HPV TESTING AND THE RENEWAL PROGRAMME. Deborah Neesham Gynaecological Oncologist RWH

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1 HPV TESTING AND THE RENEWAL PROGRAMME Deborah Neesham Gynaecological Oncologist RWH

2 Statistics AIHW women were diagnosed with cervical cancer in 2011 and there were 226 deaths from cervical cancer in In Australia, 80 per cent of women diagnosed with cervical cancer have not been screened or have not had regular screening tests.

3 Australian ASIR Incidence rates of cervical cancer Squamous-65% Adenocarcinoma- 21.4% Adenosquamous- 4.4% Unspecified 5.9%

4 Cervical Cancer Effective screening programme has led to a 50% decrease in incidence and overall down staging Participation rates in screening in target age group exceed 55% within 2 years 70% within 3 year interval >80% of the target age group have had a Pap test w/i 5 years (AIHW 2012). Cost effectiveness of screening programme is reduced due to reduced incidence of and death from cervical cancer!! Incidence of cervical cancer in ATSI women >2x non-indigenous women ( ) Death from cervical cancer of ATSI women 5x the non-indigenous rate ( ) (AIHW 2012).

5 Equity in screening vs vaccination (Barbaro, Gertig and Brotherton) National Cervical Screening Program by socioeconomic status, Victoria National HPV Vaccination Program by socioeconomic status, Victoria

6 Background to Renewal HPV 16/18 causes around 70% ca cervix Other non16/18 cause most others: 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 Nonavalent vaccine will also be active against 31, 33, 45, 52, 58 HPV prevalence very high under 30 but rarely causes HSIL Ca cervix is very rare <30 and is a rare outcome of HPV infection

7 HPV type distribution in cervical cancer - Worldwide HPV 16 and 18 account for > 70% of cervical cancer cases (including squamous cell and adenocarcinoma) 1,2 HPV 16, 18, 45 and 31 are responsible for > 90% of cervical adenocarcinoma cases 2, HPV type distribution 2 % Squamous cell carcinoma Adenocarcinoma HPV 16 HPV 18 HPV 45 HPV 31 HPV 33 Other 1. Munoz N, et al. Int J Cancer. 2004; 111: ; 2. Bosch FX, et al. Vaccine 2008; 26S:K1 K16; 3. Smith JS, et al. Int J Cancer. 2007; 121: ; 4. Vizcainzo AP, et al. Int J Cancer 1998; 75: ; 5. Vizcainzo AP, et al. Int J Cancer 2000; 86:

8 Pap vs HPV Pap smear 70% sensitivity in detecting HSIL If Pap -ve 0.51% risk of CIN 3+ in 3 years If HPV -ve 0.27% risk of CIN 3+ in 6 years

9 Longitudinal Outcomes: HPV and Cytology Negative Women Dillner, J. et al. Joint European Cohort Analysis. BMJ 2008;337:a1754 Copyright 2008 BMJ Publishing Group Ltd.

10 Pap vs HPV HPV testing almost 100% but need to triage further If 16/18 +ve 20% develop HSIL in 10 years If non16/18 +ve 4% develop HSIL in 10 years

11 Longitudinal Outcomes: HPV Positive Women HPV 16 +ve at baseline HPV 18 +ve Higher risk Cumulative CIN3+ in 20,514 women (median age 34 years) Intermediate risk Other hr HPV +ve hr HPV -ve Low risk Khan MJ, Castle PE, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. JNCI 2005

12 HPV Vaccination Gardasil: Immunises against HPV 16/18 with 6 and 11 Uptake around 84% for one dose and 73% for all 3 doses in school age girls (30-50% in catch up cohort) Now extending to boys. Male vaccination from 2013 will have an incremental effect on infection rates in women, as it will reduce the risk of unvaccinated women acquiring high-risk HPV from a male partner Nonavalent vaccine will add HPV and 58

13 National notified coverage As held at March Excludes consumers who have opted off.

14 As held at March Excludes consumers who have opted off.

15 HPV Vaccination Effect Reduction in Condylomata >90% (Donovan et al, Lancet Nov 2010)

16 Why is Cervical Screening Changing From 1 May 2017, evidence based changes to the National Cervical Screening Program, together with HPV vaccination, will reduce the number of cervical cancers by at least an additional 24% per cent. A primary HPV test every 5 years can save more lives and women will need fewer tests than in the current 2 yearly Pap test program. These changes will ensure that Australia stays at the forefront of cervical cancer prevention.

