences in su rvival betw een these
groups (p
＝
0.001).
Ten of the 12 patients treated with palliative
radiotherapy showed impr ove ments in neurolog ical
symptoms, including headache, motor weakness,
seizures, and cerebellar dysfun ction, with duration
of 1.5–4.5 months (median 3.1 months). Six of these
12 pa tients died of brain metastases accom pa nied by
deterioration of neurological symptoms, and the
other six patients died of pneum o nia without de-
terioration of neurological symptoms.
Di scussion
In the current study, 0.7% of the patients with gy-
necological cancers treated in our institutions de v el-
oped brain metastases. The incidence of brain
metastases from ovarian cancer (2.1%) was higher
than those from other primaries ( 0.4–0.7%). This is
consistent with o the r studies with the reported rates
of 0.3–2.2% for ovarian cancer and 0.6–0.9% for
other cancers.
1,6–13,16,17,19–21,23–26,31,34,35,37,38)
Clearly,
brain metastases from gynecological malignancies
are rar e, but r ecent re p orts suggest an increa sing in-
cidence of brain metastases, especially in patients
with ovarian cancer.
19,32)
Theuseofeffectivecombi-
nation chemotherapy, espe cially reg imens c ontain-
ing cispl atin for ovarian cance r, may increase sur-
vival, pr oviding tim e for occult brain metastases to
become overt. Another explanation for the possible
increase in brain metastases is the availability of bet-
ter imaging tech niqu es for diagnosis.
32)
Further
studies ar e required to monitor whether incidence
rates among these pa tients will continue to increase
in the future.
The p rimary mechanism of spread to the brain is
dissemination to the lungs, then to the brain v ia the
pulmonary vasculature.
41)
Brain metastases from g y -
necological ca ncers are usually f ound in associat ion
with widely disseminated d isease.
1,19,29,31)
Our study
found that 14 of 18 patients had active extracranial
diseases at diagnosis of brain me tastase s. These
results indicate that patients wit h brain metastases
usually have disseminated systemic diseases at the
time of clinical appearance of brain metastases.
Brain metastases are a m a jor detrimental event in
the n atur al history of most malignancies. In th e
majority of patients, the treatment of brain meta-
stases is a pa lliative measure, because the primary
disease is often advanced, and the general condition
of these p atients of t en is poor . Despite numerous
studies designed to improve treatment outcome, the
median survival is only 3–6 months.
4,33,41)
In the
present study, the m e dian survival was 4.1 m o nths,
and actuarial survival was 11% at b oth 12 months
and 24 months. Therefore, our results also indicated
that the prognoses of patients with brain metastases
from gy necological cancers were g enerally poor,
like those from non-gynecological sites.
Achieving local tumor control in the brain is now
known to improve the survival of selected p atients.
Two random ized trials that excluded p atients with
multiple brain metastases showed that surgical
resection plus r adi otherapy was signi fica n tly better
than only radio ther a py .
30,39)
Stereotac tic radiosur -
gery also provided local control equivalent to sur-
gery and facilitated the treatmen t of patients with
surgic al ly inaccessible or m ul tiple lesio ns.
2,5)
In our
study, both p atients wh o survived for more than 2
years were treated with S
＋
RT. Both patients had
inactiv e extracranial disease, and also had KPS of
90–100%. The median survival for the three patients
in RPA class I (all treated with S
＋
RT) was 22.4
months, which wa s compara ble with the 14.8
months in the previous S
＋
RT study.
3)
The median
survival of 4.9 months for the six patients in RPA
class II (2 treated with S
＋
RT) and that of 2.8
months for the nine patients in class III (1 treated
with S
＋
RT) were comparable with the 3.8–4.2
months and 2.3 m onths, respectively, in the previous
studies.
14,15)
Brain metastases from o v ar ian cancer
are responsive to chemotherapy.
28,40)
Therefore,
multimodal treatments may provide be tter results
in selected patients wh o may profit from effective
local tumor control in the brain, than in all p atients
with brain metastases fr om gyn ecologica l cancers.
