T h e NE W E NGL A ND JOU R NA L o f M E DICINE

ORIGINAL ARTICLE

G
o
s
e
r
el
i
n
f
o
r
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v
a
ri
a
n
P
r
o
te
ct
i
o
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u
ri
n
g
B

reastCancer
Adjuv
ant
Chem
othera
py
Halle C.F. Moore,
M.D., Joseph M.
Unger, Ph.D.,
Kelly-Anne Phillips,
M.D., Frances Boyle,
M.B., B.S., Ph.D.,
Erika Hitre, M.D.,
David Porter, M.D.,
Prudence A. Francis,
M.D., Lori J.
Goldstein, M.D.,
Henry L. Gomez,
M.D., Carlos S.
Vallejos, M.D., Ann
H. Partridge, M.D.,
M.P.H., Shaker R.
Dakhil, M.D., Agustin
A. Garcia, M.D., Julie
Gralow, M.D., Janine
M. Lombard, M.D.,

chemoth
erapy.
Studies
of the
use of
gonadotro
pinreleasin
g
hormon
e
(GnRH)
agonists
to
protect
ovarian
function
have
shown
mixed
results
and lack
data on
pregnan
cy
outcome
s.
METHO
DS

We
randoml
John F. Forbes, M.B., y
assigned
B.S., Silvana
257
Martino, D.O.,
premeno
William E. Barlow,
pausal
Ph.D., Carol J.
women
Fabian, M.D., Lori
with
Minasian, M.D.,
Frank L. Meyskens, operable
Jr., M.D., Richard D. hormone
-recepGelber, Ph.D.,
tor
Gabriel N.
Hortobagyi, M.D.,
negative
and Kathy S. Albain, breast
M.D., for the
cancer to
POEMS/S0230
receive
Investigators
standard
chemoth
erapy
ABS TR
with the
AC T
GnRH
agonist
BACKGROUND
gosereli
Ovarian failure is a n
common toxic effect of (gosereli

n group) orconfidence
interval,
standard
0.09 to 0.97; two-sided
chemotherapy P=0.04). Owing to
missing primary endwithout
point data, sensitivity
goserelin
analyses
were
(chemotherapy-alone performed, and the
group).
Theresults were consistent
primary studywith the main findings.
end point wasMissing data did not
the rate ofdiffer according to
ovarian failuretreatment group or
to
the
at 2 years,accord-ing
with ovarianstratification factors of
and
planned
failure definedage
as the absencechemotherapy regimen.
the
218
of menses inAmong
patients
who
could
be
the preceding
evaluated,
pregnancy
6 months and
in
more
levels
ofoccurred
women
in
the
goserelin
folliclegroup than in the
stimulating
chemotherapy-alone
hormone
(FSH) in thegroup (21% vs. 11%, P
postmenopaus =0.03); women in the
al range. Ratesgoserelin group also
had improved diseasewere
free survival (P=0.04)
compared with
and overall survival (P
the use of
=0.05).
conditional
CONCLUSIONS
logistic
Although missing data
regression.
Second-ary weaken interpretation
the
findings,
end
pointsof
administration
of
included
goserelin
with
pregnancy
outcomes andchemotherapy
disease-free appeared to protect
and
overallagainst ovarian failure,
reducing the risk of
survival.

early menopause and

improving
prospects
At baseline,
for fertility. (Funded by
218 patients
the National Cancer
were eligible
Institute and others;
and could be
POEMS/S0230
evaluated.
ClinicalTrials.gov
Among 135
number,
with complete
NCT00068601.)
primary endpoint data, the
ovarian
failure
rate
was 8% in the
goserelin
group
and
22% in the
chemotherapy
-alone group
(odds ratio,
0.30;
95%
RESULTS

The
authors
affiliations
are listed
in
the
Appendix.
Address
reprint
requests
to
Dr.
Moore at
the
Cleveland
Clinic
Foundation,
Taussig
Cancer
Institute,
R35, 9500
Euclid
Ave.,
Cleveland,
OH 44195,
or
at
mooreh1
@ccf.org.
The
Prevention
of
Early
Menopaus
e
Study
(POEMS)/
S0230 trial
was
performed
in
collaborati
on
by
investigato
rs from the
SWOG
Cancer
Research
Group, the
International
Breast
Cancer
Study
Group, the
ECOG
ACRIN
Cancer

Research Group,N Engl J Med

and the Alliance2015;372:923-32.
for Clinical TrialsDOI:
10.1056/NEJMoa141
in On- cology.
3204

N ENGL J MED

The
New
Engl
and
Jour
nal
of

M
edi
cin
e

Copyright
2015
Massachusett
s Medical
Society.