17 The Renewal Programme The renewed National Cervical Screening Program will Invite women aged 25 to 74 years, both HPV vaccinated and unvaccinated, to undertake an HPV test every 5 years. Women of any age who have symptoms (including pain or bleeding) should have appropriate clinical assessment, which may include a cervical cytology test and an HPV test. HPV vaccinated women will still require cervical screening as the HPV vaccine does not protect against all the types of HPV that cause cervical cancer. The new programme will commence on 1 May 2017 when the primary HPV screening test will become available on the Medicare Benefits Schedule.

18 Principles guiding Renewal Based on a new screening test HPV detection is first step in ca cervix development HPV testing of women every 5 years between 25 and 74 5 yearly HPV testing more effective than 2 yearly smears

19 Latest Modelling in Australia: HPV Testing Effect on Ca Cervix In unvaccinated cohorts: 31% reduction in incidence of ca cervix 265 less cases 36% reduction in mortality 82 fewer deaths In vaccinated cohorts: 24% reduction in incidence 85 less cancers 29% reduction in mortality 28 fewer deaths

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21 Rationale for starting at 25 Ca cervix is rare under 25 and largely aggressive subtypes (eg.neuroendocrine) and non-preventable Between 1991 and 2010, the number of new cases of cervical cancer in women aged years was approximately 10 per year (range 4 to 18). There have been 0 to 2 deaths per year in women aged years over this same period.

22 Age-stratified mortality from cervical cancer in Australia,

23 Rationale for starting at 25 If at high risk (eg.casa as child) then can perform HPV test between screening tests to prevent 1 cancer treatments to prevent 1 cancer WHO guidelines recommend starting at 25 IARC (International Agency on Research in Cancer) Optimal pap smear interval every 3 years b/w then 5 yearly between 50-64

24 Cervical cancer in young women is rare (in both HPV vaccinated and unvaccinated women) Screening women younger than 25 years of age has not changed the number of cases of cervical cancer or deaths from cervical cancer in this age group Investigating and treating common cervical abnormalities in young women that would usually resolve by themselves can increase the risk of pregnancy complications later in life HPV vaccination has already been shown to reduce cervical abnormalities among women younger than 25 years of age and will continue to reduce the risk of cervical abnormalities in this age group.

25 Rare Cervical Cancer Types There is no effective population screening test for rare neuroendocrine cervical cancers. Neither the current Pap test nor the new cervical screening test (primary HPV test) effectively detects rare neuroendocrine cervical cancers.

26 Role of the cervical screening registries Key to cervical screening program are cervical screening registers that were established along with the cervical screening program in each state and territory. Cervical screening registers fulfil many important roles, including: sending reminder letters to women overdue for screening (the cervical screening registers do not currently invite women to participate in the NCSP) providing a safety net for women who have not had follow-up of an abnormal result providing cytology laboratories and cervical cytology providers with previous results for a woman, to allow a more detailed evaluation of present findings providing pathology laboratories with essential correlation data for cytology and histopathology for internal and external quality assurance monitoring.

27 Registries in Renewal Invitation to participate Recalls Follow up NOT just reminders Need : education, very good invitations, very good systems for call and recall

28 Self Testing Only for underscreened (over 2 years overdue and 30 or over) or never screened (and 30 or over) NOT intended for general use Must be performed in consultation with a Pap Smear Provider.

29 Self Testing If positive a pap test sample must then be taken for LBC or woman may be referred directly for colposcopy if 16/18 positive At least as accurate as a pap smear in detecting abnormalities Comparable accuracy to a physician collected HPV test Very acceptable to women High adherence rates to recommended follow-up (76%) Even 1 screen could reduce the lifetime risk of ca cervix by 40% if done at years If invited for clinician collected sample, not eligible for self test until prior criteria again met!

30 Compass Pilot Study Ist trial of HPV as a primary screening test in Australia 3 yearly smear vs 6 yearly HPV in yo with no history of HSIL 5000 women in Victoria 1:2:2 randomised (i) 3-yearly image read LBC screening with HPV triage testing of low grade smears; or (ii) 6-yearly primary HPV screening with partial genotyping and direct referral of 16/18 positive to colposcopy, with LBC triage testing for other oncogenic types; or (iii) 6-yearly primary HPV screening with partial genotyping and direct referral of 16/18 positive to colposcopy, with dual-stained cytology testing for other oncogenic types.

