2. Ovarian
cancer
–
the
troublesome
female
genital
cancer.
Background
§
Ovarian
cancer
has
a
poor
survival
rate
because
it
is
often
diagnosed
at
an
advanced
stage.
§
About
75%
are
in
FIGO
stage
3
and
4
at
the
time
of
diagnosis.
§ 5-‐year
survival
is
over
90
percent
for
the
minority
of
women
with
stage
I
disease,
25%
for
those
with
distant
metastasis.
§
Survival
rate
is
almost
identical
for
all
gynaecological
cancers
stage-‐by-‐
stage.
§
In
order
to
improve
survival
the
malignancy
should
be
detected
and
treated
at
an
earlier
stage.
3. SCREENING
§ Screening
has
the
potential
to
pick
up
the
disease
at
a
much
earlier
stage,
and
therefore
potentially
could
save
thousands
of
lives
world-‐wide.
§ But
do
we
have
screening
methods
that
enable
us
to
detect
ovarian
cancer
at
an
earlier
stage
of
the
disease?
4. RISKS
AND
BENEFITS
OF
SCREENING
§ The
potential
benefit
of
screening
is
its
ability
to
identify
ovarian
cancer
at
a
more
localized
and
curable
stage,
leading
to
reduced
mortality
from
the
disease.
§
The
risk
is
that
a
positive
screening
test
for
ovarian
cancer
most
often
is
followed
by
surgery
(either
laparoscopy
or
laparotomy).
5.
PLCO
study
(Prostate,Lung,Colon
and
Ovary)
§ A
large
RCT
(PLCO)
was
conducted
to
determine
whether
screening
for
ovarian
cancer
compared
with
no
screening
can
achieve
earlier
diagnosis
and
decreased
mortality.
§ The
data
showed
no
change
in
the
stage
of
cancer
detected
by
screening
and
no
decrease
in
cancer-‐specific
or
overall
mortality
for
women
who
underwent
annual
screening
(four
years
of
transvaginal
ultrasound
and
six
years
of
CA
125
serum
levels).
Buys
SS
et
al
:
Effect
of
screening
on
ovarian
cancer
mortality:
the
Prostate,
Lung,
Colorectal
and
Ovarian
(PLCO)
Cancer
Screening
Randomized
Controlled
Trial.
JAMA
2011
6. PLCO
study
§
15
percent
of
women
who
underwent
surgery
for
false
positive
findings
experienced
a
serious
complication
related
to
surgery
.
§
The
problem
of
false-‐positive
screening
tests
becomes
critically
important
in
diseases
with
low
prevalence.
§
Unless
the
test
or
sequence
of
tests
is
extremely
accurate,
a
large
number
of
healthy
women
would
be
at
risk
for
unnecessary
surgery.
7. Screening
tests
§ PPV
:
10%
ie
no
more
than
9
healthy
women
with
false
positive
screens
would
undergo
unnecessary
procedures
for
each
case
of
ovarian
cancer
detected.
§ A
screening
program
that
targets
all
women
over
age
50
would
require
a
test
with
a
specificity
of
at
least
99.6
%
,
a
sensitivity
of
at
least
80
%
to
achieve
a
PPV
of
10%,
8. Screening
tests
§ Pelvic
exams
:
§
Early
stage
presymptomatic
tumors
are
rarely
detected
.
§
The
majority
are
at
an
advanced
stage
and
associated
with
poor
prognosis.
9. Screening
tests:Tumor
markers
§ CA-‐125
:
-‐
raised
in
50%
of
women
with
early
stage
ovarian
cancer
and
over
80%
of
women
with
advanced
disease.
§ Limited
specificity
:
-‐ raised
in
1
%
of
healthy
women
,
fluctuates
during
menstrual
cycle
.
-‐ Endometriosis
–
Fibroids-‐Cirrhosis-‐PID
-‐ Cancers
of
the
endometrium
,
breast
,lung
and
Pancreas.
-‐
Pleural
or
peritoneal
fluid
due
to
any
cause.
10. Screening
tests
:
CA-‐125
§ Annual
CA
125
measurements
alone
lack
sufficient
specificity
for
use
in
an
average-‐risk
population
of
postmenopausal
women.