T h e NE W E NGL A ND JOU R NA L o f M E DICINE

receptor
positive breast
cancer, with the
ARLY
of
OVARIA return
N
menses within
FAILURE
IS
ANthe first year
IMPOR- used as the
tant and
potentiall primary
y
measure
of
devastatin
ovarian
g
longterm toxicfunction.4 The
effect of
chemother use of adjuvant
apy.
Manifesta endocrine
tions
therapy
after
include
chemotherapy
menopausal
complicates the
symptoms,
assessment of
osteoporosis, longer-term
and infertility.ovar-ian
Concerns aboutfunction after
fertility
mayadministration
influence
of a GnRH agotreatment
nist
with
choices
forchemotherapy.
young womenFurthermore,
with
breastdata
on
cancer1,2
pregnancy
despite
theoutcomes after
known survivalGnRH agonist
benefit of ad-treat-ment with
juvant
chemotherapy
chemotherapy. are lacking. It
Trials of thehas even been
coadministratio suggested that
n
of
athis approach
gonadotro-pin- may
impair
releasing
fertility.5
hormone
(GnRH) agonist The
with adju-vant
Prevention of
chemotherapy
Early
for the purpose
Menopause
of
protecting
Study
ovarian function
(POEMS)/S023
have
shown
0
was
an
mixed results.3
international,
A
large
phase
3,
randomized trial
randomized
addressing this
study that was
issue sug-gested
performed
to
that
evaluate
coadministratio
whether
n of a GnRH
administration
agonist
with
chemotherapy of the GnRH
go
had an ovarianagonist
serelin
protective
effect in a cohort(Zoladex,
of patients inAstraZeneca)
which 86% hadwith
chemotherapy
es-trogen-

would reduce
the rate of
ovarian failure
after adju-vant
or neoadjuvant
treatment
of
hormone-receptornegative
early
breast
cancer.
The
study
was
designed
to
compare
the
rate of ovarian
failure at 2
years, the rate
of
ovarian
dysfunction,
and preg-nancy
outcomes
between
patients
receiving chemotherapy with
goserelin and
those receiving
chemotherapy
without
goserelin.

M
ET
H
O
DS
STUDY
OVERSIGHT

The protocol of
the study was
approved by the
institutional
review board at
each
participating
site.
All
patients
provided
written
informed consent
for
participation.
The study was
designed by the
authors
and
monitored by
an independent
data and safety
monitoring
committee. The

SWOG Cancer
Research Groupstudy and the
collection,
(SWOG)
and
coordinated theanalysis,
study and wasreporting of the
The
responsible fordata.
the design of the authors vouch
for the accuracy
and
completeness
of the reported
data and for the
fidelity of the
study to the
protocol, which
is
avail-able
with the full
text of this
article
at
NEJM.org.
PATIENTS

Premenopausal
women 18 to
49 years of age
were
eligible
for enrollment
if they had
operable stage I
to
IIIA
estrogenreceptor (ER)
negative
and
progesteronereceptor (PR)
negative breast
cancer
for
which
treatment with
adjuvant
or
neoadjuvant
cyclophospham
ide-containing
chemotherapy
was planned.
ER and PR
negativity was
defined according
to
the
treating
institutions
standard.
Partici-pants
were enrolled
from SWOG,
the
International
Breast Cancer
Study
Group
(IBCSG), the

ECOG
ACRIN Cancer
Research
Group, and the
Alliance
for
Clinical Trials
in
Oncology.
Eligible participants had taken
no estrogens,
antiestrogens,
selective
estrogenreceptor
modulators,
aromatase
inhibitors,
or
hormonal
contraceptives
within
the
month before
enrollment.
Exceptions
were made for
the
use
of
hormonal
contraception
in
women
younger than
35 years of age
that
was
discontinued
before
randomization
and for hormonal
treatment for up
to 2 months for
the purposes of
in
vitro
fertilization and
cryopreservation
of
embryos
or
oocytes before
randomiza-tion.
Interest
in
future fertility
was not an
eligi-bility
requirement.

STUDY
DESIGN

In this phase 3
trial, patients
were randomly
as-signed, in a
1:1 ratio, to
standard

adjuvant or neo-patients
adjuvant
randomly aschemotherapy signed to the
with the GnRHgoserelin
agonist
group,
goserelin
goserelin at a
(goserelin
dose of 3.6 mg
group) or towas
chemotherapy administered
without
subcutaneously
goserelin
ev-ery 4 weeks
(chemotherapy- beginning
1
alone
group).week before the
The choice ofinitial
the
standardchemotherapy
cyclophosphami dose and was
de-contain-ing continued
to
chemotherapy within 2 weeks
regimen was leftbefore or after
to the discre-the
final
tion
of
thechemotherapy
investigator. Fordose.

Randomization
was stratified
according
to
age (<40 years
vs. 40 to 49
years)
and
chemo-therapy
regimen (3 to 4
cycles [about 3
months] vs. 6 to
8 cycles [about
6 months], and
anthracy-clinebased
vs.
nonanthracyclin
e-based). Use
of trastuzumab
was permitted
in patients with
hu-

useswithout
TheNewEnglandJournalofMedicine
permission.
924Downloadedfromnejm.orgonCopyright
March27, 2015
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2015.For Massachusetts
MED 372;10
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NEJM.ORG
Society.All
only.Noother
MARCH 5,
2015
rightsreserved.

