1. Dr.Nisrin
Anfinan
Consultant
Gynecology
Oncology
King
Abdulaziz
University
Hospital

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
Estimates
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
Estimates
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. Foreseeable
Challenges:
— To
understand
the
prevalence
of
high-­‐risk
(HR)-­‐HPV
infections
and
the
prevalence
of
abnormal
cytology
findings
in
general
population.
To
understand
the
sexual
practices
of
the
population.
By
region
and
population
group.
Implementation
of
any
screening
program,
either
primary
or
secondary,
will
be
difficult
in
patients
with
a
sexually
transmitted
infection.
Vaccination
–
is
it
cost-­‐effective
given
the
low
rates
of
cervical
cancer?
Introduction
of
quality
assurance
in
screening
and
colposcopy.
Which
screening
method
should
be
used
and
how
does
one
triage
the
patients?

6. Foreseeable
Challenges:
— To
understand
the
prevalence
of
high-­‐risk
(HR)-­‐HPV
infections
and
the
prevalence
of
abnormal
cytology
findings
in
general
population.
— To
understand
the
sexual
practices
of
the
population.
— By
region
and
population
group.
Implementation
of
any
screening
program,
either
primary
or
secondary,
will
be
difficult
in
patients
with
a
sexually
transmitted
infection.
Vaccination
–
is
it
cost-­‐effective
given
the
low
rates
of
cervical
cancer?
Introduction
of
quality
assurance
in
screening
and
colposcopy.
Which
screening
method
should
be
used
and
how
does
one
triage
the
patients?

7. Foreseeable
Challenges:
— To
understand
the
prevalence
of
high-­‐risk
(HR)-­‐HPV
infections
and
the
prevalence
of
abnormal
cytology
findings
in
general
population.
— To
understand
the
sexual
practices
of
the
population.
— By
region
and
population
group.
— Implementation
of
any
screening
program,
either
primary
or
secondary,
will
be
difficult
in
patients
with
a
sexually
transmitted
infection.
Vaccination
–
is
it
cost-­‐effective
given
the
low
rates
of
cervical
cancer?
Introduction
of
quality
assurance
in
screening
and
colposcopy.
Which
screening
method
should
be
used
and
how
does
one
triage
the
patients

8. Foreseeable
Challenges:
— To
understand
the
prevalence
of
high-­‐risk
(HR)-­‐HPV
infections
and
the
prevalence
of
abnormal
cytology
findings
in
general
population.
— To
understand
the
sexual
practices
of
the
population.
— By
region
and
population
group.
— Implementation
of
any
screening
program,
either
primary
or
secondary,
will
be
difficult
in
patients
with
a
sexually
transmitted
infection.
— Vaccination
–
is
it
cost-­‐effective
given
the
low
rates
of
cervical
cancer?
Introduction
of
quality
assurance
in
screening
and
colposcopy.
Which
screening
method
should
be
used
and
how
does
one
triage
the
patients?

9. Foreseeable
Challenges:
— To
understand
the
prevalence
of
high-­‐risk
(HR)-­‐HPV
infections
and
the
prevalence
of
abnormal
cytology
findings
in
general
population.
— To
understand
the
sexual
practices
of
the
population.
— By
region
and
population
group.
— Implementation
of
any
screening
program,
either
primary
or
secondary,
will
be
difficult
in
patients
with
a
sexually
transmitted
infection.
— Vaccination
–
is
it
cost-­‐effective
given
the
low
rates
of
cervical
cancer?
— Introduction
of
quality
assurance
in
screening
and
colposcopy.

10. Foreseeable
Challenges:
— To
understand
the
prevalence
of
high-­‐risk
(HR)-­‐HPV
infections
and
the
prevalence
of
abnormal
cytology
findings
in
general
population.
— To
understand
the
sexual
practices
of
the
population.
— By
region
and
population
group.
— Implementation
of
any
screening
program,
either
primary
or
secondary,
will
be
difficult
in
patients
with
a
sexually
transmitted
infection.
— Vaccination
–
is
it
cost-­‐effective
given
the
low
rates
of
cervical
cancer?
— Introduction
of
quality
assurance
in
screening
and
colposcopy.
— Which
screening
method
should
be
used
and
how
does
one
triage
the
patients?