31 Compass Pilot Study Aimed to assess: (1) participant acceptance of the randomisation process and use of longer routine screening intervals; (2) confirm the operational feasibility of laboratory processing procedures for two alternative HPV test platforms (Qiagen HC2 and Roche Cobas 4800); (3) to assess test positivity rates for the primary screening test in each arm and (4) to estimate the sensitivity and specificity of dual stained cytology testing in HPV +ve women

32 Key elements of Compass ongoing Pre-empting management in the Renewal: Women aged years recruited through primary care practices in Victoria LBC sample only: randomized to Cytology or HPV test 2.5-yearly if negative cytology screening 5-yearly if negative HPV screening

33 In Renewal: If HPV negative Repeat HPV test in 5 years Subtrial to assess for false negatives with colposcopy and smear

34 In Renewal: If HPV positive If 16 or 18 +ve then colposcopy referral recommended If non16/18 +ve then reflex LBC on HPV fluid: If LBC HSIL: referral for colposcopy If LBC negative or LSIL: repeat HPV in 1 year and In 1 year: if still positive (second time): refer for colposcopy If negative: repeat HPV 5 years

35 Special Situations Immunosuppressed HPV test every 3 years indefinitely May have a screen under 25 if immunosuppressed for > 5 years If +ve HPV any type, referral for colposcopy of cervix, vagina, vulva, perianal areas DES Exposed Annual co-test with colposcopy cervix and vagina indefinitely

36 Test of Cure in current programme Time since treatment Pap smear Colposcopy HPV test 4-6 mths 12 mths Negative Negative 24 mths Negative Negative Return to 2 year screening interval when Co-testing (with LBC and HPV) is negative on two consecutive occasions

37 Summary HPV testing is currently indicated after treatment of a biopsy-confirmed high-grade squamous lesion Studies now show that negative HPV testing is more protective than cervical cytology: 5-year screen interval with HPV-based testing is safer than 2 or 3-year intervals with conventional cytology (Ref: Published online Nov 3; 2013)

38 Summary to this point There is reliable evidence of a drop off in the engagement with the Cervical Screening Program across the English speaking world especially in younger women Partly due to the success of the vaccination program and perceived low risk, Partly due to dislike/fear of the screening test

39 Summary to this point The success of the vaccination program will mean; There will be significantly less HPV16 &18 related disease in the population The proportion of HSIL will decrease The proportion of true high-grade disease per given number of referrals to Colposcopy is likely to fall

40 Role of the Gynaecologist: Colposcopy performance in a HPV vaccinated population not yet confirmed Colposcopy performance in the setting of primary HPV screening is unknown There is a risk of increased inappropriate treatment for low grade abnormalities

41 Role of the Gynaecologist: High grade disease is more often detected when the cytology is known to be high-grade and the numbers of cytological HSIL is falling The sensitivity of and the PPV for HSIL of individual colposcopists may be reduced and New strategies will be needed to improve diagnosis of AIS

42 Glandular Abnormalities and Cytology Terminology Pap smear report Atypical glandular or endocervical cells of uncertain significance Australian Statistics 2012 No % of all tests Possible high grade glandular lesion Adenocarcinoma in situ Adenocarcinoma with possible micro-invasion Adenocarcinoma Abnormal cytology reports with glandular abnormalities New Zealand (2011) Australia (2012)

43 Value of HPV testing in women with AGC Pooled data from 7 studies cases AGC s: 23.3% HPV positive HPV associated disease (HSIL, AIS etc) 53% if HPV pos 3% if HPV neg HPV pos 90% sensitivity, 79% specificity, 53% PPV, 97%NPV Rate of non-hpv associated cancers was significantly higher in patients who were negative, versus positive, for HPV (4% vs 0.4%; p =.016). Sharpless KE et al J Low Genit Tract Dis Apr;13(2):72-8.

44 HPV testing in Glandular Lesions Primary HPV screening has been found to be more effective in preventing adenoca cervix then cytology screening Glandular abnormalities on smear are also associated with high grade squamous lesions: Large US study: Within 5 years of atypical glandular cells on a pap smear if HPV +ve 33% developed CIN 3 9% developed Ca cervix Within 5 years of AGS and HPV ve 0.9% developed CIN % developed Ca cervix

45 Risk of cancer or AIS (AIHW 2012) Pap smear Report Australia Atypical glandular or endocervical cells of uncertain significance Histology Proven CANCER ACIS 6.2% 24% Possible high grade glandular lesion 11.4% 45% Adenocarcinoma in situ 27% 63%

46 Risk of cancer or AIS (AIHW 2012) Pap smear Report Australia No Histology within 6/12 Subsequent diagnosis Atypical glandular or endocervical cells of uncertain significance CANCER ACIS 1.8% 7% Possible high grade glandular lesion 5.5% 21.5% Adenocarcinoma in situ 24% 57%