GOSERELIN FOR OVARIAN PROTECTION DURING CHEMOTHERAPY

estimated that with Owing to missing

this sample size, endman epidermal growththe study, based on
factor
receptor
2a
two-group
(HER2) overexpressingbinomial de-sign,
tumors.
would have more
The primary objectivethan 80% power to
was to compare the rate ofdetect an absolute
ovarian failure between thereduction of 15
two treatment groups.percentage points
Ovarian
failure
wasin the rate of
defined as amenor-rhea forovarian
failure,
the preceding 6 monthsassuming rates of
and
follicle-stimulatingovarian failure in
hormone (FSH) levels inthe chemotherapythe post-menopausal rangealone group in the
at 2 years. Patients whorange of 20 to 95%
became pregnant wereand an expected
considered not to have hadmor-tality by year 2
ovarian failure. Patientsof 10%, at a onewho
underwentsided significance
hysterectomy or bilaterallevel of 0.025. The
oophorectomy
werestudy closed early
categorized as unable to beowing to loss of
evaluated. Additional endfunding for studypoints included pregnancydrug distribution.
within 5 years, assessedPost hoc power
annually, and ovariancalculations
that
dysfunction, defined aswere based on
amenorrhea
for
theactual enrollment
preceding 3 months andindicated that the
FSH, estradiol, or inhibinstudy had suffipower
B
levels
in
thecient
postmenopausal
range,(80%) to detect an
assessed at both year 1 and absolute reduc-tion
year 2. Events in theof 20 percentage
analysis of overall survivalpoints in the rate of
failure
included deaths due to anyovar-ian
cause; events in theunder the same
analysis of disease-freedesign
survival also includedspecifications.
primary
breast-cancer recur-rence The
but not contralateral breastanalysis was based
conditional
or
nonbreast
primaryon
cancers. Only adverselogistic regression,
events related to hormonalwith data from all
pa-tients
effects and serious adverseeligible
could
be
events that occurred duringwho
chemotherapy with orevaluated and who
without goserelin werehad com-plete 2routinely assessed, withyear data, stratified
assessment according toaccording to age
the Common Terminologyand
type
of
Criteria
for
Adversechemotherapy
regimen.
An
Events, version 3.0.6
assessment window
STATISTICAL ANALYSIS within 6 months
The
original
targetbefore or after the
enrollment
was
4162-year time point
eligible
patients.
Wewas
allowed.

and 4-year rates

point data, sensitivitywere
estimated.
analyses were performed toHazard ratios, 95%
incorporate
partialconfidence
information.
Theseintervals, and P
included adding death and,values for difseparately, death plusferences in overall
hyster-ectomy
orand
disease-free
oophorectomy as treatmentsurvival
were
failures. In addition, givenderived with the
that amenorrhea and FSHuse
of
levels
are
positivelymultivariable Cox
correlated and that theseregres-sion, with
data were also available at adjustment
for
year 1, we examined thestratification
risk of either amenorrheafactors and cancer
or postmenopausal levelsstage. Pregnancy
of FSH at year 2, as well as and survival rates
at year 1 or 2.
were assessed in all
We analyzed patientpatients who were
characteristics according toeligible and could
randomization group. Tobe evaluated.
assess whether miss-ing According to
data influenced the resultsthe study-design
for the primary analysis,specifications, a
we also evaluated theone-sided
alpha
association
betweenlevel of 0.025 was
treatment and stratificationused to indicate
variables according tostatistical
status with respect tosignificance
for
follow-up data (availabil-the primary endity vs. nonavailability ofpoint analysis of
data for the 2-year endovarian failure; for
point). We analyzed theall other P values,
number of patients report-a two-sided alpha
ing
pregnancy
andlevel of 0.05 was
attempting
pregnancyused to indicate
accord-ing
to
thestatistical
randomization group oversignificance. The
the course of 5 years.cutoff date for all
Finally,
exploratoryanalyses
was
KaplanMeier curves forJanuary 22, 2014.
disease-free and overall
survival were calculated

R
E
S
U
L
T
S
PATIENTS

A total of 257
patients (14 from
CALGB, 86 from
ECOG, 104 from
IBCSG, and 53
from SWOG) underwent
randomization
between February
2004 and May
2011. A total of 24
patients
were
ineli-gible, and 15
were considered
unable
to
be
evalu-ated for the
study end points,
leaving
218
patients who could
be evaluated (113
in the chemotherapy-alone group
and 105 in the
goserelin group)
(Fig. 1).
The
median
follow-up
time
among patients still
alive at the time of
the
end-point
analysis was 4.1
years.
Patient
characteristics
according to

N ENGL J MED 372;10 NEJM.ORG MARCH 5, 2015

ew
of
27,2015.For
Massachusetts
T
Engl
Med
personaluseonly.No MedicalSociety.
h
and
icine
otheruseswithout Allrights
e
Jour
Downloadedfromnejm.org
permission.
reserved.
N
nalonMarch Copyright2015

925

T h e NE W E NGL A ND JOU R NA L o f M E DICINE

257 Patients underwent randomization

e
r
a
p
y

2
131 Were
a
s
s
i
g
n
e
d

H
a
d

b
a
s
e
l
i
n
t e
o
c
h
e
m
o
t
h
e
r
a
p
y
a
l
o
n
e

1
H
a
d

o
r

w
i
t
h

n
o
p
l
a
n
s

i
n
s
u
f
f
i
c
i
e
n
t

f
o
r

t
h

t
e
s
t
s

r
e
p
o
r
t
s

11 Were ineligible
1 Was in incorrect
stage

p
r
o
t
o
c
o
l
p
r
e
s
c
r
i
b
e
d

p
a
t
h
o
l
o
g
i
c
a
l

i
n
f
o
r
m
a
t
i
o
n
4
D
i
d
n
o

t
s
u
b
m
i
t
b
a
s
e
l
i
n
e
p
a
t
h
o
l
o
g
i
c
a
l
t
e
s
t
r
e
s
u
l
t
s
o
r
r
e
p
o
r
t
s

