GYNAEPATH

CERVICAL CANCER SCEENING IN THR ERA OF HPV

VACCINATION

ANNABELLE FARNSWORTHDirector Cytopathology

Douglass Hanly Moir PathologyAdjunct Professor of Pathology

Sydney School of Medicine Notre Dame University

CERVICAL CANCER SCREENING: The Past

CERVICAL CANCER SCREEING in Australia

Highly successful public health cancer prevention program

Screening available for approximately 60 years

based on conventional Pap smear

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

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

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

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

0

2

4

6

8

10

12

14Incidence of Cervical Cancer

Squamous

Adenocarcinoma

Adenosquamous

Other

Num

ber o

f cas

es p

er 1

00,0

00 w

omen 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 20-69 years, 1991 – 2008.

CERVICAL CANCER SCREENING:The Present

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

TESTING FOR HPV

HPV TESTING

Virus can’t be cultured

NO Serological test available in routine practice even though serology was used for Vaccine trials

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

HOW DO YOU DO A HPV TEST?

Or use ThinPrep vial

HPV TESTS

Roche “cobas 4800 HPV test” Athena Trial

Cervista (Hologic) – FDA Approved

Abbott RealTime High Risk HPV

Digene

Numerous others

ROCHE COBAS 4800 HPV TESTAthena TrialFDA Approval for Triage TestTypes 16,18 and then other high risk types, negative controlCollection into a ThinPrep vial

Current Digene HPV test

Result reported by system as “Negative or positive”Sub-typing (16, 18, other ) available nowNo internal control

Ok when “diagnostic test” but screening may be a problem

Unsatisfactory HPV testIn 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 collectionsSurepath NOT FDA approved for HPV testing

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

HPV TESTING: When to use it?

Triage of Equivocal Cytology Possible Low grade or Possible High Grade

No Medicare rebate

Currently approximately $65.00

HPV TESTING: When to use it?CvCx Cases/100,000

0

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

Pre

vale

nce

(%)

0

2

4

6

8

10

12

14

16

18

20

HPV

Cervical Cancer

Sources: NCI SEER Data, 1990-94; Melkert et al., 1993. Int J Canc 53:919.

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

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

CERVICAL CANCER SCREENING: The Future

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

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”

Participation in the National Cervical Screening Program by quintile of socioeconomic

disadvantage, Victoria, July 2006 – June 2008

Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 552%

54%

56%

58%

60%

62%

64%

66%

68%

70%

Pa

rtic

ipa

tio

nNational HPV Vaccination Program coverage at

March 2011 by quintile of socioeconomic disadvantage, Victoria, 2007 – 2009

Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 530.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

12-17 year-olds, Dose 1 12-17 year-olds, Dose 3 18-26 year-olds, Dose 1

18-26 year-olds, Dose 3

Cove

rage

Source: MJA 196(7); pg 445

How will Australia manage cervical

screening in the era of molecular testing

and vaccination

?

Renewal Cervical Screening Program

Website: http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/ncsp-renewal

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

2007 - National HPV Vaccination Program

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.

Objectives

1. 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.

2. Determine a cost-effective screening pathway and program model.

3. Investigate options for improved national data collection systems and registry functions to enable policy, planning, service delivery and quality management.

4. Assess the feasibility and acceptability of the renewed program for women.

CERVICAL SCREENING RENEWAL Website: http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/ncsp-renewal

ComparatorCurrent program

Scenario 1 Scenario 2 Scenario 3

Primary screening test

Conventional cytology

Conventional cytology

LBC(cell filtration and cell enrichment

separately)HPV DNA testing

Age range Women aged 18-69 years

Women aged 25-64 years(IARC recommendations)

Interval 2 years3 years (aged 25-49) and

5 years (aged 50-65)(IARC recommendations)

No less than 5 years*(a range of intervals should

be considered)

*HPV positive result 1) +/- LBC co-testing 2) +/- LBC reflex

testing

Renewal decision April 2014

Assessed through Medical Services Advisory Committee

Economic Evaluation, Cost effectiveness

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

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

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

Self testing HPV

For Under Screened women

– 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

COMPASS TRIAL

Study Arm 1

• Image read LBC

screening

• Reflex HPV triage

testing for low

grade smears

(p/dLSIL)

Study Arm 2

• HPV Screening with

genotyping +- LBC

triage

Study Arm 3

• HPV Screening with

genotyping +-

biomarkers triage

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

WHAT NOW? DO…..

Continue to screen women 18-70 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)

WHAT NOW? DON’T…..

Stop screening vaccinated women– Screening rates in vaccinated women is falling– Budd et al MJA 2014; 201: 279-282

“shows a significant reduction in screening participationin 20–24-year-old and 25–29-year-old vaccinated womencompared with unvaccinated women in Victoria (37.6%v 47.7% and 45.2% v 58.7%, respectively, over the period2010–2011).”

HPV test in women under age 30.. unless “test of cure”

HPV test in women with definite (LSIL,HSIL) cytological abnormalities

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.

THANKYOU

ANY QUESTIONS?

GYNAEPATH

Application 1157 – Cell enrichment Liquid-based Cytology(Surepath) in

Routine Screening for the Prevention of Cervical CancerAustralian 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.”

RESULTS OF AN AUSTRALIAN TRIAL USING SUREPATH LIQUID BASED CERVICAL CYTOLOGY WITH FOCALPOINT

COMPUTER ASSISTER SCREENING TECHNOLOGYBowditch et al Diagnostic Cytopathology 2011

No increased detection of abnormalities

Scientists Failed to detect “seeded abnormalities”

but it did decrease unsatisfactory samples

PERFORMANCE STANDARDS AUSTRALIA WIDE DATA (RCPA Cytopathology QA Program 2008)

Follow – up High Grade Cytology78 % all Paps reported as High Grade IL (CIN2, CIN3, AIS) had a high grade lesion confirmed on biopsyPositive Predictive Value for High grade lesions – 78%

Previous Negative Smears with Histology High Grade22% of all women with high grade biopsies in 2008 had a negative Pap smear in preceding 30 monthsSensitivity for high grade lesions 78%Screening False negative rate 3%