78strategiesn in ksa

Dr.Nisrin
Anﬁnan

Consultant
Gynecology
Oncology

King
Abdulaziz
University
Hospital

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:

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

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

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

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?

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?

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

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.

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?

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.

of
any
screening
program,
either
primary

or
secondary,
will
be
difficult
in
patients
with
a
sexually

transmitted
infection.

–
is
it
cost-‐effective
given
the
low
rates
of

cervical
cancer?

—  Introduction
of
quality
assurance
in
screening
and

colposcopy.

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.

of
any
screening
program,
either
primary
or

secondary,
will
be
difficult
in
patients
with
a
sexually

transmitted
infection.

–
is
it
cost-‐effective
given
the
low
rates
of
cervical

cancer?

of
quality
assurance
in
screening
and
colposcopy.

—  Which
screening
method
should
be
used
and
how
does
one

triage
the
patients?

Cervical
Cancer
Preven8on

Normal

Cervix

HPV

Infection

Cervical

Dysplasia

Cervical

Cancer

Primary

Prevention:

Vaccination

Secondary

Prevention:

Screening

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)

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).

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.

HPV
Vaccines:
Cross
Protec8on

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%

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

HPV
Vaccina8on
Eﬃcacy

Harper
D;
Expert
Review
Vaccines
2009

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

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

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

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

HPV
vaccine
in
Saudi
Arabia

Statement

Saudi
Gynecology
Oncology
Group(
SGOG)
statement

—  Health
care
providers
should
be
encouraged
to
discuss
HPV

vaccine
for
women
who
wish
to
be
vaccinated
and
help
them
in

the
decision
making.

Primary
Vaccination
with
three
doses
of
cancer
cervix
vaccine

should
be
given
for
females
15
to
26
years
of
age
to
decrease
the

risk
of
HPV
infection
and
subsequently
prevent
cervical
cancer.

In
addition
catch-‐up
immunization
for
women
above
age
26

years
could
be
done
.

Women
who
received
the
HPV
vaccine
should
continue
to
follow

the
existing
cervical
cancer
screening
programs.

Saudi
Gynecology
Oncology
Group(
SGOG)
statement

—  Health
care
providers
should
be
encouraged
to
discuss
HPV

vaccine
for
women
who
wish
to
be
vaccinated
and
help
them
in

the
decision
making.

—  Primary
Vaccination
with
three
doses
of
cancer
cervix
vaccine

should
be
given
for
females
15
to
26
years
of
age
to
decrease
the

risk
of
HPV
infection
and
subsequently
prevent
cervical
cancer.

In
addition
catch-‐up
immunization
for
women
above
age
26

years
could
be
done
.

—  Women
who
received
the
HPV
vaccine
should
continue
to

follow
the
existing
cervical
cancer
screening
programs.

Op8ons

in
screening

—  PAP
smear

—  VIA

—  HPV
testing

Collec8on
methods

Physician
/
nurse
collection

Patient
self
collection

Cervical
cancer
decrease
with
PAP
smear

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?

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

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

Visual
Inspec8on
with
Ace8c
Acid
(VIA)

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

Test
Quali8es
of
VIA
in
Primary
Healthcare
Sefng

(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.

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)

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

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

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+

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

HPV
tes8ng
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

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

Screening
program
in
Saudi
Arabia

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

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

Conclusions

of
a
cervical
cancer
prevention
program

in
Saudi
Arabia
is
possible

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.

78strategiesn in ksa

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