Prevention and Early

Detection in Cervical
Cancer
Bambang Dwipoyono
SMF ginekologi onkologi
RS Kanker Dharmais

Seminar Nasional, Dharmais 9 Nopember 2010 1

Cervical Cancer So Important
to Prevent?

Seminar Nasional, Dharmais 9 Nopember 2010 2

Seminar Nasional, Dharmais 9 Nopember 2010 3
 Cervical Cancer
To day we are not talking about
THE TREATMENT DILEMMA

SURGERY RADIOTHERAPY

Seminar Nasional, Dharmais 9 Nopember 2010 4

 Cancer Control? Early detection?
Prevention?
 Prevention and early detection are part of
Cancer Control?
 What evidence should be provide before
starting Cancer Control Programs?
 What studies should be done to elaborate
the opportunities making Cancer Control
Programs successful?

Seminar Nasional, Dharmais 9 Nopember 2010 5

 What is Cancer Control?
 the reduction of cancer incidence, morbidity, and
mortality through an orderly sequence from research on
interventions and their impact in defined populations to
the broad systematic application of the research results.
(old)

 the conduct of basic and applied research in the

behavioral, social, health and population sciences to
create or enhance interventions that, independently or in
combination with biomedical approaches, reduce cancer
risk, incidence, morbidity and mortality, and improve
quality of life (Cancer Control Review Group, 1998 -
modified).
Seminar Nasional, Dharmais 9 Nopember 2010 6
What is Cancer Control Research?

 Research that aims to reduce risk,

incidence, and deaths from cancer as well
as enhance the quality of life for cancer
survivors.

Seminar Nasional, Dharmais 9 Nopember 2010 7

 Epidemiologic study should and would help us
applying Cancer Control Programs
 Descriptive
 Analytic
 We would have:
 Incidence, prevalence, rate or ratio
 Causal relationship (time dependent)
 Diagnostic
 Prognostic
 Survival, etc
Seminar Nasional, Dharmais 9 Nopember 2010 8
 Main areas of Cancer Control
 Surveillance
 Molecular epidemiology
 Quality of care
 Tobacco control
 Behavioral research
 Energy balance
 Survivorship
 Health disparities

Seminar Nasional, Dharmais 9 Nopember 2010 9

 Cervical Cancer
Worldwide
Estimated Number of New Cancer Cases and Cancer Deaths in 2002

Clear difference
between
developed and
developing world

Source: Parkin DM, Bray F, Ferlay J, Pisani P. Global

Seminar cancer
Nasional, statistics,
Dharmais 9 2002. CA Cancer J Clin.102005
Mar-Apr;55(2):74-108. Nopember 2010
Public Health Problem: Excess
Cervical Cancer Mortality

Source: Freeman HP, Wingrove BK. Excess cervical cancer mortality: A marker for low access to
health care in poor communities. Rockville, MD:Nasional,
Seminar National Dharmais
Cancer Institute,
9 Center to Reduce Cancer
11
Health Disparities; 2005. Report: NIH Pub. No. 05-5282. 2010
Nopember
 Cervical cancer: What is the chance
of survival after treatment?
FIGO Stage 5-Year Survival

Stage I 81-96%

Stage II 65-87%

Stage III 35-50%

Stage IVA 15-20%

Seminar Nasional, Dharmais 9 Nopember 2010 12

 Cervical Cancer:
Improved Mortality & Morbidity with Early
Identification

FIGO Stage % Cases 5-Year Survival

I 46% 83%
II 28% 64%
III 21% 38%
IV 4% 14%

FIGO Annual Report. J Epi & Biostat

1998; 3(1)

Seminar Nasional, Dharmais 9 Nopember 2010 13

Early Detection and Prevention

Seminar Nasional, Dharmais 9 Nopember 2010 14

 Milestones in cancer prevention

 1761 John Hill: nasal carcinomas in snuff users (109)

 1775 Percival Pott: scrotal cancer in chimney

sweeps

 1911 Peyton Rous: viral etiology of certain tumors

 1919 James Ewing identifies pre-malignant

neoplasia

Seminar Nasional, Dharmais 9 Nopember 2010 15

 Milestones in cancer prevention
 1925 Lockhart-Mummery describes
genetic nature of familial polyposis