3 Did not
submit
prestudy
forms

120 (92%)
Were eligible

7 Could
not be
evaluated
2
Under
went
hystere
ctomy
5
Withdr
ew
consen
t

44

113
13
(86W
%) e
r
Cou
ld e
be
m
eval
uati
ed s
s
i
n
g
C
o
u
l
d

2
y
r

n
o
t

d
a
t
a

b
e

o
n

e
v
a
l
u
a
t
e
d

F
S
H
l
e
v
e
l
s

f
o
r

a
n
d

o
v
a
r
i
a
n

m
e
n
s
t
r
u
a
l

f
a
i
l
u
r
e
11 Died
3 Were lost to
follow-up
17

W
e
r
e
m
i
s
s
i
n
g
2
y
r
d
a
t
a
o
n
F
S
H
l
e
v
e
l
s

126 Were
a
s
s
i
g
n
e
d
t
o
c
h
e
m
o
t
h
e
r
a
p
y
p
l
u
s
g
o
s
e
r
e
l
i
n

s
t
a
t
u
s

13
Were
ineligi
ble
69
Were
included in
analysis
of
primary end
point of the
rate
of
ovarian
failure at 2 yr

6 Had
baselin
e
patholo
gical
tests or
reports
with
insuffici
ent

informatio
n
2 Did not
submit
baselin
e
pathological
test
results
or
reports
5 Did not
submit
prestudy
forms

113 (90%)
Were
eligible

8
C
o
u
l
d
n
o
t
b
e
e
v
a
l
u
a
t
e
d
3
Un
de
rw
en
t
hy
st
er
ec
to
m
y
1
Un
de
rw
en
t
oo
ph
or
ec
to
m
y
4
6
Wi
th6
dr
W
ew
e
co
r
ns
e
en
t

d
n
o
t
b
e
e
v
a
l
u
a
t
e
d
f
o
r
o
v
a
ri
a
n
f
a
il
u
r
e
3 Died
2 Were
lost to
followup 27
Were
missing
2-yr data
on

FSH levels
7 Were
missing
2-yr
data on
FSH
levels
and
menstr
ual
status

p
r
i
m
a
r
y
e
n
d
p
o
i
n
t
o
f
t
h
e
r
a
t
e
o
f
o
v
a
r
i
a
n

a
t

C
o i
u
n
l

m
ed
study- ia
group n
assignm ag
ent aree
shown of
in Tableth
1. Thee
pa

o
f

f
a
i
l
u
r
e

i
n
105 (83%) Could be c
l
evaluated
u
d
e
39
d

,
Eligibilit
y, and
Figure 1.
Randomization Follow-

a
n
a
l
y
s
i
s

2
y
r

s follicleFSH stimulating
denote hormone.
up.

ti ars. Abased
e total oftherapy
nt 91% of. The
s the
charact
w patient eristics
as s
of the
3 receive patients
8d
were
y anthrac well
e ycline- balance

d
betwee
n the
two
groups.
TOXIC
EFFEC
TS

Two

patients ch
in thee
gosereli m
n groupocould
not be
evaluate
d
for
adverse
events
because
they
received
no
interven
tion,
and data
on toxic
effects
were
never
collecte
d
for
two
patients
in the
926

s who4 toxic
could effects.
th
be
Of the
er
evalua 103
a
ted forpatient
p
advers s who
y
e
could
events be
al
in theevaluat
o
che- ed for
n
mother advers
e
apy- e
g
alone events
r
group, in the
o
6 hadgo
u
grade serelin
p.
3 toxicgroup,
O
ef1 had a
f
fects; grade 4
th
none toxic
e
of theeffect
1
patient (throm
1
s
in1
the
boemb
p
group olism)
at
had and 6
ie
grade had
nt

TheNewEnglandJournalofMedicine
N ENGL
J MED Downloadedfrom
372;10
NEJM.O
RG

MARC
H 5,
2015

grade 3
toxic
effects.
Thus,
5% of
the
patient
s in the
chemot
herapy
-alone
group
and
7% in
the
goserel
in
group
had
grade 3
or
higher
toxic
effects
(P=
0.89),
and
15
Massach
usetts
Medical
Society.
Allrights
reserved.

GOSERELIN FOR OVARIAN PROTECTION DURING CHEMOTHERAPY

Table 1. Baseline Characteristics of the Patients, According to Study Group.*

Characteristic

Age
Median (range)
<40 yr no. (%)
40 yr no. (%)
Race or ethnic group no./total no.
(%)
White
Black
Asian
Native American
Unknown
Hispanic or non-Hispanic ethnic group
no./total no. (%)
Hispanic
Non-Hispanic
Unknown
Planned chemotherapy no. (%)
34 cycles of anthracycline-based
therapy
34 cycles of nonanthracyclinebased therapy
68 cycles of anthracycline-based
therapy
68 cycles of nonanthracyclinebased therapy
Stage of cancer no. (%)
I
II
IIIA
Unknown
HER2 status no./total no. (%)
Positive
Negative
Unknown

All Eligible Patients

Patients with 2-Yr Data on Ovarian Failure

Overall
(N=218)

Chemotherapy
Alone
(N=113)

Chemotherapy
plus Goserelin
(N=105)

Overall
(N=135)

Chemotherapy
Alone
(N=69)

Chemotherapy
plus Goserelin
(N=66)

37.7
(25.149.9)
138 (63)
80 (37)

38.7
(25.149.9)
70 (62)
43 (38)

37.6
(26.148.6)
68 (65)
37 (35)

36.9
(25.149.9)
94 (70)
41 (30)

37.5
(25.149.9)
45 (65)
24 (35)

36.1
(26.148.6)
49 (74)
17 (26)

122/136(90)
11/136(8)
2/136(1)
1/136(1)
82/218(38)

57/66 (86)
6/66 (9)
2/66 (3)
1/66 (2)
47/113 (42)

