1. GYNAEPATH

2. CERVICAL CANCER SCEENING IN THR ERA OF HPV VACCINATION
ANNABELLE FARNSWORTH
Director Cytopathology
Douglass Hanly Moir Pathology
Adjunct Professor of Pathology
Sydney School of Medicine Notre Dame University

3. CERVICAL CANCER SCREENING: The Past

4. CERVICAL CANCER SCREEING in Australia
Highly successful public health cancer prevention program
Screening available for approximately 60 years
based on conventional Pap smear

5. THE CONVENTIONAL PAP SMEAR
Technique described by George Papanicolaou and Babes 1930’s
Method not changed since then
Has been the “test” used for Cervical cancer screening worldwide until 1990’s

6. THE CONVETIONAL PAP SMEAR: A Screening test
Any screening test balance between
Sensitivity - ability to detect abnormalities in an asymptomatic population
Specificity - the abnormalities detected are significant. Management of the abnormalities are of benefit to the population
Conventional Pap smear – Low sensitivity but very high specificity

7. CERVICAL CANCER SCREENING: An Organised Approach
Australia has invested very heavily in a National “Organised” Screening Program since 1991
Pap Test registries
Government regulated Laboratory
Quality Assurance
Education smear takers
Recruitment

8. Incidence over all 9/100000 (20-69years)
Squamous cell carcinoma incidence 5.4/100,000 (20-69 yrs)
All of the decrease has been in Squamous Cell Cancer
No rise in the other subtypes but there has been no significant fall
Mortality has fallen – 1.9 / 100,000 women (20-69 yrs)
*Source: National Cancer Statistics Clearing House (AIHW).
*Incidence (age-standardised) of cervical cancer, by histological type, women years, 1991 – 2008.

9. CERVICAL CANCER SCREENING: The Present

10. CERVICAL CANCER SCREENING 2014
Human Papillomavirus
Infection with HPV is a critical factor in the majority of cases of Cervical Cancer
HPV Vaccination
New Technologies
Testing for HPV
Automated methods for Cervical Cytology

11. TESTING FOR HPV

12. HPV TESTING Virus can’t be cultured
NO Serological test available in routine practice even though serology was used for Vaccine trials

13. MOLECULAR METHODS CONT
Target Amplification
eg PCR
Amplification of target sequences in L1 ORF
Flexible, greatest analytical sensitivity
Can be used for detection, quantitation, sequencing, mutation analysis
Multiplex formats – multiple, simultaneous target detection

14. HOW DO YOU DO A HPV TEST?
Or use ThinPrep vial

15. HPV TESTS Roche “cobas 4800 HPV test” Athena Trial
Cervista (Hologic) – FDA Approved
Abbott RealTime High Risk HPV
Digene
Numerous others

16. ROCHE COBAS 4800 HPV TEST Athena Trial FDA Approval for Triage Test
Types 16,18 and then other high risk types, negative control
Collection into a ThinPrep vial

17. Current Digene HPV test
Result reported by system as “Negative or positive”
Sub-typing (16, 18, other ) available now
No internal control
Ok when “diagnostic test” but screening may be a problem

18. Unsatisfactory HPV test
In our practice 1 % ( similar to rate of unsatisactory LBC)
Scant cellularity, insufficient material
PCR inhibited by blood, mucous, inflammatory exudate
Recent reports from US of false negatives with Surepath vial collections
Surepath NOT FDA approved for HPV testing

19. HPV TESTING: When to use it?
Test of cure – Medicare schedule
Following treatment for known High grade disease
These women known to be at increased risk for recurrent disease, thought to be associated with persistent HPV.
2x negative HPV tests and 2x normal cervical cytology over 2 years women can return to normal (2 Yearly) screening

20. HPV TESTING: When to use it?
Triage of Equivocal Cytology Possible Low grade or Possible High Grade
No Medicare rebate
Currently approximately $65.00

21. HPV TESTING: When to use it?
CvCx Cases/100,000 5 10 15 20 25
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
>65
Age (years)
HPV Prevalence (%) 2 4 6 8 12 14 16 18
HPV
Cervical Cancer
Sources: NCI SEER Data, ; Melkert et al., Int J Canc 53:919.