 1930’s CIS of breast and cervix described by

Younge and Broder

 1940’S Surgery for FAP, cervical neoplasia,

DCIS/LCIS

 1993 Winawer: CRC prevention by endoscopic

polypectomy

 2007 Vaccine for cervical cancer

Seminar Nasional, Dharmais 9 Nopember 2010 16
 Current Research Paradigm at
Most Academic Cancer Centers

 Main focus on
 Developing & improving cancer therapies
 Carcinogenesis
 Early detection

 Little attention on cancer prevention or

risk reduction
Seminar Nasional, Dharmais 9 Nopember 2010 17
LEVELS OF PREVENTION (Review)

PRIMARY PREVENTION
Prevention of disease by
controlling risk factors (e.g.,
non-smoking promotion)

Seminar Nasional, Dharmais 9 Nopember 2010 18

Epidemiology Describes Four Levels For
Cancer Prevention
 Primordial or Societal Prevention
 Avoids the emergence and establishment of social, economic,
and cultural patterns of living that are known to contribute to
elevated risk of disease
 Primary Prevention
 Controlling causes and risk factors
 Condoms, needle exchange or vaccine to prevent spread of
HIV, HBV or HPV
 Secondary Prevention (from onset of disease to normal diagnosis)
 Develop safe accurate methods of detection (at early curable
stage) and development of preventive drugs, vaccines
 Tertiary Prevention
 Reducing ongoing morbidity or mortality once cancer is
diagnosed
• Monitoring for early detection of second primary cancers
Seminar Nasional, Dharmais 9 Nopember 2010 19
Modified from Basic Epidemiology, R. Beaglehole, et al, 1993
Cancer Prevention Research

Nutritional
Science
Cellular and
Molecular Infectious
Biology Disease
Surgery Public Health Epidemiology
Policy

Behavioral Imaging/
Medicine Screening

Pharmacology

Seminar Nasional, Dharmais 9 Nopember 2010 20

Risk Factors for Cervical Cancer
 Human Papilloma Virus
 Chlamydia trachomatis infection
 Number of partners
 Age of first sexual contact
 Male partner factors
 Hygiene
 Smoking
 Low socioeconomic class

Seminar Nasional, Dharmais 9 Nopember 2010 21

 Factors Contributing to Cervical
Cancer
5%-10%

50%-60% False negative

cytology test
10%-15%

Never or Cytology test abnormal,

patient lost to follow-up
Rarely
Screened Cytology test abnormal,
mismanaged
10%-15%

Uncommon
cancers
difficult to 5%-10%
detect
Sources:NIH Consensus Conference
Janerich, Connecticut 9%-12%
Sung, California Seminar Nasional, Dharmais 9 Nopember 2010 22
 Pathogenesis of Cervical
Cancer

Persistent Cellular
HPV Infection
HPV Infection Dysregulation

High-Grade CIN
Immunologic
Factors
Invasive Cancer

Co- carcinogens
Seminar Nasional, Dharmais 9 Nopember 2010 23
 Continuum of Care for Cervical
Cancer Control

15 years 30 years 45 years

Vaccination Screening and Cancer
treatment treatment
Source: WHO 2006 Seminar Nasional, Dharmais 9 Nopember 2010 24
Seminar Nasional, Dharmais 9 Nopember 2010 25
 Natural history of CIN
 Some examples of CIN I will appear to progress to CIN
3
 Some examples of CIN will regress
 Some examples of CIN will appear to develop into
invasive sqaumous cell carcinoma
 Some examples of CIN may remain unchanged
 Many examples of invasive squamous cell carcinoma
are preceded by CIN

CIN 1 CIN 2 CIN 3

Regress 57% 43% 32%
Persistent 32% 35% <56%
Progress - CIS 11% 22% -
- Invasion 1% 5% >12%
Östör. Int J Gyn Path, 1993 (literature review)
 HPV Human Papillomavirus
Closed circular double stranded DNA virus that is recogni
zed to cause genital warts and cervical cancer
 HPV Incubation

