2. 64,928
Europe
67,078
Africa
49,025
South America
14,845
United States/
Canada
1,077
Australia/
New Zealand
39,648
Southeast
Asia
51,266
Eastern Asia
21,596
Central America
151,297
Southcentral
Asia
Cervical
Cancer:
Worldwide
Prevalence,
Incidence,
and
Mortality
Es8mates
Prevalence:
2,274,000
women
have
cervical
cancer1
Incidence:
510,000
new
cases
each
year1
Mortality:
Second
leading
cause
of
female
cancer-‐related
deaths
(288,000
annually)1
1.
World
Health
Organization.
Geneva,
Switzerland:
World
Health
Organization;
2003:1–74.
2.
Bosch
FX,
de
Sanjosé
S.
J
Natl
Cancer
Inst
Monogr.
2003;31:3–13.
2000 estimated incidence of invasive cervical cancer !
by selected region2:
3. Saudi Arabia
Cervical
Cancer:
In
Saudi
Arabia
,
Incidence,
and
Mortality
Es8mates
1.9
cases
per
100,000
women,
accounting
for
2.6%
of
diagnosed
cancer
cases
in
women
Every
year,
152
women
are
diagnosed
with
cervical
cancer
and
55
die
from
the
disease.
new
cervical
cancer
cases
and
deaths
in
2025
are
309
Cancer
Incidence
Report
Saudi
Arabia
2007.
Available
at
www.scr.org.sa/reports/SCR2007.pdf
Accessed
on
June
26,
2011
4. Cervical
Cancer:
Saudi
Arabia
— Very
low
incidence,
1.9/100,000
women
— ?
Any
demographic
data
on
“high
risk
groups”?
— Very
little
known
about
HPV
incidence
and
transmission
— Data
on
conventional
pap
triage
is
poor
— Hospital
based
— No
population
based
data
5. Cervical
Cancer:
Global
Stats
Age
Standardized
Incidence
rate/
100000
women
Total
Cases
Deaths
World
15.3
530232
275008
Saudi
Arabia
1.9
152
55
Western
Asia
39.18
4.5
2.1
Canada
6.6
1419
544
Globocan
2008
IARC
6.
— Human
papillomavirus
infection
(HPV)
–
Primary
factor
— HPV
16,
HPV
18,
HPV
31,
HPV
33,
HPV
45
— 50%
are
caused
by
HPV
16
AND
18
— Sexual
behavior
— Smoking
— HIV
infection
— Chlamydia
infection
— Diet
— Oral
contraceptives
— Multiple
pregnancies
— Low
socioeconomic
status
— Diethylstilbestrol
(DES)
— Family
history
Source:
American
Cancer
Society
7. STAGING
PROCEDURE
— Pelvic
examination
–
speculum,
bimanual,
and
rectovaginal
examination
for
palpation
and
inspection
of
the
primary
tumor,
uterus,
vagina,
and
parametria
— Cystoscopy
— Proctoscopy
— Imaging
studies
— Intravenous
pyelogram
(IVP)
–
evaluation
for
urinary
tract
obstruction;
in
many
centers
computed
tomography
or
magnetic
resonance
imaging
is
used
instead.
— Imaging
with
a
plain
chest
radiograph
and
radiograph
of
the
skeleton
–
evaluation
for
metastases
8.
9. — Selected
women
with
microscopic
disease
(stage
IA1)
may
be
treated
with
extrafascial
hysterectomy,
cone
biopsy,
or
simple
trachelectomy.
— Women
with
a
tumor
that
is
confined
to
the
cervix,
uterus,
upper
third
of
the
vagina
(stage
IA2,
IB1,
IIA1)
that
is
nonbulky
(≤4
cm)
and
who
do
not
have
lymph
node
metastases
are
candidates
for
radical
hysterectomy.
— Women
with
local
extension
(eg,
to
the
low
two-‐thirds
of
the
vagina,
parametrium,
or
bladder)
that
is
bulky
(stage
IB2,
IIA2
to
IVA)
or
with
lymph
node
metastases
are
generally
treated
with
chemoradiation.
Assessment
of
lymph
nodes
helps
to
design
the
radiation
fields
(ie,
pelvic
radiation
versus
extended
field
radiation).
20. Cervical
Cancer
Preven8on:
Challenges
— What
will
the
future
look
like?
— Will
there
be
a
dramatic
increase
in
cervical
cancer
as
the
population
matures?
— Primary
prevention?
— How
— Secondary
prevention
— How
to
screen?