22. AUSTRALIAN ThinPrep IMAGER STUDY:
55,164 Cytology pairs
Collaborative study with
University of Sydney:
17% Increased detection
of High grade lesions
40% Decrease in Unsatisfactory
samples

23. COST-EFFECTIVESNESS ANALYSIS: Results
ThinPrep Imager Cost Effective for both Life year saved and Quality Life Year saved at both 2 yearly (current interval) and 3 yearly screening
BUT
The ThinPrep Imager System for Cervical Screening
Rejected by MSAC 2009 – too expensive

24. CERVICAL CANCER SCREENING: The Future

25. FALLING RATES OF DISEASE
Estimated that Australian high grade rate will fall gradually from 0.7% to 0.6% over next five years and then likely to fall even further once fully vaccinated cohort enters screening age
Will be monitored by Pap test registers

26. BUT STILL NEED SCREENING …
“Unfortunately, the vaccine doesn’t prevent all cervical cancers. That’s why it’s still very important for all women to keep up to date with regular Pap smears. You should have a Pap smear every two years from the age of 18, or two years after having sex, whichever is later”

27. Participation in the National Cervical Screening Program by quintile of socioeconomic disadvantage, Victoria, July 2006 – June 2008
National HPV Vaccination Program coverage at March 2011 by quintile of socioeconomic disadvantage, Victoria, 2007 – 2009
Source: MJA 196(7); pg 445

28. ? How will Australia manage cervical
screening in the era of molecular testing
and vaccination ?

29. Renewal Cervical Screening Program
Website:

30. Changing Environment New scientific knowledge on the development of
cervical cancer.
New international and local evidence for cervical
cancer prevention and screening
New technologies
- liquid-based technology
- computer assisted image analysis
- HPV DNA tests
National HPV Vaccination Program

31. Aim
The Renewal aims to ensure the success of the program continues and all Australian women, human papillomavirus (HPV) vaccinated and unvaccinated, have access to a cervical screening program that is based on current evidence and best practice.

32. Objectives
Assess the evidence for the effectiveness of screening tests and pathways, the screening interval, age range and commencement for both vaccinated and non-vaccinated women.
Determine a cost-effective screening pathway and program model.
Investigate options for improved national data collection systems and registry functions to enable policy, planning, service delivery and quality management.
Assess the feasibility and acceptability of the renewed program for women.

33. CERVICAL SCREENING RENEWAL
Website:
Comparator
Current program
Scenario 1
Scenario 2
Scenario 3
Primary screening test
Conventional cytology
LBC
(cell filtration and cell enrichment separately)
HPV DNA testing
Age range
Women aged years
Women aged years
(IARC recommendations)
Interval
2 years
3 years (aged 25-49) and
5 years (aged 50-65)
No less than 5 years*
(a range of intervals should be considered)
*HPV positive result
1) +/- LBC co-testing
2) +/- LBC reflex testing

34. Renewal decision April 2014
Assessed through Medical Services Advisory Committee
Economic Evaluation, Cost effectiveness

35. THE PROPOSED NEW CERVICAL SCREENING PROGRAM
Primary HPV testing with Partial genotyping and Cytology Triage
Commencing at age 25 years
Every 5 years
Exit HPV test 70-74
Self testing for under screened women

37. What does this mean for us?
Currently 2.4 million Pap smears → 0
Currently 55,000 HPV tests → 1.2million
Currently ?? LBC → 340,000
Currently 80,000 colposcopies → >100,000