65/70 (93)
5/70 (7)
0
0
35/105 (33)

69/79 (87)
7/79 (9)
2/79 (3)
1/79 (1)
56/135 (41)

33/39 (85)
3/39 (8)
2/39 (5)
1/39 (3)
30/69 (43)

36/40 (90)
4/40 (10)
0
0
26/66 (39)

67/126(53)
59/126(47)
92/218(42)

26/60 (43)
34/60 (57)
53/113 (47)

33/66 (50)
33/66 (50)
39/105 (37)

39/71 (55)
32/71 (45)
64/135 (47)

18/35 (51)
17/35 (49)
34/69 (49)

14/36 (39)
22/36 (61)
30/66 (45)

46(21)

22 (19)

24 (23)

27 (20)

15 (22)

12 (18)

12(6)

7 (6)

5 (5)

8 (6)

5 (7)

3 (5)

152(70)

80 (71)

72 (69)

96 (71)

47 (68)

49 (74)

8(4)

4 (4)

4 (4)

4 (3)

2 (3)

2 (3)

55(25)
107(49)
54(25)
2(1)

32 (28)
52 (46)
29 (26)
0

23 (22)
55 (52)
25 (24)
2 (2)

34 (25)
70 (52)
31 (23)
0

18 (26)
34 (49)
17 (25)
0

16 (24)
36 (55)
14 (21)
0

32/215(15)
183/215(85)
3/218(1)

19/112 (17)
93/112 (83)
1/113 (1)

13/103 (13)
90/103 (87)
2/105 (2)

23/132 (17)
109/132 (83)
3/135 (2)

11/68 (16)
57/68 (84)
1/69 (1)

12/64 (19)
52/64 (81)
2/66 (3)

1*

Among patients with 2-year end-point data, there were no significant differences between the groups in any of the
characteristics listed in this table. Percentages may not sum to 100% for a given characteristic owing to rounding. HER2 denotes
human epidermal growth factor receptor 2.

Data on race and ethnic group were self-reported or were reported by the investigator. Data on race and ethnic group
were not collected at many of the sites outside the United States; for patients at those sites, data were recorded as unknown.

the 83 patients for whom

data were unavailable, 14
24% and 48%, respectively, had grade 2 or higher toxic effects
(17%) died within the 2(P<0.001) (Table 2).
year time window and 5
(6%) were lost to followOVARIAN FAILURE
Data on both menstrual status and FSH levels at 2 years, which up. The remaining 64
patients lacked data on
together composed the end point of ovarian failure, were
FSH levels, with 20 of
available for 135 of the 218 patients who could be evaluated
those
also
missing
(62%). Among
menstrual data (Fig. 1).

There was no evidence that

missing data changed the
main findings of the study:
69 of 113 patients (61%) in
the
chemotherapy-alone
group and 66 of 105 (63%)

N ENGL J MED 372;10 NEJM.ORG MARCH 5, 2015

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T h e NE W E NGL A ND JOU R NA L o f M E DICINE

Table 2. Grade 2 or Higher Toxic Effects.*

Adverse Event

Chemotherapy Alone (N=111)

Grade 2

Chemotherapy plus Goserelin (N=103)

Grade 3

Grade 4

Grade 2

Grade 3

Grade 4

Diarrhea

Fatigue

Hot flashes

14

29

Irregular menses

Decrease in libido

Agitation

Anxiety

Depression

Joint pain

Muscle pain

Headache

12

Sweating

10

Thromboembolism

Vaginal dryness

12

1*

Included are grade 2 or higher toxic effects that were reported in more than 1% of the patients in
either study group. Patients may have had more than one toxic event for a given grade.

ed as treatment failure
in the goserelin group had complete primary (odds ratio, 0.29; 95%
end-point data, and the association betweenCI, 0.16 to 0.75; P=
treat-ment and stratification variables (age and 0.007). Similarly, a
che-motherapy category) did not differbenefit with goserelin
significantly according to whether patients hadwas observed when
missing data for the primary end point.
treatment failure was
A total of 15 of 69 patients (22%) in the defined as amenorrhea
chemotherapy-alone group and 5 of 66 patientsor postmenopausal FSH
(8%) in the goserelin group had protocol-defined levels at year 2 (odds
ovarian failure. In the protocol-specified strati-fiedratio, 0.29; 95% CI, 0.12
logistic-regression analysis, this difference wasto 0.70; P=0.006) and
significant (odds ratio, 0.30; 95% confidence when treatment failure
interval [CI], 0.09 to 0.97; one-sided P=0.02, was
defined
as
two-sided P=0.04). The results were similar in the amenorrhea
or
univariate regression analysis (odds ratio, 0.30; postmenopausal
FSH
95% CI, 0.10 to 0.87; one-sided P =0.01, two- levels at year 1 or 2
sided P=0.03) and the multivariate regression(with inclusion of year 1
analysis (odds ratio, 0.36; 95% CI, 0.11 to 1.14; data if year 2 data were
one-sided P=0.04, two-sided P=0.08).
missing) (odds ratio,
Secondary and sensitivity analyses related to 0.43; 95% CI, 0.22 to
the primary end point showed consistent results 0.85; P=0.01).
(additional details are provided in the Supplementary Appendix, available at NEJM.org). A benefit OVARIAN
with goserelin therapy was observed when deathsDYSFUNCTION
were included as treatment failure (odds ratio,Ovarian dysfunction was
0.25; 95% CI, 0.11 to 0.60; P=0.002) and when evaluated at years 1 and
deaths plus hysterectomy or oophorectomy were2. Included in the
analyses were patients
countwith both menstrualNEJM.ORG