The present stud y also indicated that for patients
with unfavorable prognoses, palliati ve radiotherapy
was effective in improving the quality of remaining
life, as in patients with other p rimaries. WBRT is ef-
fectiveforthepalliationofsymptomsresultingfrom
intracranial metastases.
22)
Theresultofthefirsttwo
RTOG metastatic brain studies, which mainly incor-
porated patients with metastatic lung and breast
cancer, su ggested that the administration of W BRT
could improve neurologic function in 50% of
patients, and 70% to 80% of patients spent their
remaining lives in an improved or stable neurologic
state.
4)
Symptomatic response w as obtained in 23 of
32 patients with brain metastases from o varian can-
cer.
11)
All of 15 ovarian cancer patients with brain
metastases who received radiotherapy showed im-
provement in neurological symptoms.
34)
The present
study, which included ovarian cance r, uterine cervi-
cal cancer, and uteri ne corpus cancer, observ ed im-
provements of neurological function in 10 of 18

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Brain Metastases From Gynecological Cancers
patients after t reatm e nt.
The present study indicates tha t th e prognoses for
patients with b rain metastases from gynecological
cancers are generally poor, although selected
patients may survive longer with intensive brain
tumor treatment. Palliative radi otherapy is recom-
mended for patients with unfavorable prognoses.
However, this retrospective study includ ed a rela-
tively small nu m ber of patients, so further studies
are necessary to confirm o ur results.
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Address reprint requests to
: Kazuhiko Ogawa, M.D.,
Department of Radiology , University of the Ryukyus
School of Medicine, 207 Uehara, Nishihara–cho,
Nakagam i–gun, Okinawa 903– 0215, Japan.
e-mail
:kogawa
＠
med.u-ryukyu.ac.jp
Commentary
Inascientificallysound,retrospectivestudyof2729
patients with gynecological cancer, the authors report
on 18 patients who developed brain metastases. This
subgroup had a remarkably poor prognosis (median
survival about 4 months) despite treatment modalities
(i.e., surgical resection and radiation or radiation
alone). In the 2 patients who survived for more than 2
years, both had a single brain metastasis, inactive ex-
tracranial disease, and high Karnofsky performance
scores. The authors noted that palliative radiotherapy
was effective in improving quality of remaining life in
patients with an unfavorable prognosis.
We recommend that the authors and readers con-
sider the use of intraoperative radiation implants in
select patients with single brain metastasis for local
tumor control.
1)
In our experience, w e believe that this
radiation protocol is preferred versus whole brain
radiation therapy for r educing the potential for long-
term radiation induced toxicity. As the authors report
on their experience for a small group of patients with
brain metastases from gynecological cancer, they
recommend further study.
Reference
1) Dagnew E, Kanski J, McDermott MW , Sneed PK,
McPherson C, Breneman JC, Warnick RE: Management
of newly diagnosed single brain metastasis using resec-

6363
Neurol Med Chir
(
Tokyo
)
48, February, 2008
Brain Metastases From Gynecological Cancers
tion and permanent iodine-125 seeds without initial
whole-brain radiotherapy: a two institution experience.
Neurosurg Focus
22 (3): E3, 2007
John M. T
EW
,Jr.,M.D.
Medical Director
TheNeuroscienceInstitute:
University of Cincinnati College o f Medicine
and the Mayfield Clinic
Cincinnati, Ohio, U.S.A.
This paper is a retrospective review from records of
18 cases with brain metastases from gynecological
cancers. The authors demonstrated that treatment
modality, extracranial disease status, total radiation
dose,numberofbrainmetastases,andKPShadsig-
nificant impacts o n survival. These factors have been
shownbothinotherandtheirownmaterialtobesig-
nificant prognostic factors for brain metastasis. These
new data could be helpful for our clinical practice in
the future. However, because brain metastases from
gynecological cancers are very rare, more rando mized
trials are needed in the future.
Ruxiang X
U
,M.D.
Department of Neurosurgery
Neuromedicine Re search Institute
Zhujiang Hospital of Southern Medical University
Guangzhou, P.R.C.