38. Implementation of this New Screening Program
All aspects of Cervical Screening pathway need to updated
Pap Test Registers
National register
Call and recall
Invitation letters
Quality standards HPV testing, cytology, colposcopy
Education
etc
Will take at least 2 years

39. Self testing HPV For Under Screened women I-Pap trial
Patients will be offered test kit for self sampling
Test submitted to laboratory
If positive will HAVE to return for cytology sample
I-Pap trial

40. COMPASS TRIAL Study Arm 1 Study Arm 3 Study Arm 2
Image read LBC screening
Reflex HPV triage testing for low grade smears (p/dLSIL)
Study Arm 3
HPV Screening with genotyping +- biomarkers triage
Study Arm 2
HPV Screening with genotyping +- LBC triage

41. WHAT NOW? “ Business as usual”
Medicare item numbers won’t change until implementation achieved and date set
Assure women and doctors that nothing is wrong with current screening program

42. WHAT NOW? DO…..
Continue to screen women years of age every two years
Pap test reminders will continue to be sent to women
They should continue to screen and not wait
HPV testing not on Medicare schedule for screening
HPV testing in certain clinical situations
Test of cure (Medicare)
Women over the age of 30 with equivocal cervical cytology (non-Medicare)

43. WHAT NOW? DON’T….. Stop screening vaccinated women
Screening rates in vaccinated women is falling
Budd et al MJA 2014; 201:
“shows a significant reduction in screening participation
in 20–24-year-old and 25–29-year-old vaccinated women
compared with unvaccinated women in Victoria (37.6%
v 47.7% and 45.2% v 58.7%, respectively, over the period
2010–2011).”
HPV test in women under age unless “test of cure”
HPV test in women with definite (LSIL,HSIL) cytological abnormalities

44. WHAT NOW? DO….. Keep an open mind Be prepared for changes
Need for educated clever professionals as tailoring tests and management to individuals more important than ever.

45. THANKYOU
ANY QUESTIONS?
GYNAEPATH

47. Application 1157 – Cell enrichment Liquid-based Cytology(Surepath) in Routine Screening for the Prevention of Cervical Cancer Australian Government – Medical Services Advisory Committee(MSAC)
“MSAC noted that there is no increase from CC to CE LBC in the detection of cervical intraepithelial neoplasia CIN 2+ and CIN 3+, the high grade cervical squamous intraepithelial lesions (HSIL), which are the clinically significant lesions.”
“MSAC considered the validity of the economic evaluation from the full health care system perspective (including costs to patient) and concluded that the cost-minimisation analysis (CMA) proposed in the submission was not valid.”
“MSAC noted that there is no increase from CC to CE LBC in the detection of cervical intraepithelial neoplasia CIN 2+ and CIN 3+, the high grade cervical squamous intraepithelial lesions (HSIL), which are the clinically significant lesions.”
“MSAC considered the validity of the economic evaluation from the full health care system perspective (including costs to patient) and concluded that the cost-minimisation analysis (CMA) proposed in the submission was not valid.”

48. RESULTS OF AN AUSTRALIAN TRIAL USING SUREPATH LIQUID BASED CERVICAL CYTOLOGY WITH FOCALPOINT COMPUTER ASSISTER SCREENING TECHNOLOGY Bowditch et al Diagnostic Cytopathology 2011
No increased detection of abnormalities
Scientists Failed to detect “seeded abnormalities”
but it did decrease unsatisfactory samples

49. PERFORMANCE STANDARDS AUSTRALIA WIDE DATA (RCPA Cytopathology QA Program 2008)
Follow – up High Grade Cytology
78 % all Paps reported as High Grade IL (CIN2, CIN3, AIS) had a high grade lesion confirmed on biopsy
Positive Predictive Value for High grade lesions – 78%
Previous Negative Smears with Histology High Grade
22% of all women with high grade biopsies in 2008 had a negative Pap smear in preceding 30 months
Sensitivity for high grade lesions 78%
Screening False negative rate 3% 49