 Average incubation is 3 weeks to 1 year

 Possibly years before appearance of warts or cervic

al abnormalities

 Some will be transient and may never be detected

Impact of Persistence of Oncogenic HPV
Types
 Persistent infection with high-risk HPV types is necessa
ry for the development of CIN 3
 There is a strong relationship between persistent high-
risk HPV infections (particularly with HPV 16 and `18) an
d SIL/HSIL incidence
– Infections with high-risk types are more likely to persist
than infections with low-risk types
– A study of HPV persistence reported that HPV 16 infe
ctions persist longer than infections with other types
– The persistence of high-risk types of HPV infections
increases the risk of HSIL and is necessary for the d
evelopment of CIN 3
Etiological model of human papillomavirus (HPV) infection and cervical cancer,
illustrating probable role of remote behavioural risk factors for persistent
infection and of coexisting factors that mediate lesion progression

Franco, E. L. et al. CMAJ 2001;164:1017-1025

Copyright ©2001 Canadian Medical Association or its licensors

 A programmatic menu of options for secondary cervical cancer
prevention based on human papillomavirus (HPV) DNA testing for
primary screening and the current tools available for management of
screen positives.

Gage J C , Castle P E JNCI J Natl Cancer Inst

2010;102:1524-1527

Published by Oxford University Press 2010.

New Strategies for CC Prevention
The old strategy:
• Organised cervical cancer screening programs
based on the traditional Pap can prevent 75-80% of
cervical cancers
 75-80% is for the whole population, i.e. includes
women who are not screened or who are poorly
screened)
 For women who are regularly screened in an
organised program, reductions in cervical
cancer will be higher, perhaps 85-90%
 Based on highly organised programs with good
coverage of the population and excellent quality
control at all levels
33
New Strategies for CC Prevention
So, do we need new strategies for prevention?
• To further reduce cervical cancer rates
• In screened populations, cervical cancers are in:
1/3 unscreened; 1/3 follow-up; 1/3 false negative
• To simplify the screening process or reduce the
cost of screening
• Organised cervical cancer screening programs
are incredibly complicated and costly to run
• If new technologies or strategies can reduce the
complexity, they will both facilitate program
operation / implementation and yield cost savings
• To extend protection to women who will not / cannot
attend screening or follow-up
34
New Strategies for CC Prevention
New screening technologies
•Liquid-based cytology (LBC)
•HPV DNA testing (Hybrid Capture 2)
• HPV RNA testing (Norchip, Genprobe)
• p16INK4A testing (mtm Technologies)
• MCM2/TOP2A staining (ProExC)
• etc.

35
 Liquid-Based Cytology (LBC)
Ronco G. et al. BMJ 2007
• Randomised controlled trial with >45,000 women
randomised to LBC or conventional cytology within
regional organised screening programmes in the
north of Italy
• Liquid based cytology is not statistically significantly
different from the conventional Pap in terms of
sensitivity for detection of CIN2+

36
 Liquid-Based Cytology (LBC)
Arbyn M. et al. Obstet Gynecol 2008
• Systematic review of 9 studies comparing LBC to
the conventional Pap in which the results were
based on histological outcomes
• LBC is neither more sensitive nor more specific
for the detection of high-grade CIN compared with
the conventional Pap test

37
 Large, prospective, randomised controlled trials (RCTs)
HPV Testing for Primary Screening
Study Country N Age HPV Test Cytology Main Study Outcomes
Finnish RPHT Finland 200,000 25-65 HC2 Pap smear Cumulative incidence of
CIN2+ after initial screen
ing

Swedescreen Sweden 12,527 32-38 PCR (GP5 Pap smear Comparative prevalence
+/6+) of CIN2+ at the exit scree
n

POBASCAM The Nether 44,102 30-60 PCR (GP5 Pap smear Proportion of CIN3+ foun
-lands +/6+) d from recruitment to exi
t screen

ARTISTIC United Kin 25,000 20-64 HC2 LBC Comparative prevalence

gdom of CIN3+ at exit

NTCC Italy 95,000 25-60 HC2 Pap & LBC Cumulative prevalence o
f CIN2+ up to and includi
ng exit screen

