Transcript Screening in Developed Countries

Screening in
Developed Countries
Lynette Denny
Gynaecology Oncology Unit
Department Obstetrics & Gynaecology and
Institute Infectious Diseases and Molecular
Medicine
University of Cape Town/Groote Schuur
Hospital
Introduction

European Union has grown from 6 countries in 1951 to a
diverse group of 25 countries that is continuing to expand

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In 2004
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2.9 million cases of all types if cancer diagnosed of whom
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1.7 million died
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Huge variation region to region
EU currently recommends, where appropriate, populationbased organised screening programmes, with quality
assurance at all levels
Introduction
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IARC analysis of successful cervical cancer screening
programmes in 1986
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Greatest fall in Iceland (84% reduction cervical cancer between
1965- 1982) characterised by:
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Shortest screening interval
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Widest target age range
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Lowest fall was in Norway where population coverage < 5%
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Falls in Finland, Sweden and Denmark were 50%, 34% and 27%
respectively
IARC working group estimated that for inter-screen intervals of
up to 5 years, protective effect of organised cytology-based
screening was over 80%
Introduction

In British Columbia, incidence of cervical cancer dropped from
28.4 to 6.9 and mortality from 11.4 to 3.3 per 100 000 over 20
year period
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UK screening programme was organised in 1988 and
achieved coverage of over 80% of target age group
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Between 1988 and 1995, cervical cancer incidence fell by
40% and by 2004 death rate fell by 50%
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Estimated that over 1000 deaths from cervical cancer
prevented per year in UK through cytology based screening
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However, the performance of cytology is very variable and
highly dependent on many factors
Introduction
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Key to successful screening programmes
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Organised, population-based, national
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Targeted age group
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Call and recall at defined intervals
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Quality assurance from smear takers, to laboratory
reading, referral to and of colposcopy
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Strong administrative infrastructure
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Clinical practice guidelines
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Ongoing accreditation of all players
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Which in UK costs approx. £150 million per year
Cervical cancer screening in Europe*
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Questionnaire of 18 EU countries found
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Low or inadequate coverage
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Shortcomings in routine registration, evaluation and
monitoring at all levels of screening programme
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Excessive number of lifetime screens recommended in
some settings
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And/or short screening intervals in others
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Variable payment strategies, resulting in inequity of access
to care for many
*A Antilla
et al. Br J Cancer 2004
Incidence of cancer in Western Europe
Incidence of cancer in Southern Europe
Incidence of cancer in Eastern Europe
Incidence of cancer in Northern Europe
Incidence of cancer in North America
Incidence of cancer in South Central Asia
Incidence of cancer in sub-Saharan Africa
Incidence of cancer in South and Central America and Caribbean
Screening in developed countries
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While coverage and identifying appropriate target group are
critical the key issue in developed countries is accuracy of the
test
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Historically, conventional cytology probably one of the most
successful public health interventions
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Yet performance is extremely variable and highly dependant
on quality assurance
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Quest for ‘zero defect’ has led to development of new
technologies
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But not all that glitters is gold!