§ Its
use
in
premenopausal
women
carries
a
substantially
higher
likelihood
of
false-‐
positive
tests
due
to
menstrual
cycle
variations
and
the
prevalence
of
benign
gynecologic
conditions.
11. Screening
tests:
CA-‐125
§ Three
large
screening
studies
have
shown
that
the
specificity
of
a
single
CA
125
level
for
detection
of
ovarian
neoplasms
in
postmenopausal
women
ranged
from
98.6
to
99.4
percent,
resulting
in
an
unacceptably
low
positive
predictive
value
of
3
percent.
.Elevated
serum
CA
125
levels
prior
to
diagnosis
of
ovarian
neoplasia:
relevance
for
early
detection
of
ovarian
cancer.
Zurawski
VR
Jr
et
al
Int
J
Cancer.
1988;42(5):677.
.Prevalence
screening
for
ovarian
cancer
in
postmenopausal
women
by
CA
125
measurement
and
ultrasonography.
AUJacobs
I
et
al
BMJ.
1993;306(6884):1030.
.
12. Screening
tests:
CA-‐125
§ In
the
ovarian
component
of
PLCO,
78,237
healthy
women
between
55
and
74
years
of
age
were
randomly
assigned
to
screening
and
control
groups.
§
39,115
women
were
assigned
to
screening
with
annual
CA
125
and
annual
transvaginal
ultrasound.
§ Data
from
the
baseline
prevalence
screen
in
28,816
women
found
an
abnormal
CA
125
in
436
women
(1.5
percent)
§
The
positive
predictive
value
for
invasive
cancer
was
3.7
percent
.
At
four
years
of
follow-‐up,
the
positivity
rates
of
CA
125
remained
essentially
unchanged
from
baseline
and
the
positive
predictive
value
was
2.6
percent
.
13. Other
tumor
markers:
HE4
§ HE4
—
Human
Epididymis
Protein
4
-‐
Similar
sensitivity
to
CA
125
when
comparing
serum
from
ovarian
cancer
cases
to
healthy
controls,
and
a
higher
sensitivity
when
comparing
ovarian
cancer
cases
to
benign
gynecologic
disease.
-‐In
a
study
of
531
women
with
pelvic
masses,
an
algorithm
using
HE4
and
CA
125
correctly
classified
93.8
percent
of
cases
of
epithelial
ovarian
cancer
as
high
risk.
-‐This
model
can
be
used
to
effectively
to
triage
patients
to
centers
of
excellence.
A
novel
multiple
marker
bioassay
utilizing
HE4
and
CA125
for
the
prediction
of
ovarian
cancer
in
patients
with
a
pelvic
mass.
AUMoore
RG
et
al
Gynecol
Oncol.
2009;112(1):40.
14. CA-‐125+HE4+CEA+VCAM-‐1
§ A
four-‐marker
panel
had
the
highest
diagnostic
power,
with
86
percent
sensitivity
for
early-‐stage
ovarian
cancer
at
98
percent
specificity.
§ Another
study
looked
at
tumor
markers
in
stored
serum
samples
and
compared
between
70
case-‐
matched
controls
and
34
women
who
developed
ovarian
cancer
after
the
trial
onset
.
Development
of
a
multimarker
assay
for
early
detection
of
ovarian
cancer.
AUYurkovetsky
Z
et
al
J
Clin
Oncol.
2010;28(13):2159.
15. CA
125
+
mesothelin
and
HE4
§ Three
tumor
markers
(CA
125,
mesothelin,
and
HE4)
began
to
increase
three
years
before
the
diagnosis
of
ovarian
cancer.
§
CA
125
was
most
strongly
predictive
of
ovarian
cancer,
with
evidence
for
some
incremental
contribution
of
HE4
and
mesothelin
to
risk
prediction.
-‐
Development
of
a
multimarker
assay
for
early
detection
of
ovarian
cancer.
AUYurkovetsky
Z
et
al
J
Clin
Oncol.
2010;28(13):2159.