— How
to
triage
and
treat
screening
abnormalities
21. Pelvic
Autonomic
Innervation
² Sympathetic system
ü Superior hypogastric plexus
ü Hypogastric nerves
² Paraympathetic system
ü Pelvic splanchnic nerves
² Inferior hypogastric plexus
² Visceral nerve branches
31. Normal
epithelium
Basement
membrane
Basal
(stem)
cells
Parabasal
cells
Squamous
layer
Mature
squamous
layer
Infected
epithelium
Cervical
canal
HPV
infects
basal
layer
of
cervical
epithelium
HPV
lifecycle
in
the
cervix
Adapted
from
Frazer
IH.
Nat
Rev
Immunol
2004;
4:46–54.
Virus
par8cles
are
assembled
and
virus
released
Virus
uses
host
cell
to
replicate
viral
DNA
and
express
virally
encoded
proteins
32. Transmission
of
HPV
— Prevalence
in
asymptomatic
North
American
women
is
2-‐40
%
mean
10.41%
— Highest
in
young
women
— Sexual
contact
primary
route
of
transit,
important
factors
— Earlier
age
at
sexual
debut
— Increased
number
of
partners
— More
transmissible
than
any
virus
but
less
than
bacterial
infections
Burchell
et
al
Vaccine
24S3
(2006)
33. HPV
— >100
types
identified2
— ~30–40
anogenital2,3
— ~15–20
oncogenic*,2,3
types,
including
16,
18,
31,
33,
35,
39,
45,
51,
52,
584
— HPV
16
(54%)
and
HPV
18
(13%)
accounted
for
the
majority
of
worldwide
cervical
cancers.5
— Nononcogenic**
types
include:
6,
11,
40,
42,
43,
44,
544
— HPV
6
and
11
are
most
often
associated
with
external
genital
warts.3
1.
Howley
PM.
In:
Fields
Virology.
Philadelphia,
Pa:
Lippincott-Raven;
1996:2045–2076.
2.
Schiffman
M,
Castle
PE.
Arch
Pathol
Lab
Med.
2003;127:930–934.
3.
Wiley
DJ,
Douglas
J,
Beutner
K,
et
al.
Clin
Infect
Dis.
2002;35(suppl
2):S210–S224.
4.
Muñoz
N,
Bosch
FX,
de
Sanjosé
S,
et
al.
N
Engl
J
Med.
2003;348:518–527.
5.
Clifford
GM,
Smith
JS,
Aguado
T,
Franceschi
S.
Br
J
Cancer.
2003:89;101–105.
Nonenveloped
double-stranded
DNA
virus1
*High
risk;
**low
risk
34. Basic
of
HPV
vaccina8on
— Stimulate
B
cells
to
produce
neutraliize
antibodies.
— Neutralizing
antibodies
bind
to
HPV’s
outer
shell
(L
1
capsid
protein)
and
prevent
infection
of
host
cells
Infec8on
No
infec8on
HPV
infects
target
cells
in
the
basal
layer
of
the
cervical
epithelium
Neutralizing
an8bodies
prevent
HPV
from
infec8ng
basal
epithelial
cells
Basal
cell
layer
of
cervical
epithelium
1.
Stanley
M,
et
al.
Vaccine
2006;
24(Suppl
3):S106–S113.
35. Ac8ve
protec8on
via
vaccina8on
is
mediated
by
neutralizing
an8bodies
at
the
cervix
HPV
Cervical
canal
Neutralizing
an8bodies
Blood
vessel
Epithelial
tear
Basement
membrane
Cervical
epithelium
1.
Stanley
M.
Vaccine
2006;
24:S16–S22;
2.
Giannini
S,
et
al.
Vaccine
2006;
24:5937–5949;
3.
Nardelli-‐Haefliger
D,
et
al.
J
Natl
Cancer
Inst
2003;
95:1128–1137;
4.
Poncelet
S,
et
al.
IPC
2007(poster).
36. Product
characteristics
–
prophylactic
HPV
vaccines
CervarixTM1 Gardasil®2
Antigen VLPs of HPV 16 & 18 VLPs of HPV 16, 18, 6 & 11
Administration 0, 1 & 6 months
by intramuscular injection
0, 2 & 6 months
by intramuscular injection
1.
CervarixTM.
European
Summary
of
Product
Characteris8cs,
2007;
2.
Gardasil®.
European
Summary
of
Product
Characteris8cs,
2008.