11. Cervical
Cancer
Prevention
Normal
Cervix
HPV
Infection
Cervical
Dysplasia
Cervical
Cancer
Primary
Prevention:
Vaccination
Secondary
Prevention:
Screening

12. PRIMERY
PREVENSION

13. 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
parNcles
are
assembled
and
virus
released
Virus
uses
host
cell
to
replicate
viral
DNA
and
express
virally
encoded
proteins

14. Transmission
of
HPV
— 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)

15. 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

16. AcNve
protecNon
via
vaccinaNon
is
mediated
by
neutralizing
anNbodies
at
the
cervix
HPV
Cervical
canal
Neutralizing
anNbodies
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).

17. 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
Characteristics,
2007;
2.
Gardasil®.
European
Summary
of
Product
Characteristics,
2008.

18. HPV
Vaccines:
Cross
Protection
Gardasil(Merck)
Quadrivalent
Cervarix
(GSK)
Bivalent
HPV
45
(related
to
18)
V/P
3/2
V/P
1/17
Reduction
94%
HPV
31
(related
to
16)
V/P
5/21
Reduction
76%
V/P
14/30
Reduction
54%

19. HPV
Vaccination
Efficacy
Harper
D;
Expert
Review
Vaccines
2009

20. 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

21.
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
14.0
Diarrhea 1.2
1.5
Dizziness 2.8
2.6
Data
taken
from
product
monograph
Canada
and
Australia

22. 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

23. DuraNon
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

24.
Cervical
Cancer
Prevention
Normal
Cervix
HPV
Infection
Cervical
Dysplasia
Cervical
Cancer
Primary
Prevention:
Vaccination
Secondary
Prevention:
Screening

25. Options
in
screening
— PAP
smear
— VIA
— HPV
testing

27. Cervical
cancer
decrease
with
PAP
smear

28. Recommendation
— ACOG
guidelines
recommend
— age
21
— Discontinue
screening
in
women
at
65
to
70
years
of
age
who
have
had
three
or
more
consecutive
normal
smears,
and
no
abnormal
results
in
the
previous
ten
years.
— Women
aged
30
and
older
who
have
had
three
consecutive
normal
Pap
tests,every
2-­‐3
years
and
if
they
also
are
tested
for
HPV
DNA

29. 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?

30. Limitations
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

31. Limitations
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

32. Limitations
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

33. Limitations
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

34. Limitations
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

35. Limitations
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

36. 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

37. Cervical
Cytology
Where
does
it
fail?
Ø Due
to
mediocre
sensitivity,
there
are
false
negative
cases
so
the
test
needs
to
be
repeated
frequently
to
identify
all
cases
of
high
grade
disease
Ø Compliance:
Patient
has
to
come
back
for
results,
for
repeat
tests
or
colposcopy
-­‐
case
based
system

38. Visual
Inspection
with
Acetic
Acid
(VIA)

39. Options
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

40. Visual
Inspection
with
Acetic
Acid
(VIA)
Ø Negative
Ø Positive
Ø Cancer

41. Test
Qualities
of
VIA
in
Primary
Healthcare
Setting
(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.

43. HPV
testing
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)

44. HPV
Testing
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

45. Role
of
HPV
testing
• 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

46. 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 women
30-­‐69
Ø
9,667
women
HPV
testing
is
significantly
more
sensitive
to
detect
CIN
2+

47. 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
— HPV
testing
versus
standard
care
had
a
50%
reduction
in
stage
II
or
higher
cervical
cancer
(15
versus
33
/
100,000
person-­‐year)
and
cervical
cancer
mortality
(13
versus
26
per
100,000
person-­‐year).
— Significant
reduction
in
Ca
Cervix
in
the
HPV
negative
compared
to
negative
Pap
and
VIA
NEJM
Apr2009
360(14)1385-­‐94

48. HPV
tesNng
RCT
Ronco
etal
— Trial
in
Italy
— 94000
women
25-­‐60
randomized
in
2
phases
Ø Cytology
vs.
HPV
testing
and
cytology
(phase
1)
Ø
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

49. Cost
EffecNveness
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

50. Jeddah
Cervical
Screening
program
JCSP

51. 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

52.
HR-­‐HPV
testing
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

53. Conclusions
— Introduction
of
a
cervical
cancer
prevention
program
in
Saudi
Arabia
is
possible
— Vaccination
has
the
promise
to
prevent
cervical
cancer
in
a
large
group
of
women
— Screening
should
be
done
using
HPV
testing
as
the
initial
method
— All
aspects,
i.e.
Screening,
colposcopy,
treatment
and
invasive
cancer
surveillance
require
very
careful
quality
assurance
processes.

54.
Thank
you