-‐
Assessing
lead
time
of
selected
ovarian
cancer
biomarkers:
a
nested
case-‐control
study.AUAnderson
GL
et
al
J
Natl
Cancer
Inst.
2010:;102(1):26.
16. Pelvic
ultrasonography
§ UKCTOCS
the
largest
study
to
date,
48,230
women
aged
50
to
74
years
were
randomly
assigned
to
screening
with
annual
TVUS
as
one
arm
of
a
randomized
trial
comparing
multimodal
screening
(MMS),
TVUS,
and
no
screening.
§ The
sensitivity,
specificity,
and
positive
predictive
value
were
75,
98.2,
and
2.8
percent
respectively
for
primary
invasive
cancer.
17. The
Kentucky
study
§
37,293
women
received
annual
ultrasonographic
screening
between
1987-‐2011.
§ 47
invasive
EOC
and
15
epithelial
ovarian
tumors
of
LMP
were
detected.
§ stage
I,
22
(47%)
stage
II,
11
(23%)
§ stage
III,
14
(30%)
and
stage
IV,
0
(0%).
§ Follow-‐up
varied
from
2
months
to
20.1
years
(mean,
5.8
years)
18. The
Kentucky
study
§ SURVIVAL
DATA.
The
5-‐year
survival
rate
for
invasive
EOC
detected
by
screening
was:
-‐
Stage
I:
95%±4.8%
-‐
Stage
II:
77.1%±14.5%;
-‐
Stage
III:
76.2%±12.1%.
19. The
Kentucky
study
Survival
data:
§ The
5-‐year
survival
rate
for
all
women
with
EOC
detected
by
screening
as
well
as
interval
cancers
was
74.8%±6.6%
compared
with
53.7%±2.3%
for
unscreened
women
with
ovarian
cancer
from
the
same
institution
treated
by
the
same
surgical
and
chemotherapeutic
protocols
(P<.001).
Long-‐Term
Survival
of
Women
With
Epithelial
Ovarian
Cancer
Detected
by
Ultrasonographic
Screening
van
Nagell
et
al
.
Obstetrics
&
Gynecology
:December
2011
-‐
Volume
118
-‐
Issue
6
-‐
p
1212–1221
20. Pelvic
ultrsonography
§ Specificity
was
lower
for
TVUS
compared
to
multimodal
screening,
resulting
in
nine
times
as
many
surgeries
performed
for
the
TVUS
compared
to
the
MMS
group
to
detect
one
cancer.
Sensitivity
and
specificity
of
multimodal
and
ultrasound
screening
for
ovarian
cancer,
and
stage
distribution
of
detected
cancers:
results
of
the
prevalence
screen
of
the
UK
Collaborative
Trial
of
Ovarian
Cancer
Screening
(UKCTOCS).
Menon
U
et
al
Lancet
Oncol.
2009;10(4):327
21. Multimodal
screening
§ Three
large
randomized
trials
have
evaluated
combination
screening
with
serum
CA
125
and
ultrasonography,
either
performed
sequentially
(ultrasound
only
if
the
CA
125
is
elevated)
or
concurrently.
One
trial
has
reported
final
data
and
two
are
ongoing.
22. PLCO
§ Screening
of
28,816
women
found
1740
with
either
an
abnormal
CA
125
or
ultrasound,
and
34
had
both
.
§ Nearly
one
in
three
women
who
had
a
positive
screening
test
underwent
surgery
.
§
Among
570
women
who
had
surgery,
29
tumors
were
found,
of
which
20
were
invasive
(90
percent
of
these
stage
III
or
IV)
23. PLCO
§ There
was
no
difference
in
the
stage
of
ovarian
cancer,
with
advanced
disease
(stage
III
or
IV)
in
77
percent
of
the
cancers
in
the
intervention
group
and
78
percent
in
the
usual
care
group.
§ Both
the
incidence
of
ovarian
cancer
and
the
mortality
rate
were
non
significantly
greater
for
women
allocated
to
the
intervention
(rate
ratios
1.21,
95%
CI
0.99-‐1.48
and
1.18,
CI
0.91-‐1.54,
respectively)
§ The
trial
was
stopped
prior
to
scheduled
completion
because
the
monitoring
board
determined
futility.
