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

In 2004

2.9 million cases of all types if cancer diagnosed of whom

1.7 million died

Huge variation region to region

EU currently recommends, where appropriate, population-

based organised screening programmes, with quality

assurance at all levels

Introduction IARC analysis of successful cervical cancer screening

programmes in 1986

Greatest fall in Iceland (84% reduction cervical cancer between

1965- 1982) characterised by: Shortest screening interval

Widest target age range

Lowest fall was in Norway where population coverage < 5%

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

UK screening programme was organised in 1988 and

achieved coverage of over 80% of target age group

Between 1988 and 1995, cervical cancer incidence fell by

40% and by 2004 death rate fell by 50%

Estimated that over 1000 deaths from cervical cancer

prevented per year in UK through cytology based screening

However, the performance of cytology is very variable and

highly dependent on many factors

Introduction

Key to successful screening programmes Organised, population-based, national

Targeted age group

Call and recall at defined intervals

Quality assurance from smear takers, to laboratory

reading, referral to and of colposcopy

Strong administrative infrastructure

Clinical practice guidelines

Ongoing accreditation of all players

Which in UK costs approx. £150 million per year

Cervical cancer screening in Europe*

Questionnaire of 18 EU countries found Low or inadequate coverage

Shortcomings in routine registration, evaluation and

monitoring at all levels of screening programme

Excessive number of lifetime screens recommended in

some settings

And/or short screening intervals in others

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

While coverage and identifying appropriate target group are

critical the key issue in developed countries is accuracy of the

test

Historically, conventional cytology probably one of the most

successful public health interventions

Yet performance is extremely variable and highly dependant

on quality assurance

Quest for ‘zero defect’ has led to development of new

technologies

But not all that glitters is gold!

New technologies Liquid based cytology

Problem of study design

Split sample technique versus direct to vial or historical

controls

Lack of ‘gold standard’ to enable test performance to be

calculated

Studies report ‘detection rates’ rather than true cervical

disease

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)

Direct comparison of performance of LBC and conventional

cytology for detecting CIN 2+ in unscreened women aged 35

– 65 years

5652 women screened with ThinPrep or conventional cytology

rotated on a 6 month basis for 36 months

All women underwent colposcopy and histological sampling 6

monthly

Assessment cytology and histology blinded

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

Unsatisfactory (%) 2.2 0.8

LBC versus conventional cytology

UK study of over 100 000 women, LBC was shown to decrease

‘inadequate’ reads by 80% (from 9 – 1%), eliminating need for

repeat sampling

Greater through put and efficiency at laboratory level

Enables reflex HPV DNA testing for ASC-US cytology

Reported as cost-effective and implemented nationally

Potential for automated reading, although insufficient evidence

currently to justify implementation

LBC currently screening method of choice in USA and UK

HPV DNA testing Robust technology

Objective test compared to subjective nature of

cytology

Reproducible with built in quality control

High throughput and suitable automation

Most studies use HC II, as only FDA approved

commercially available test

Human Papillomaviruses

Presentation of Genital Warts

HPV DNA testing

Primary screening alone

Primary screening followed by cytology for positive

tests

Triage of ASC-US/borderline cytology

Follow up post treatment or post colposcopy

Psychosocial issues

HPV testing

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) Sensitivity of HPV testing was 96% compared to 53% for

cytology Specificity was lower for HPV testing 91% vs 96% for cytology Sensitivity of HPV testing was similar across studies, whereas

performance of cytology was highly variable 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

HART Study (Cuzick 2003)

10538 women aged 30 – 60 years

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

Key Findings

Sensitivity of HPV testing was 97% versus 77% of borderline or

worse cytology for detection CIN 2+

HPV testing less specific (93% vs 96% for cytology)

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

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

Recommendations HART study HPV testing used for primary screening in women older

than 30 years

Cytology to be used to triage HPV positive women

HPV positive women with borderline or negative cytology

undergo repeat testing after 12 months

Only if persistent HPV positivity, refer for colposcopy

Data suggests that this algorithm will result in improved

detection rates of CIN 2+ without increase in colposcopy

referral rates

Primary screening

Key issues Cost (?reduced by increased screening interval)

Duration of protection afforded by negative HPV test

Dissemination of information about HPV

Psycho-social implications of cervical cancer caused

by STI and acceptability to women

Appropriate screening algorithm for women younger

than 30 years

Self sampling

HPV testing as an adjunct to cytology screening

HPV testing in combination with Pap (i.e. dual testing) – would lead to very high referral rate for colposcopy however,

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

Triage of ASC - US cytology 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

Evidence suggests 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

Normal Cervix

Initial HPV infection

HPV infected cervix Persistent infection with HR typesHPV

Precancerous lesionInvasive disease

Primary prevention Secondary Prevention

HPV Vaccines

Merck vaccine now licensed in over 70 countries

Targets types 6,11, 16 and 18

Estimated to prevent at least 70% of cervical cancers, but if

cross-protection by types 31 and 45, a further 10% may be

prevented

GSK vaccine in process of being licensed in a number of

countries, targeting only 16 and 18, but with possible cross-

protection against 31 and 45

Impact of the vaccines on cervical cancer incidence will not be

seen for approximately 20 years or longer

HPV Vaccines

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)

Same individuals who would most likely have access to

secondary prevention

Like with Hep B vaccine, regions where HPV vaccines likely

to have greatest impact will be last to receive it!

At all levels cervical cancer remains a disease of ‘inequity of

access’ to health care

HPV Vaccines

Lessons from developed world Widespread ignorance in lay public and health care

professionals on Transmission dynamics of HPV Relationship between HPV infection and disease Fear of anything related to ‘sexually transmitted’

Vaccine community divorced from cancer community and do not intersect

Vaccine implementation controlled by paediatricians who are most likely to promote vaccines that prevent diseases they treat eg rotavirus etc

HPV Vaccines

Delayed impact of HPV vaccines may dampen political will

Need to vaccinate prior to onset of sexual activity requires

adolescent vaccine infrastructure

Permission of parents to vaccinate against ? Cancer ? STI

Anti-vaccine lobby and Religious Right (in many guises)

Who to vaccinate? Girls or Boys or both?

Impact of vaccination on secondary prevention programmes

Conclusions Possibility of cervical cancer prevention never been as real as

in the early 21st century In much of developed world cervical cancer is a relatively rare

disease Vaccine will have a major impact but the need for secondary

prevention remains paramount 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

Even the rich should not waste!!

New technologies

mRNA expression of E6/E7 transcripts

Persistent expression of viral oncogenes E6 and E7

necessary step in HPV-induced oncogenesis

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

Main clinical utility will be to increase specificity

Commercial kit PreTect HPV-proofer

New technologies

P16ink4a

Cyclin-dependent kinase inhibitor whose expression is negatively

controlled by pRB gene product

Strongly over-expressed in cervical cancer cell lines in which RB

has been iinactivated by the high-risk HPV E7 oncoprotein

P16 overexpression, recognised by immunostaining, is a marker

of HPV infection and activated expression of viral genes and

viral-induced deregulation of cell cycle

May be expressed in metaplastic, atrophi and endocervical cells

leading to loss of specificity

Main clinical utility appears to be in triage of LSIL or for women

HPV DNA positive