1. Primary and Secondary Prevention of Cervical
Cancer in Saudi Arabia
James Bentley
Professor Department of Obstetrics and
Gynecology
Dalhousie University
Halifax Canada

3. Disclosure
• Dr Bentley is involved in research for GSK and Merck
• Dr Bentley has been a consultant for and is on speakers
bureau for both GSK and Merck

4. Outline
• Epidemiology of cervical cancer in Saudi Arabia
– How does that compare with the world
• What causes cervical cancer?
• Primary and Secondary Prevention
• Secondary Prevention:
– Is “pap” testing the best way to screen?
– What about HPV testing
• Primary Prevention
– Who/ when/ how
• Unanswered questions and solutions

7. Cervical Cancer in Saudi Arabia
• Muslim country
population > 25
Million
• 2 million non Saudi
women
• 1.9 cases per
100,000 women
• Currently no
organized screening
programs
0 1 2
15-19
20-24
25-29
30-34
35-39
40-44
2010
2005
Millions

8. Global Impact of Cervical Cancer
• 3rd commonest cancer
worldwide
• 510,000 new cases
per year
• 288,000 women die
each year, 80% of
deaths occurring in
developing countries

9. Canadian epidemiology of cervical cancer
• Incidence of cervical cancer peaks among women in their 40s and
among women ≥ 70 years of age1
• The median age at diagnosis of cervical cancer is 47; the median age
at diagnosis for all types of cancer is between ages 60 and 692
1. TBD. 2. Cancer Care Ontario (Ontario Cancer Registry, 2005).
Incidence and mortality rates of cervical cancer in Canada1
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
0.0
5.0
10.0
15.0
20.0
Age
Rate(per100,000)
Incidence rate Mortality rate

10. Canadian Cervical Cancer
Mortality

11. Age standardised incidence of invasive cervical cancer and coverage of screening, England,
1971-95.
Quinn M et al. BMJ 1999;318:904
©1999 by British Medical Journal Publishing Group

12. 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

13. Papillomavirus – phylogenetics
HPV18- Related
45, 39, 59, 51, 56
HPV16- Related
31, 33, 35, 52, 58

14. HPV types in cervical cancer
53.5
2.3
2.2
1.4
1.3
1.2
1.0
0.7
0.6
0.5
0.3
1.2
4.4
2.6
17.2
6.7
2.9
0 10 20 30 40 50 60 70 80 90 100
X
Other
82
73
68
39
51
56
59
35
58
52
33
31
45
18
16 53.5%
70.7%
77.4%
80.3%
82.9%
85.2%
87.4%
88.8%
Munoz N et al. Int J Cancer 2004; 111: 278–85.
Cervical cancer cases attributed to the most frequent HPV genotypes (%)
HPVgenotype

15. HPV Transmission and Risk factors
• Skin to skin sexual contact
– Genital-genital, manual-genital, oral genital
– May result from non penetrative contact
– Condoms reduce risk but… are not fully protective
– Vertical transmission to newborn is rare (occurs with laryngeal
papillomatosis)
• Risk factors
– Young age (peak age group
20–24 years of age)
– Lifetime number of sex partners
– Early age of first sexual intercourse
– Male partner sexual behavior
– Smoking
– Oral contraceptive use
– Uncircumcised male partners

16. Natural Course of Genital HPV Infection
First
Lesion
Immune
Response
CMI
Virological
clearance
DNA-ve
80% of cases
Viral
persistence
DNA+ve
LSIL/HSIL
infection
Seroconversion
Antibody to L1
DNA-ve Productive viral
infection, low grade
lesions DNA+ve
HrHPVs 12-18months
LrHPVs 4-9months
Time

17. Biology of HPV Infection: High-Grade
Lesions1–3
*CIN = cervical intraepithelial neoplasia; †ICC = invasive cervical cancer
1. Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564. Adapted with permission from the Massachusetts
Medical Society. 2. Doorbar J. J Clin Virol. 2005;32(suppl):S7–S15. 3. Bonnez W. In: Richman DD, Whitley RJ, Hayden
FJ, eds. Clinical Virology. 2nd ed. Washington, DC: American Society for Microbiology Press; 2002:557–596.
Normal
Cervix
HPV Infection
(CIN* 2) (CIN* 3)
Cervical Cancer
(ICC†)
Infectious Viral
Particles
Episome
Perinuclear Clearing
(Koilocytosis)
Basal cell layer

18. Normal
CIN 1
CIN 2
CIN 3
Cancer

19. Risk Factor
Cancer Precursor
Invasive Cancer
Death
Primary Prevention
Sexual Behaviour
HPV Infection and CIN
Incidence Rate
Mortality Rate
Secondary Prevention
Tertiary Prevention
Franco et al., Vaccine,

20. Current Screening

21. Pap smear
• MD/RN to collect
• Supplies-low cost
• Cytotech to process and read
• Pathologist to confirm
• Oversight of the lab – Quality
control due to this subjective test
• Weeks to report
• Notify woman
• Counsel woman
• Possible other assessments or
treatment
• Expensive Sherris
J.
Intn
Persp
Sex
Reprod
Health
2009;35,3:147

22. Current Recommendations
• 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

23. Authora
Duration
Total no
Abnormal
PAP
ASC-US
ASC-H
LSIL
HSIL
AGUS
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

24. 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

25. 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

26. 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

27. 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?

28. Role of HPV testing
• Triage equivocal or low grade cytology smears
(ALTS trial)
• Follow-up of women with abnormal cytology but normal
colposcopy
• Predict outcome after treatment of high grade disease
• Primary Screening
Cuzick
J.
Vaccine
2008

29. CCCAST trial
PAPHPV
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+

30. 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

31. HPV testing 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

32. 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

33. PRIMARY PREVENTION

34. Active protection via vaccination is mediated by
neutralizing antibodies at the cervix
HPV
Cervical
canal
Neutralizing
anKbodies
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).

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

36. Effect on Treatments
Harper D; Expert Review Vaccines 2009

37. Early
effect
of
the
HPV
vaccinaKon
programme
on
cervical
abnormaliKes
in
Victoria,
Australia:
an
ecological
Study
– Australian
Data
– All
women
12-­‐26
were
offered
vaccinaKon
with
Gardasil
– Using
State
based
Pap
Test
Registers
– VaccinaKon
rates:
•
71-­‐79%
in
the
school
based
program
• 74%
I
dose,
69%
2
doses,
56%
3
doses
in
18-­‐28
year
olds
– Screening
starts
at
age
18
or
2
years
aaer
sexual
acKvity
Brotherton
JM
et
al
Lancet
(2011)
Vol
337
June
18
2085-­‐2091

38. Early
effect
of
the
HPV
vaccinaKon
programme
on
cervical
abnormaliKes
in
Victoria,
Australia:
Low
Grade
effect
by
age
Brotherton
JM
et
al
Lancet
(2011)
Vol
337
June
18
2085-­‐2091

39. Early
effect
of
the
HPV
vaccinaKon
programme
on
cervical
abnormaliKes
in
Victoria,
Australia:
High
Grade
effect
by
stage
Brotherton
JM
et
al
Lancet
(2011)
Vol
337
June
18
2085-­‐2091

40. HPV Vaccination: Summary
• Safe, effective vaccines
• In many societies has been shown to decrease HPV
effects, i.e. warts and cervical cancer precursors
• Best given in school based programs:
– Ensures maximal coverage with all 3 doses
– Able to give before any sexual activity
• But…..
• Costly
• Does it make economic sense in SA?
• Is it necessary in SA?
• However no significant harm from vaccination

41. 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?

43. 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

44. 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.