38. HPV
Vaccines:
Published
data
Gardasil(Merck) Cervarix (GSK)
Dose and
administration
0.5 ml IM 0.5 ml IM
Schedule 0,2,6 months 0,1,6 months
Trial size 17622 18644
comparator Placebo with alum Hepatitis A
Site Up to 16 countries 14 countries
Age range 16-24; 15-26 15-25
eligibility < 4 sexual partners
( median 2)
< 6 sexual partners
exclusion Hx of abnormal pap
smears; pregnancy
Hx of colposcopy,
immunocompromised or
pregnant
duration 48 month study, 3 year
data
Mean 14.8 months
40. Vaccine
efficacy
— Safe
effective
vaccines
— Trials
show
a
reduction
in
CIN
and
treatment
— Other
trials
have
shown
safety
and
immunogenicity
in
women
9-‐15
years
old
41. Safety/Adverse
Events
GARDASIL Quadravalent CERVARIX Bivalent
14 days after
injection
Gardasil (14
days after
injection)
(n=5088)%
Alum Placebo
(n=3470)%
Saline Placebo
(n=320)%
Cervarix (7
days after
injection)
(n=22806)%
Alum Placebo
(n=4485)%
HAV 720
(n=8750)%
Injection site
Pain 83.9 75.4 48.6 78 52.5 58.9
Swelling 25.4 15.8 7.3 25.8 8.2 10.1
Erythema 24.6 18.4 12.1 29.6 10.6 16.1
Puritis 3.1 2.8 0.6 Not noted Not noted Not noted
Systemic
Fever
(>37.8oC)
10.3 8.6 5.1 5.2 4.6
Nausea 4.2 4.1
12.9 11.6 14.0Diarrhea 1.2 1.5
Dizziness 2.8 2.6
Data
taken
from
product
monograph
Canada
and
Australia
42. When
to
vaccinate?
— Should
vaccinate
before
sexual
activity
— Works
best
in
a
school
based
program
— High
rates
of
vaccination
in
UK,
Canada
Australia
etc;
where
school
based
programs
are
used
— Rates
of
only
25%
3
doses
in
some
areas
of
US
where
women
need
to
see
physician
43. Dura8on
and
Safety
— Both
vaccines
have
demonstrated
efficacy
beyond
7
years
— Antibody
levels
vary,
but
there
has
been
no
evidence
of
breakthrough
infections
thus
far
— All
evidence
from
the
millions
of
doses
given
confirms
that
they
are
very
safe
vaccines
44. Cervical
Cancer
Preven8on
Normal
Cervix
HPV
Infection
Cervical
Dysplasia
Cervical
Cancer
Primary
Prevention:
Vaccination
Secondary
Prevention:
Screening
45. Op8ons
in
screening
— PAP
smear
— VIA
— HPV
testing
48. Cervical
Screening:
Status
and
Challenges
— Well
established
system
of
cytology
screening
with
colposcopy
follow-‐up
— Successful
in
reducing
the
incidence
and
mortality
from
cervical
cancer
However:
— Realistically
in
Canada
,
they
have
been
unable
to
screen
more
than
70%
of
the
population
well
— How
would
a
cytology
based
program
work
in
Saudi
Arabia?
—
What
effect
will
vaccination
have?
49. Limita8ons
of
Cytology
— Sensitivity
of
pap
test
to
detect
CIN3+:
55%
— Should
be
done
in
the
context
of
an
organized
screening
program
— Quality
assurance
of
cytology
needs
to
be
very
good
— system
of
communication
to
the
women
screened
so
that
they
may
receive
sufficient
treatment.
— Requires
colposcopy
and
biopsy
to
confirm
dysplasia
— The
necessity
for
multiple
visits
with
cytology
based
screening
results
in
significant
loss
to
follow-‐up
50. Authora
Duration
Total no
Abnormal PAP
smear
ASC-US
ASC-H
LSIL
HSIL
AGUS
INVASIVE
CANCER
Al-Jaroudi (8)
2008-2009
241
7
(2.9%)
3
(1.2%)
1
(0.4%)
2
(0.83%)
NR
1
(0.4%)
NR
Jamal
1984-2000
22089
368
(1.66%)
88
(0.4%)
NR
81
(0.37%)
72
(0.32%)
36
(0.16%)
26
(0.1%)
Altaf
2001
3088
97
(3.14%)
14
(0.45%)
NR
29
(0.93%)
17
(0.55%)
4
(0.13%)
5
(0.16%)
Abdullah L (1)
1998 – 2005
5590
261
(4.7%)
103
(1.84%)
6
(0.10%)
5
(0.09%)
31
(0.55%)
30
(0.53%)
2
(0.04%)
Altaf
2000-2004
5132
241
(4.7%)
124
(2.4%)
NR
31
(0.6%)
22
(0.4%)
58
(1.1%)
6
(0.1%)
Summary
of
reported
data
on
Pap
smear
abnormalities
in
Saudi
Arabia
52. Op8ons
in
Screening
— VIA:
Visual
inspection
with
acetic
acid
— VILI:
Visual
inspection
with
Lugols
iodine
— Both
Low
tech
can
be
done
by
nurses
— May
need
to
utilize
colposcopy
to
triage
post
positive
test
to
rule
out
cancer
53. Test
Quali8es
of
VIA
in
Primary
Healthcare
Sehng
(Phase
2)
TEST
SENSITIVITY
(%)
SPECIFICITY
(%)*
POSITIVE
PREDICTIVE
VALUE (%)*
NEGATIVE
PREDICTIVE
VALUE (%)*
VIA
(n = 2,130)
77
(70–82)
64
(62–66) 19 96
Pap smear
(n = 2,092)
44
(35–51)
91
(37–51) 33 94
95%
Confidence
Interval
University
of
Zimbabwe/JHPIEGO
Cervical
Cancer
Project
1999.