MARCH 5, 2015

928

N ENGL J MED 372;10

status data and at least

two
avail-able
laboratory values (i.e.,
two or more measurements
of
FSH,
inhibin B, or estradiol
levels). At year 1, data
were available for 153
patients (70%). Ovarian
dysfunction was present
in 28 of 75 patients
(37%)
in
the
chemotherapy-alone
group and in 18 of 78
patients (23%) in the
goserelin group (odds
ratio, 0.64; 95% CI, 0.30
to 1.37; P=0.25). At
year 2, data were
available for 130 patients (60%). Ovarian
dysfunction was present
in 22 of 67 patients
(33%)
in
the
chemotherapy-alone
group and in 9 of 63
(14%) in the goserelin
group (odds ratio, 0.35;
95% CI, 0.13 to 0.93; P
=0.03).

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GOSERELIN FOR OVARIAN PROTECTION DURING CHEMOTHERAPY

Table 3. Pregnancy Outcomes.

Outcome

Chemotherapy
Alone
(N=113)

Chemotherapy
plus Goserelin
(N=105)

Odds Ratio
with
Goserelin

P Value*

Attempted pregnancy no. of patients (%)

18 (16)

25 (24)

1.78

0.12

Achieved pregnancy no. of patients (%)

12 (11)

22 (21)

2.45

0.03

1 delivery no. of patients (%)

8 (7)

16 (15)

2.51

0.05

Delivery or ongoing pregnancy no. of patients (%)

10 (9)

19 (18)

2.45

0.04

Babies born no.

12

18

Miscarriage

Elective termination

Delivery complication

Ongoing pregnancies at last report no.

Adverse pregnancy event no. of events

1*

P values were adjusted for the stratification factors of age and type of planned chemotherapy. The
cutoff date for data analysis was January 22, 2014; data up to that date are included.
This category may include more than one baby born to a woman.

the goserelin group had a

PREGNANCY OUTCOMES
recurrence of disease or
Among the 218 patients who could be evaluated, 34died.
The
4-year
(16%) had at least one pregnancy: 12 of 113 (11%) KaplanMeier estimate
in the chemotherapy-alone group and 22 of 105 of the rate of disease(21%) in the goserelin group (odds ratio, 2.45; 95%free survival was 78% in
CI, 1.09 to 5.51; P=0.03). Women who became the che-motherapy-alone
pregnant were younger than those who did not group and 89% in the
(median age, 32.9 years vs. 39.6 years; P<0.001) goserelin
group
but were similar with respect to planned(adjusted hazard ratio,
chemotherapy regimen. The analysis of the cumu- 0.49; 95% CI, 0.24 to
lative incidence of pregnancy at 5 years is shown in 0.97; P=0.04) (Fig. 2A).
the Supplementary Appendix. A total of 18 pa-tients A total of 17 patients in
in the chemotherapy-alone group (16%) and 25 inthe chemotherapy-alone
the goserelin group (24%) reported attempt-inggroup and 8 in the
pregnancy (odds ratio, 1.78; 95% CI, 0.85 to 3.72; goserelin group died.
P=0.12). The number of reported miscar-riages, The 4-year Kaplan
elective terminations, and pregnancy com-plicationsMeier estimate of the
were similar in the two groups. More patients in the rate of overall survival
goserelin group than in the che-motherapy-alonewas
82%
in
the
group successfully delivered 1 or more babies (P = chemotherapy-alone
0.05). A total of 12 babies were born to women in group and 92% in the
the chemotherapy-alone group and 18 were born to goserelin
group
women in the goserelin group. At the time of data(adjusted hazard ratio,
submission, there were an additional 3 ongoing 0.43; 95% CI, 0.18 to
pregnancies reported in the chemotherapy-alone1.00; P=0.05) (Fig.2B).
group and 5 ongoing pregnancies in the goserelinAmong all 257 patients
group (Table 3).
who
underwent
randomization, the trend
DISEASE-FREE AND OVERALL SURVIVAL
toward a higher rate of
Among the 218 patients who could be evaluated, disease-free
survival
24 in the chemotherapy-alone group and 12 in with goserelin was not
significant
(haz-ard
ratio, 0.64; 95% CI, 0.35

to 1.17; P=0.15), but

the rate of overall
survival
was
significantly higher in
the goserelin group
(hazard ratio, 0.45; 95%
CI, 0.21 to 0.97; P=
0.04). There were three
second primary cancer
events in each study
group: two contralateral
breast cancers in each
group, one melanoma in
the goserelin group, and
one anal cancer in the
chemotherapy-alone
group.