24. UKCTOCS
(
Promising
trial)
§ The
trial
randomly
assigned
202,638
postmenopausal
women
aged
50
to
74
years
to
no
screening,
annual
TVUS,
or
multimodal
screening
(MMS)
.
§ This
study
found
42
primary
ovarian
and
tubal
cancers
in
the
MMS
group;
8
tumors
were
borderline
and
16
of
the
34
invasive
cancers
(47
percent)
were
stage
I
or
II.
§ The
PPV
for
detection
of
primary
invasive
cancer
was
35.1
%
§ Specificity
was
significantly
greater
for
MMS
compared
to
TVUS.
Mortality
data
for
this
trial
will
be
available
in
2015.
Prospective
study
using
the
risk
of
ovarian
cancer
algorithm
to
screen
for
ovarian
cancer.AUMenon
J
Clin
Oncol.
2005;23(31):7919.
25. Japanese
study
§ In
a
randomized
controlled
trial
of
83,000
postmenopausal
women
in
Japan,
42,000
women
were
invited
to
participate
in
annual
screening
with
pelvic
ultrasound
and
CA
125.
§
No
significant
difference
in
the
detection
of
ovarian
cancer,
at
an
average
follow-‐up
of
9.2
years,
between
patients
who
received
screening
(27
cases)
and
control
patients
(32
cases).
§ There
was
a
non-‐significant
trend
toward
earlier-‐stage
disease
in
the
screened
group.
Thirty-‐three
surgeries
were
performed
to
detect
each
case
of
ovarian
cancer.
Mortality
data
are
not
yet
available.
26. High
risk
women
§ In
one
surveillance
program
for
women
over
35
years
of
age
with
a
family
history
of
ovarian,
breast,
colon,
or
endometrial
cancer,
or
a
personal
history
of
breast
cancer.
§
1261
participants
were
screened
with
transvaginal
sonography,
color
doppler
imaging,
and
CA
125
every
one
to
two
years
for
a
total
of
6082
screens
.
§ Three
stage
I
ovarian
carcinomas
were
detected
by
ultrasound,
but
an
additional
seven
peritoneal
serous
papillary
carcinomas
with
metastasis
occurred
despite
the
screening
intervention.
CA125
and
transvaginal
ultrasound
monitoring
in
high-‐risk
women
cannot
prevent
the
diagnosis
of
advanced
ovarian
cancer.AUOlivier
RI
et
al
Gynecol
Oncol.
2006;100(1):20.
27. High
risk
women
§ Four
years
of
screening
with
CA
125
and
transvaginal
ultrasound
had
a
sensitivity
of
40
percent
and
specificity
of
99
percent
in
a
series
of
312
women
35
years
or
older
who
were
carriers
for
BRCA
1
or
2
(screened
semiannually)
or
members
of
a
family
with
hereditary
breast
and/or
ovarian
cancer
syndrome
(screened
annually).
§ Three
out
of
the
four-‐early
stage
tumors
found
at
prophylactic
bilateral
salpingo-‐oophorectomy
(n
=
156)
were
in
women
who
had
normal
Ca-‐125
and
ultrasound.
AULacey
et
al
Obstet
Gynecol.
2006;108(5):1176.o
had
normal
CA
125
and
ultrasound
findings.
28. High
risk
women
§ In
a
cohort
of
888
women
carriers
of
BRCA
1
or
2
mutations
who
underwent
screening
with
annual
transvaginal
ultrasound
and
CA
125.
§ 5
of
10
incident
cancers
were
interval
cases
diagnosed
in
women
who
had
had
normal
screening
results
3
to
10
months
previously
.
§ Eight
of
the
ten
cancers
were
stage
III
at
diagnosis.
Use
of
a
stochastic
simulation
model
to
identify
an
efficient
protocol
for
ovarian
cancer
screening.AUUrban
N
et
al
Control
Clin
Trials.
1997;18(3):251.
29. SYNTHESIS
OF
THE
EVIDENCE
§ Women
at
average
risk
-‐
Screening
for
ovarian
cancer
with
CA
125
or
ultrasound
is
NOT
recommended
for
premenopausal
and
postmenopausal
women
without
a
family
history
of
ovarian
cancer.