38
HPV Testing for Primary Screening
Ronco G et al. JNCI 2008
•Randomised controlled trial with 90,000 women
randomised to conventional Pap or HPV testing (HC2)
with immediate referral to colposcopy if positive for
HPV or low-grade cytology (age 36-60)
• Positive threshold – 1.0pg/mL / CIN3+
• Relative sensitivity 1.52 (1.06 to 2.19)
• Relative PPV 0.63 (0.44 to 0.89)
• Positive threshold – 2.0pg/mL / CIN3+
• Relative sensitivity 1.50 (1.04 to 2.16)
• Relative PPV 0.81 (0.56 to 1.15)

39
HPV Testing for Primary Screening
Bulkmans et al. BJC 2005
•Randomised controlled trial with >44,000 women
randomised to conventional Pap or HPV testing (in-
house PCR) conducted within the routine Dutch
cervical cancer screening programme with cytology
triage (aged 29-56 years):
• More sensitive for CIN3+ (92.9 vs 64.3%)
• Equivalent specificity (96.7 vs 95.1%)
• Higher PPV (14.6 vs 7.3%)

40
HPV Testing for Primary Screening
Conclusions from the data:
•HPV testing can increase the sensitivity for CIN3+
by about 50% over that of high-quality conventional
Pap cytology
•With cytology triage of women testing HPV positive,
the specificity and PPV are equivalent to that of high-
quality cytology
•HPV testing will allow the screening interval to be
safely lengthened

41
HPV Testing for Primary Screening
Other aspects to consider:
•Produces a non-subjective + or – result which simplifies
training and QA procedures
•Allows the high-volume testing to be automated while the
labour-intensive cytology is restricted to only the HPV+
samples
• One technician can do 720 HPV samples in one
laboratory shift compared to 40-100 Paps
•Volume of cytology is reduced by 75-90%
•The HPV+ cytologies are the ones with the cytological
abnormalities - cytotechs spend less time looking at
normal slides and more time looking at abnormal slides
• improved job satisfaction & maintenance of skills
42
 HPV Vaccination
Two prophylactic HPV vaccines:
• Merck (MSD/Sanofi Pasteur MSD)
• HR-HPV 16 & 18, responsible for ≈70% of cervical
cancers
• LR-HPV 6 & 11, responsible for ≈90% of genital
warts and a number of low-grade abnormal Pap
smears
• GSK
• HR-HPV 16 & 18, responsible for ≈70% of cervical
cancers
• New AS04 adjuvant which is claimed to produce an
enhanced immune response

45
 HPV Vaccination
Future II Study Group, NEJM 2007: Merck/MSD, HPV 6 11 16
18, women aged 15-26 with 4 or fewer sexual partners
Per protocol, effic Unrestricted susc Intention to treat, Intention to treat,
acy for vaccine ty eptible populatio vaccine types all types
pes n % (95% CI)
% (95% CI) % (95% CI) % (95% CI)

CIN2 100 (86-100) 99 (93-100) 57 (38-71) 17 (1-31)

CIN3 97 (79-100) 97 (90-100) 45 (23-61) 22 (3-38)
AIS 100 (<0-100) 100 (55-100) 28 (<0-82) 21 (<0-38)

A-B Moscicki J Adoles Health 2008

46
 HPV Vaccination
Harper et al. Lancet 2004, 2006: GSK, HPV 16 18, women
aged 15-25 with 6 or fewer sexual partners
Age Ra Efficacy-Persiste Efficacy-Cytolog Efficacy-CIN 1+
nge nt Infection y LSIL+
Per-protocol p 15-25 y 100% 93% 100%
opulation at 53 ears (95% CI: 34-100) (95% CI:71-92) (95% CI: 42-100)
months for typ
es 16 & 18

Hildesheim et al. JAMA 2007: Cervarix had greatly reduced

efficacy in women with pre-existing HPV 16 and/or 18
infections

47
 HPV Vaccination
The two prophylactic HPV vaccines:
• Have largely equivalent efficacy for the HPV types
contained in the vaccines
• Have high efficacy if given before exposure to HPV
– i.e. if given to girls or women before the start of
sexual activities
• Have reduced efficacy if given to women who are
sexually active
• Have a clear role in cervical cancer prevention
strategies through the mass vaccination of pre-
sexually active adolescent girls
• Will not replace cervical screening programmes
48
Terima Kasih