DISC
USSI
ON
The study findings
confirm and extend the
re-sults of
several
previous randomized
studies that suggested
that administration of a
GnRH agonist during
the
course
of
chemotherapy protects
ovar-ian function.4,7,8
Other
randomized
studies that

929

N ENGL J MED 372;10 NEJM.ORG MARCH 5, 2015

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T h e NE W E NGL A ND JOU R NA L o f M E DICINE

Disease-freeSurvival(%)

No. at Risk
Chemotherapy
plus goserelin
Chemotherapy
alone

100
90
80
70
60

4-Yr estimate, 89%

Chemotherapy plus goserelin

4-Yr estimate, 78%

Chemotherapy alone

50
40
30
20
10
0

P=0.04 by multivariable Cox regression

0

37
26

5
5

Years since Randomization

OverallSurvival(%)

105
113

No. at Risk
Chemother
apy plus
goserelin
Chemother
apy alone

103
109

94
94

80
72

59
49

100

4-Yr estimate, 92%

Chemotherapy plus goserelin

4-Yr estimate, 82%

Chemotherapy alone

90

80
70
60
50
40
30
20
10
0

P=0.05 by multivariable Cox regression

0

37
28

6
6

Years since Randomization

105
113

105
111

es
Figure of
dis
2.
Diseas ea
e-free seand
fre
Overall e
Surviv sur
al.
viv
The 4- al
year
(P
estimat an

t
of
did o
not v
show ar
ovari ia
an n
prote fu
ction n
with ct
the io
use n.
of 9
GnR -1
H
1
agoni
sts A
durin re
c
g
chem e
other nt
apy m
were et
small aa
er
and n
had al
relati y
vely si
short s
follo of
w-up ra
times n
for d
the o
asses m
smen iz

101
102

el A) and su
overall
rvi
survival va
(Panel B) l,
are
th
Kaplan er
Meier
e
estimates w
. With
er
respect to e
disease- 12
free
rel

ed
a
trials lt
of theh
use ofo
GnRH u
analog g
ues forh
protect t
ion ofh
ovaria e
n
d
functioe
n dur-fi
ing
n
chemo it
therap i
y
o
showe n
d
ao
57% f
reducti o
on inv
the
a
risk ofri
ovaria a
n
n
failure f
,
aa
findin il
g thatu
is
r
consis-e
tent v
with a
our
ri
results e
,
d

83
77

61
53

apses or with respect to

deaths in overall survival,
the
there were 8
chemothe deaths in the
rapy-plus- chemotherapygoserelin plus-goserelin
group and group and 17 in
24 in the the
chemothe chemotherapyrapyalone group.
alone
group;

among
affe
We foundct
the
the
trials.1 no
2
evidence over
anall
Inte of
imbalance
leve
rpretat
in
thel of
ion of
primary obthe
end-point serv
main data
ed
findin according ovar
gs isto
studyian
compli group, norfailu
-cated did we findre,
evidence ther
by
thee
incom that
association
was
plete
enroll be-tween no
treatment evid
ment
assignment ence
and
and
that
missin stratificatio
miss
g data. n factorsing
differed data
according influ
to whetherence
patients d
had
the
primary relat
end-point ive
data.
com
Therefore, pari
although son
the
bet
missing wee
data may

n
rand
omi
zed
grou
ps.
Furt
her
mor
e,
the
resu
lts
of
sens
itivit
y
anal
yses
that
inco
rpor
ated
parti
al
info
rmat
ion
fro
m
pati
ents
with
miss
ing

930

M
E
D

7
N
ENGL 2
J

arch27,2015.
TheNewEnglandJournalofMedicine
Forpersonal
MARC Downloadedfrom useonly.No
otheruses
H 5,
2015
without
;10

NEJM.
ORG

Massachusetts
Medical
Society.All
rights
reserved.

GOSERELIN FOR OVARIAN PROTECTION DURING CHEMOTHERAPY

metastasis,
and
apoptotic cell death
data were consistent with in
xenograft
the main findings. Thus,models of triplethe available data indicatenegative
breast
a consistent ben-efit ofcan-cer.14-16
goserelin in preservingDisease risk factors
ovarian function.
were not stratified
Current guidelines fromin
the
study,
the American Soci-ety ofmaking it difficult
Clinical
Oncologyto draw concluencourage early referral ofsions about any
female cancer patients whotherapeutic effect
are interested in fertilityof
the
GnRH
preservation
toagonist. However,
reproductive specialists foradjustment
for
consideration of embryobreast-cancer stage
cryopreservation.13 Cost,did not alter the
timing issues, and the need disease-free
or
for a partner, however,overall
sur-vival
limit assisted reproductionfindings.
The
options for many youngfavorable diseasewomen who are receivingrelated out-comes
chemo-therapy.
confirm the safety
Coadministration of aof
concurrent
GnRH
agonist
withadminis-tration of a
chemotherapy may be aGnRH agonist with
more accessible option forchemotherapy
in
patients and can be used in patients with ERconjunction
withnegative
breast
traditional
fertility-cancer.
preservation
techniques. Since our study
Side effects of GnRHincluded
only
agonists include vasomotorpatients with ERsymp-toms and loss ofnegative disease,
bone density; however, it isit cannot address
anticipated that long-termthe
safety
of
preservation of ovar-ianGnRH
agonist
function may help avoidtherapy
with
unwanted
menopausalchemotherapy in
symptoms and loss of bonepatients with ERdensity even in women
positive
breast
who are not interested in
cancer. Concurfertility preservation.
rent
use
of
The improved rates of
endocrine therapy
disease-free and overall
and chemotherapy
survival in the goserelin
group in this study were
unexpected
in
this
population of patients with
ER-negative breast cancer.
Luteinizing
hormone
releasing
hormone
receptors are frequently
pres-ent in triple-negative
breast
cancers,
and
preclini-cal studies have
shown that the use of
GnRH
analogues
is
associated with growth
inhibition, reduction in