54.
55. HPV
tes8ng
in
cervical
cancer
screening
Approaches
already
implemented
or
being
examined:
Ø Serial:
Cytology
screening
followed
by
HPV
testing
to
triage
ASC-‐US
(USA,
Nfld)
Ø Parallel:
Cytology
and
HPV
cotesting
(approved
in
USA,
implemented
in
California(Kaiser),Quebec)
Ø Serial:
HPV
testing
followed
by
cytologic
triage
(being
examined
in
the
Finnish
trial,
BC
RCT,
a.k.a.,
HPV
FOCAL
Study)
56. HPV
Tes8ng
ADVANTAGES
— Very
sensitive
— Better
quality
control
— Decreases
the
number
of
cytologists
needed
— Increase
screening
interval
which
decreases
cost
and
improves
convenience
DISADVANTAGES
— Need
a
second
test
due
to
lower
specificity
57. Role
of
HPV
tes8ng
• Triage
equivocal
or
low
grade
cytology
smears
(ALTS
trial)
• FUP
of
women
with
abnormal
cytology
but
normal
colposcopy
• Predict
outcome
after
treatment
of
high
grade
disease
• Primary
Screening
Cuzick
J.
Vaccine
2008
58. CCCAST
trial
PAP
HPV
55.6%
94.6%
Sensitivity
96.8%
94.1%
Specificity
Mayrand
et
al.;
Ø compare
the
relative
efficacy
of
HPV
DNA
testing
and
Pap
cytology
in
primary
screening
for
cervical
cancer
and
its
high-‐grade
precursors
NEJM
2007
Ø Pap
screening
followed
by
HPV
(hc
2)
vs
hc2
testing
followed
by
HPV
in
women
30-‐69
Ø
9,667
women
HPV
testing
is
significantly
more
sensitive
to
detect
CIN
2+
59. HPV
Screening
for
Cervical
Cancer
in
India
Sankaranarayanan,R:
— RCT
,4
Arms
of
screening
tool
in
India
— HPV
test
vs.
Pap
test
vs.
VIA
vs.
Observation
— Cervical
cancer
as
an
endpoint
— 32000
women
in
each
arm
— Screen
positive
received
colposcopy
and
treatment
— Only
significant
screening
method
to
reduce
deaths
from
cervical
cancer
was
HPV
testing
— Significant
reduction
in
Ca
Cervix
in
the
HPV
negative
compared
to
negative
Pap
and
VIA
NEJM
Apr2009
360(14)1385-‐94
60. HPV
tes8ng
RCT
Ronco
etal
— Trial
in
Italy
— 94000
women
25-‐60
randomized
in
2
phases
to
cytology
vs.
HPV
testing
and
cytology
(phase
1)
and
HPV
testing
alone
(phase
2).
— Same
rate
of
cancer
in
round
one
of
testing
— Increased
cancer
in
cytology
group
in
round
two
— HPV
testing
was
more
effective
in
preventing
cancer
by
detecting
high
grade
lesions
earlier.
— However:
HPV
testing
leads
to
over
diagnosis
of
CIN
2
which
is
likely
to
resolve
Ronco
G;
Lancet
March
2010
61. Cost
Effec8veness
Several
studies
proved
the
cost
effectiveness
of
HPV
testing
as
screening
test
for
Cervical
cancer
— In
developing
countries
— Screening
program
not
well
established
— Middle
income
Br
J
Cancer.2010
Dec
7;103(12):1773-‐82.
Cancer
Causes
Control.2011
Feb;22(2):261-‐72.
Eur
J
Cancer.
2011
Jul;47(11):1633-‐46
63. Suggested
Screening
Strategy
— Use
the
high
sensitivity
of
HPV
test
initially
— Digene
Hybrid
capture
2
test
is
suitable
— Positive
HPV
test
has
reflex
pap
testing
— If
both
positive
colposcopy
is
performed
— If
HPV
neg
repeat
screen
in
5
years
— If
HPV
+ve
and
pap
neg,
repeat
HPV
and
pap
in
1
year
64.
HR-‐HPV
tes8ng
and
Reflex
Pap
HR-‐HPV
DNA
in
women
30
+
years
old
Negative
Negative
Negative
Pap
test
Positive
Positive
Colposcopy
Positive
Repeat
HR-‐DNA
testing
@
5
year
intervals
till
age
65
Repeat
HR-‐
HPV
testing
at
12
months