-‐
The
predictive
value
of
either
test
alone
(less
than
3
percent)
yields
an
unacceptably
high
rate
of
false-‐
positive
results
and
attendant
morbidity
and
costs.
30. SYNTHESIS
OF
THE
EVIDENCE
§ Women
at
increased
risk
For
women
with
a
family
history
of
ovarian
cancer,
it
is
important
to
differentiate
those
with
a
possible
rare
familial
ovarian
cancer
syndrome
and
those
with
the
more
common
presentation
of
an
isolated
family
member
with
ovarian
cancer,
without
evidence
of
a
hereditary
pattern.
31. Risk
assessment
criteria
for
inherited
breast-‐ovarian
cancer
syndome,
combining
several
guidelines
Non-‐Jewish
families.
Any
of
the
following:
§ One
case
of
breast
cancer
≤40
yo
in
a
FDR
or
SDR
§ One
FDR
or
SDR
with
breast
and
ovarian
cancer,
at
any
age
§ Two
or
more
cases
of
breast
cancer
in
FDRs
or
SDRs
if
one
is
diagnosed
at
≤50
years
old,
or
is
bilateral
§ One
FDR
or
SDR
with
breast
cancer
at
≤50
years
old,
or
bilateral
and
one
FDR
or
SDR
with
ovarian
cancer
§ Three
cases
of
breast
and
ovarian
cancer
(at
least
one
case
of
ovarian
cancer)
in
FDRs
and
SDRs
§ Two
cases
of
ovarian
cancer
in
FDRs
and
SDRs
§ One
case
of
male
breast
cancer
in
an
FDR
or
SDR
if
another
FDR
or
SDR
has
(male
or
female)
breast
or
ovarian
cancer
32. SYNTHESIS
OF
THE
EVIDENCE
§ High-‐risk
family
history
-‐
Women
with
a
suspected
hereditary
ovarian
cancer
syndrome
should
be
referred
to
a
genetic
counselor
for
consideration
of
testing
for
BRCA1
and
BRCA2
mutations.
-‐
Women
who
have
not
elected
risk-‐reducing
surgery,
screening
with
TVUS
plus
CA
125
assays
every
six
months
starting
at
age
35
years
or
5
to
10
years
earlier
than
the
earliest
age
of
first
diagnosis
of
ovarian
cancer
in
the
family.
33. Summary
§ Screening
average
risk
women
for
ovarian
cancer
is
not
recommended.
§ 1
of
3
randomized
trials
of
screening
with
annual
CA
125
and
TVUS
in
average-‐risk
postmenopausal
women
has
shown
no
decrease
in
mortality
from
ovarian
cancer.
§
Two
other
large
trials
are
ongoing.
34. § Ca-‐125
is
elevated
in
50
to
90
percent
of
women
with
early
ovarian
cancer,
but
also
can
be
elevated
in
numerous
other
conditions.
§
Screening
with
a
single
measurement
of
CA
125
alone,
either
in
average-‐
or
high-‐risk
women
is
not
recommended.
35. § TVUS
when
used
as
a
sole
screening
intervention
for
higher-‐risk
women,
has
not
been
effective
in
identifying
early-‐stage
cancer.
§
TVUS
may
be
more
effective
when
used
as
part
of
MMS,
in
conjunction
with
CA
125.
However,
the
PPV
for
MMS
in
high
risk
groups
remains
low.
36. § Periodically
screening
women
with
a
familial
ovarian
cancer
syndrome,
who
have
not
undergone
prophylactic
oophorectomy,
with
a
combination
of
CA
125
and
transvaginal
ultrasound
is
recommeded.
§ Initiation
at
age
35
years
or
5
to
10
years
earlier
than
the
earliest
age
of
first
diagnosis
of
ovarian
cancer
in
the
family.
37. §
Women
with
a
family
history
of
ovarian
cancer
but
do
not
have
a
confirmed
ovarian
cancer
syndrome
should
be
managed
in
a
similar
manner
to
women
at
average
risk.