fell out of favor

after publication of
the results of the
SWOG-led
INT0100 randomized
trial
in-volving
postmenopausal
women
with
endocrineresponsive breast
cancer,
which
suggested a disease-free survival
advantage
with
sequential,
as
compared
with
concurrent,
chemotherapy and
tamoxifen.17,18 The
mechanism
of
action of GnRH
agonists, however,
is different from
that of tamoxifen.
Multiple
studies
suggesting
favorable effects of
chemotherapyinduced
amenorrhea
on
breast-cancer
outcomes19 -21 and
the recently reported
excellent
survival
results
with
triptorelin
administered
concurrently with
chemotherapy
in
the Tamoxifen and
Exemestane Trial22
indicate
that
ovarian
suppression during
chemotherapy
is
probably safe in
women
with
hormone-sensitive
breast
cancer;
however, caution is
recommended
in
this population, for
whom longer-term
ovari-an
suppression may be
desirable. Ovarian
pro-tection would
also be anticipated
with the use of
GnRH analogues in

young women with non-findings,

the
breast cancer who areadministration of a
receiving treatment withGnRH agonist with
similar cyclophosphamide-chemo-therapy
based chemotherapy.
appears to protect
The results of aagainst
ovarian
randomized
studyfailure,
reducing
addressing the therapeuticthe risk of early
role of GnRH agonists inmenopause
and
ER-posi-tive breast cancerimprov-ing
have
recently
beenprospects
for
reported23; however, anyfertility.
potential therapeutic role Supported by grants
for GnRH agonists infrom National Cancer
Institute at the National
hormone-receptor
Institutes
of
Health
negative breast can-cer(CA189974, CA180821,
requires
furtherCA31946, CA075362,
CA180820,
CA27525,
investigation.
AlthoughCA189808, CA180830,
miss-ing
data
limitCA180801, CA189872,
interpretation
of
theCA189822, CA189953,

T
h
e
a
u
t
h
o
r
s

a
f
f
i
l
i
a
t
i
o
n
s
a
r
e
a
s
f
o
l
l
o
w
s
:
t
h
e
C
l
e
v
e

l
a
n
APPENDIX
d
C
l
i
n
i
c
F
o
u
n
d
a
t
i
o
n
,
C
l
e
v
e
l
a
n
d
(
H
.
C
.
F
.
M
.
)
;
S
W
O
G
C
a
n

c
e
r
R
e
s
e
a
r
c
h
G
r
o
u
p
S
t
a
t
i
s
t
i
c
a
l
C
e
n
t
e
r
,
F
r
e
d
H
u
t
c
h
i
n
s
o

CA189858,
CA180858,
189954,
CA189957,
CA189972)
and
by
AstraZeneca, the Australia
and New Zealand Breast
Cancer Trials Group, and
the Breast Cancer Institute
of Australia. Dr. Phillips is
an Australian National
Breast Cancer Foundation
Practitioner Fellow.

Disclosure
forms
provided by the authors
are available with the
full text of this article at
NEJM.org.
We thank the patients
and investigators of the
SWOG Cancer Research
Group, the International
Breast Cancer Study
Group, ECOGACRIN
Cancer Research Group,
and the Alliance for
Clinical
Trials
in
Oncology.

n
Cancer
Research
Center
(J.M.U.,
W.E.B.), and
Seattle Cancer
Care Alliance
and
University of
Washington
(J.G.) all in
Seattle; Peter
MacCallum
Cancer
Centre,
University of
Melbourne,
Melbourne,
VIC (K.-A.P.,
P.A.F.),
Australia and
New Zealand
Breast Cancer
Trials Group
(ANZBCTG)
(K.-A.P.,
P.A.F., J.F.F.),
Calvary Mater
Hospital,
Newcastle,
NSW (F.B.,
J.M.L., J.F.F.),
and
University of
Sydney,
Sydney (F.B.)

all
in
Australia;
International
Breast Cancer
Study Group
(IBCSG),
Bern,
Switzerland
(K.-A.P.,
P.A.F.);
National
Institute
of
Oncology,
Budapest,
Hungary
(E.H.);
Auckland
Regional

C
a
n
c
e
r
a
n
d
B
l
o
o
d
S
e
r
v
i
c
e
,
A
u
c
k
l
a
n
d
,
N
e
w
Z
e
a
-

N ENGL J MED 372;10 NEJM.ORG MARCH 5, 2015

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Medi
27,2015.Forpersonaluse Massachusetts
T
Engla
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only.Nootheruses
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h
nd
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rightsreserved.
onMarchCopyright2015

alof

GOSERELIN FOR OVARIAN PROTECTION DURING CHEMOTHERAPY

land (D.P.); Fox Chase Cancer Center, Philadelphia (L.J.G.); Instituto de Enfermedades Neoplasicas (H.L.G.) and Oncosalud SAC
(C.S.V.), Lima, Peru; DanaFarber Cancer Institute (A.H.P., R.D.G.) and IBCSG Statistical Center (R.D.G.) both in Boston;
Wichita Community Clinical Oncology Program, Wichita (S.R.D.), and University of Kansas, Westwood (C.J.F.) both in Kansas;
University of Southern California Norris Cancer Center, Los Angeles (A.A.G.), the Angeles Clinic and Research Institute, Santa
Monica (S.M.), and University of California at Irvine Chao Family Comprehensive Cancer Center, Orange (F.L.M) all in
California; National Cancer In-stitute, Division of Cancer Prevention, Bethesda, MD (L.M.); M.D. Anderson Cancer Center, Houston
(G.N.H.); and Loyola University Medical Center, Cardinal Bernardin Cancer Center, Maywood, IL (K.S.A.).
fertility
preservation
in
cancer
patients. J Clin cer cells in vivo.
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