47 Atypical Glandular Cells and Mx If +ve HPV and AGUS and normal colp Repeat co-test at 6-12 months If either abnormal then excision recommended If both normal co-tests until 2 consecutive cotests Unless If +ve HPV and?ais most require excision If normal colp and decline treatment then repeat colposcopy and co-test in 6 months

48 Primary HPV testing & AIS Should capture 95+% of women with AIS BUT triage cytology will have similar sensitivity as before How will the AIS lesions be identified? Better Colposcopic training? Adjunct Technologies? Random biopsies across upper limit of TZ (when accessible) in all HPV 16,18 &45 +ve? Endocervical curettage? This is an important problem: AIS diagnosis alters management Increased risk of invasive disease

49 Treatment of AIS Cold knife cone with endocervical curette is considered gold standard but LLETZ/LEEP may be appropriate if single pass with minimal diathery artefact in experienced hands Top Hat should not be performed Positive margins more common with LLETZ/LEEP 51% vs 30% with cone, and 28% with laser cone

50 AIS Follow up Multifocal AIS occurs in 13-17% Majority unifocal If close clear margins close observation is appropriate Annual co-test indefinitely even if hysterectomy If +ve margins recurrence 55% If ve margins recurrence 28%

51 Don t forget about the rest! Exclude upper genital tract disease before excision particularly if: Over 45 Over 35 with BMI >30 PCO Abnormal bleeding Endometrium, Fallopian Tube, Ovary

52 Role of Colposcopy Colposcopy is central to the successful diagnosis and treatment of cervical abnormalities. The primary objective of colposcopy is to undertake a comprehensive visual examination of the cervix in women referred with any of the following: 1. cytological abnormalities detected on cervical sampling 2. visible abnormalities of the cervix 3. symptoms and signs of cervical cancer eg. PCB In order to confirm & locate a possible lesion requiring treatment and Mapping the Transformation Zone.

53 Colposcopy is Integral to any National Cervical Cancer Screening Program Quality Assurance of units and individuals can not be arbitrary or voluntary While there is no convincing data to set minimum volumes of work there can be no doubt that repetitive practice improves performance Data collection will be mandatory and the National Cancer Screening Register (NCSR) will be collecting and collating molecular, cytological, histological and colposcopic data.

54 Colposcopy is Integral to any National Cervical Cancer Screening Program Self-reflective practice and benchmarking is a useful clinical process for improvement (and the avoidance of disciplinary and medico-legal problems) Annual performance reports will be generated by AIHW RANZCOG will still be responsible for the quality of training in specialist practice in the interests of the patients (and not the protection of providers interests) and will be responsible for certification and recertification

55 Proposed Colposcopy Data Set Colposcopy episode identifier (NCSR) Date of colposcopy Indication for colposcopy Assessment of adequacy of colposcopy TZ visibility Type 1 Ectocervix Type 2 Endocervix Type 3 Extends out of Range

56 Proposed Colposcopy Data Set Colposcopy impression Biopsy taken Y/N Pregnant Y/N Treatment this Episode Y/N Anaesthetic type Treatment Modality Excision type (if excised) Type 1 <10mm deep Type mm deep Type 3 >15mm deep

57 Proposed Benchmarking 95% have a biopsy taken if referred with HSIL (unless pregnant) >90% of biopsies suitable for histology assessment PPV of colposcopy for CIN 2+ >65% Type of treatment Type of anaesthetic (LA vs GA) 100% having ablation have prior biopsy confirming HSIL If excision performed >90% suitable for histol assessment CIN 2+ found in >80% of excisional treatment specimens Recurrence/Persistence of HSIL w/i 15/12 of treatment <5%

58 Conclusions Dysplasia at colposcopy will be a Smaller Needle in a Bigger Haystack And probably a smaller proportion of disease at risk of progression to cancer? Initially more colp referrals Subsequent drop off in rates of referral Maturing vaccinated cohort Nonavalent vaccine? Fewer required treatments Less CIN 3 (and?less colposcopically obvious) Less risk of progression of non-16,18 & 45 hr-hpv lesions?

59 Conclusions New NHMRC Guidelines being endorsed Better documentation mandated Quality Assurance local vs centralised Certification/Accreditation of Colposcopists via RANZCOG National Cancer Screening Register to include Colposcopy findings Feedback to units and individuals

60 Acknowledgements VCS/Victorian Cervical Cytology Registry Assoc Prof Marion Saville Assoc Prof Dorota Gertig Dr Julia Brotherton Dr Lara Roeske Dr Stella Heley Dr David Wrede (Oncology/Dysplasia RWH) Melbourne Sexual Health Prof Kit Fairley