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 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 ) 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 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 AuthorSubgroupIndicatorKey findings Nanda et al (2000)ThinPrepHistologyHigher sensitivity LBC Hartmann et al (2001) All studies (962)HistologyCurrent evidence inadequate to state LBC superior Klinkhamer et al (2003) All studiesHistologySurePath 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 + histologyLBC (n = 3114) Conventional (n = 2444) Sensitivity (%)6069 Specificity (%)9495 PPV (%)1922 NPV (%)99 ‘Satisfactory but limited by’ (%) 728 Unsatisfactory (%)2.20.8

LBC versus conventional cytology UK study of over 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 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) 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 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 types HPV Precancerous lesion Invasive disease Primary preventionSecondary 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 21 st 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 P16 ink4a 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