New technologies
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Liquid based cytology
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Problem of study design
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Split sample technique versus direct to vial or historical
controls
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Lack of ‘gold standard’ to enable test performance to be
calculated
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Studies report ‘detection rates’ rather than true cervical
disease
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Widely conflicting results
Systematic reviews of LBC versus
conventional cytology
Author
Subgroup
Indicator
Key findings
Nanda et al (2000)
ThinPrep
Histology
Higher sensitivity
LBC
Hartmann et al
(2001)
All studies (962)
Histology
Current evidence
inadequate to state
LBC superior
Klinkhamer et al
(2003)
All studies
Histology
SurePath lower
sensitivity than
conventional for
ASC or >’er
No definitive data on
detection LSIL or
HSIL d/t conflicting
data for SurePath
ThinPrep likely to be
more sensitive for
LSIL and HSIL
Cape Town Study (Taylor et al, 2006)
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Direct comparison of performance of LBC and conventional
cytology for detecting CIN 2+ in unscreened women aged 35
– 65 years
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5652 women screened with ThinPrep or conventional cytology
rotated on a 6 month basis for 36 months
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All women underwent colposcopy and histological sampling 6
monthly
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Assessment cytology and histology blinded
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Histology was gold standard
Cape Town Study
CIN 2 + histology
LBC
(n = 3114)
Conventional
(n = 2444)
Sensitivity (%)
60
69
Specificity (%)
94
95
PPV (%)
19
22
NPV (%)
99
99
‘Satisfactory but
limited by’ (%)
7
28
2.2
0.8
Unsatisfactory (%)
LBC versus conventional cytology
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UK study of over 100 000 women, LBC was shown to decrease
‘inadequate’ reads by 80% (from 9 – 1%), eliminating need for
repeat sampling
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Greater through put and efficiency at laboratory level
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Enables reflex HPV DNA testing for ASC-US cytology
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Reported as cost-effective and implemented nationally
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Potential for automated reading, although insufficient evidence
currently to justify implementation
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LBC currently screening method of choice in USA and UK
HPV DNA testing
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Robust technology
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Objective test compared to subjective nature of
cytology
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Reproducible with built in quality control
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High throughput and suitable automation
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Most studies use HC II, as only FDA approved
commercially available test
Human Papillomaviruses
Presentation of Genital Warts
HPV DNA testing
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Primary screening alone
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Primary screening followed by cytology for positive
tests
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Triage of ASC-US/borderline cytology
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Follow up post treatment or post colposcopy
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Psychosocial issues
HPV testing
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In an overview of European and North American studies on HPV
testing in primary cervical cancer screening of more than 60 000
women (Cuzick 2006)
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Sensitivity of HPV testing was 96% compared to 53% for
cytology
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Specificity was lower for HPV testing 91% vs 96% for cytology
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Sensitivity of HPV testing was similar across studies, whereas
performance of cytology was highly variable
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Sensitivity of HPV testing did not vary with age, whereas cytology
had a higher sensitivity (79%) in women over 50 compared to
younger women (60%)
Primary screening
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HART Study (Cuzick 2003)
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10538 women aged 30 – 60 years
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Women with borderline smears or HR-HPV + with negative
cytology randomised to immediate colposcopy or to
surveillance with repeat HPV testing, cytology and
colposcopy at 12 months
Primary Screening
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Key Findings
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Sensitivity of HPV testing was 97% versus 77% of borderline or
worse cytology for detection CIN 2+
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HPV testing less specific (93% vs 96% for cytology)
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Of women HPV positive at baseline and negative cytology, 45%
were HPV negative at 6- 12 months and no CIN 2+ was
diagnosed in these women
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35% of women with borderline cytology and HPV positive at
baseline were HPV negative at 6 – 12 months and no CIN 2+
diagnosed
Primary Screening
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Recommendations HART study
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HPV testing used for primary screening in women older
than 30 years
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Cytology to be used to triage HPV positive women
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HPV positive women with borderline or negative cytology
undergo repeat testing after 12 months
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Only if persistent HPV positivity, refer for colposcopy
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Data suggests that this algorithm will result in improved
detection rates of CIN 2+ without increase in colposcopy
referral rates
Primary screening
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Key issues
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Cost (?reduced by increased screening interval)
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Duration of protection afforded by negative HPV test
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Dissemination of information about HPV
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Psycho-social implications of cervical cancer caused
by STI and acceptability to women
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Appropriate screening algorithm for women younger
than 30 years
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Self sampling
HPV testing as an adjunct to cytology
screening
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HPV testing in combination with Pap (i.e. dual testing) – would
lead to very high referral rate for colposcopy however,
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Canadian, USA and Cost Rica studies show that dual
negative HPV and Pap negligent risk of CIN 2+ or cancer at 5
years, and probably up to 10 years
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Triage of ASC - US cytology
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ALTS trial showed cost-effective and reduced colposcopy
referral rate from 100 to 56%
Women with normal cytology and positive HC 2, risk of
developing abnormal smear in 10 years is 18% in young
women (22 – 32) and 25% in older women (40 – 50) (Kjaer
2006)
HPV testing - Summary
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Evidence suggests
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More effective as primary screen in women over 30 with
cytology to triage positive tests prior to referral for
colposcopy
Triage of ASC-US borderline cytology
10 Studies of HPV testing post treatment showed
significantly higher sensitivity and longer follow up intervals
safe and feasible
Cost-effectiveness of dual screening needs to be
determined
Ultimate impact on cervical cancer prevention only
predicted through mathematical modelling
Natural history of cervical cancer
Initial HPV infection
Normal Cervix
Primary prevention
HPV infected cervix
Invasive disease
Secondary Prevention
Persistent infection with HR types
HPV
Precancerous lesion
HPV Vaccines
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Merck vaccine now licensed in over 70 countries
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Targets types 6,11, 16 and 18
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Estimated to prevent at least 70% of cervical cancers, but if
cross-protection by types 31 and 45, a further 10% may be
prevented
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GSK vaccine in process of being licensed in a number of
countries, targeting only 16 and 18, but with possible crossprotection against 31 and 45
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Impact of the vaccines on cervical cancer incidence will not be
seen for approximately 20 years or longer
HPV Vaccines
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In first 10 years of HPV vaccine availability, the people
vaccinated will be those least at risk i.e those who can afford
to pay for the vaccine ($360 for three shots)
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Same individuals who would most likely have access to
secondary prevention
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Like with Hep B vaccine, regions where HPV vaccines likely
to have greatest impact will be last to receive it!
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At all levels cervical cancer remains a disease of ‘inequity of
access’ to health care
HPV Vaccines
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Lessons from developed world
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Widespread ignorance in lay public and health care
professionals on
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Transmission dynamics of HPV
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Relationship between HPV infection and disease
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Fear of anything related to ‘sexually transmitted’
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Vaccine community divorced from cancer community and
do not intersect
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Vaccine implementation controlled by paediatricians who
are most likely to promote vaccines that prevent diseases
they treat eg rotavirus etc
HPV Vaccines
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Delayed impact of HPV vaccines may dampen political will
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Need to vaccinate prior to onset of sexual activity requires
adolescent vaccine infrastructure
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Permission of parents to vaccinate against ? Cancer ? STI
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Anti-vaccine lobby and Religious Right (in many guises)
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Who to vaccinate? Girls or Boys or both?
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Impact of vaccination on secondary prevention programmes
Conclusions
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Possibility of cervical cancer prevention never been as real as
in the early 21st century
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In much of developed world cervical cancer is a relatively rare
disease
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Vaccine will have a major impact but the need for secondary
prevention remains paramount
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New technologies are strongly industry driven and while the
evidence is compelling, critical appraisal and appropriate
allocation of resources, is the cornerstone of high quality
medical practice
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Even the rich should not waste!!
New technologies
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mRNA expression of E6/E7 transcripts
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Persistent expression of viral oncogenes E6 and E7
necessary step in HPV-induced oncogenesis
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Detection of E6/E7 mRNA for high risk types of HPV may
be an indicator of infection and of a further step in
progression towards cancer
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Main clinical utility will be to increase specificity
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Commercial kit PreTect HPV-proofer
New technologies
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P16ink4a
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Cyclin-dependent kinase inhibitor whose expression is negatively
controlled by pRB gene product
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Strongly over-expressed in cervical cancer cell lines in which RB
has been iinactivated by the high-risk HPV E7 oncoprotein
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P16 overexpression, recognised by immunostaining, is a marker
of HPV infection and activated expression of viral genes and
viral-induced deregulation of cell cycle
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May be expressed in metaplastic, atrophi and endocervical cells
leading to loss of specificity
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Main clinical utility appears to be in triage of LSIL or for women
HPV DNA positive