vaccination Effects on cervical screening and the Compass Trial A/ Prof Marion Saville Executive Director VCS Inc. I am co-pi of the Compass Trial which has received support from Roche Molecular Systems and Ventana Inc., USA.
IN THIS TALK Update the impact of the vaccine type specific prevalence of screen detected abnormalities so far Describe the Compass trial Update on the pilot Adjustments for the main trial Lessons learned so far
National notified coverage Australia As held at Sept 2011. Excludes consumers who have opted off.
Adjusted prevalence ratio for vaccine targeted types Fully vaccinated women 0.07 (0.04 0.14) Unvaccinated women 0.65 (0.43 0.96) A/Prof S Tabrizi Dr Julia Brotherton et al. www.thelancet.com/infection Published online August 6, 2014 http://dx.doi.org/10.1016/s1473-3099(14)70841-2
0.00 0.50 1.00 1.50 2003 2004 2005 2006 2007 2008 2009 2010 Time (years) bandwidth =.5 17 years & younger AIS/CIN2+ histopathology: Victoria 2003-2009 by age Apparent decline in youngest age groups Under 18 yo HGA incidence declined from 0.85% in 2006 to 0.22% in 2009 IRR 1.14 decline in incidence was 14% greater after commencement of vaccination 0.40 0.80 1.20 1.60 18-20 years HGA incidence (%) 0.40 0.80 1.20 1.60 2.00 26-30 years 2003 2004 2005 2006 2007 2008 2009 2010 2003 2004 2005 2006 2007 2008 2009 2010 bandwidth =.5 Time (years) bandwidth =.5 Time (years) 0.40 0.80 1.20 1.60 2.00 21-25 years HGA incidence (%) 0.10 0.20 0.30 0.40 0.50 31 years and older J Brotherton et al. The Lancet 2011; 377: 2085 92. 2003 2004 2005 2006 2007 2008 2009 2010 2003 2004 2005 2006 2007 2008 2009 2010 bandwidth =.5 Time (years) bandwidth =.5 Time (years)
vaccine effectiveness for cervical histological outcome, by age in 2007, for completed vaccine course Footnotes: All high grade histology defined as CIN2, CIN3, AIS, and mixed CIN3/AIS. Vaccine effectiveness defined as (1- adjusted hazard rate) x 100. Age in 2007 years.
The Compass Trial A sentinel experience of the renewed NCSP A joint initiative of VCS and UNSW www.compasstrial.org.au
Cumulative Detection Rate (per 10 5 ) Testing versus Cytology for the Prevention of Cervical Cancer 100 90 80 70 60 50 40 30 20 10 Women with negative test at entry Cytology screening screening 0 0 2 4 6 8 Time Since Negative Test at Entry (Years)
Why another primary RCT? Evaluate primary in partially vaccinated population using updated testing technology More focus on optimal management of positive women Specific evaluation of safety, effectiveness and costs in Australian context Pragmatic trial/demonstration of concept
Longitudinal outcomes: positive women 16 +ve at baseline Higher risk Else 18 +ve Intermediate risk Else other +ve Oncogenic -ve Low risk Cumulative CIN3+ in 20,514 women (median age 34 years) Khan MJ, Castle PE, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus () type 16 or 18 and the possible utility of type-specific testing in clinical practice. JNCI 2005
Why another primary RCT? Evaluate primary in partially vaccinated population using updated testing technology More focus on optimal management of positive women Specific evaluation of safety, effectiveness and costs in Australian context Pragmatic trial/demonstration of concept
The Compass Pilot 6-yearly screening (partial genotyping) Two arms with different follow-up for women who test positive for intermediate risk 3-yearly LBC (ThinPrep) screening
Pilot study 5,000 women at 1:2:2 randomisation allocation 2 primary screening technologies involved Roche COBAS QIAGEN partial genotyping
Woman attends for cervical screening Practitioner collects LBC sample Lab Randomise 3 yearly cytology 6 yearly test 6 Yearly test Intermediate risk Intermediate risk Intermediate risk test p16/ki67 Staining LBC
Population Women aged 25-64 years Resident in Victoria Attending for routine cervical screening
Aims of the Pilot: To quantify participant and GP acceptance of randomization process and use of longer routine screening intervals Measuring the recruitment rate Assess laboratory feasibility for 2 technologies Time and motion study Unsatisfactory rate Quantify baseline test performance Positivity rates Diagnostic yield for histologically-confirmed CIN3 In vaccinated cohorts separately from unvaccinated cohorts
Randomisation Randomization occurs in the laboratory on receipt of first sample For the duration of the study the woman remains in the allocated study arm
What does the laboratory report contain? An overall cervical screening risk assessment Low risk, negative test Intermediate risk, infection (not 16/18 +/- 45) Higher risk, infection (16/18 +/- 45) A statement of test(s) performed and the results A recommendation for follow-up taking account of Screening history, clinical notes and laboratory findings
Follow-up of women in Compass Management of follow-up via VCCR Collecting and storing email addresses and mobile telephone numbers Active recall for rescreening three months prior to the due date for the next test
Safety monitoring 5% of women in the arm will be recalled at 3 years for LBC If the CIN 3+ rate is higher than anticipated then the IDSMC may elect to recall all women in these arms and potentially stop the trial early In the renewed programme a similar model of safety monitoring could be utilised although the % of women required for early testing would be much lower
PROGRESS OF THE PILOT Consented participants: 5184 Eligible participants: 4970 No. clinics referring samples: No. clinicians referring samples 47 240
Lessons learned so far Acceptance by women and GPs of the longer interval seems to have been high The partial genotyping tests can be introduced into the lab using standard approaches to the introduction of new tests including appropriate training for laboratory staff 16, 18 +/- 45 rates are very low in both the older (unvaccinated) cohorts and the younger (vaccinated) cohorts A model safety-monitoring framework has been established
Compass main trial A sentinel experience of the Renewed NCSP Aiming to recruit 108,000 women before Renewal is implemented To confirm with empirical evidence the modelled performance of primary screening with an test and partial genotyping in a substantially vaccinated population To compare the performance of dual stain (p16/ki-67) with LBC in the triage of women with intermediate risk
p16/ki-67 Dual Stained Cytology
Adjustments to protocol Adjust screening interval for arms to 5 years, and in the LBC arm to 2.5 years Undertake LBC in samples from women who have tested positive for 16/ 18 +/- 45 To inform the interpretation and next steps after colposcopy
Study Arm A Image Read LBC Randomisation 1:2 (LBC:) Unsatisfactory cytology Negative cytology p/d LSIL p/d HSIL 1 Repeat LBC in 6-12 weeks Routine screening in 2.5 years-lbc Oncogenic DNA testing Colposcopy 2 Unsatisfactory Negative oncogenic Concealed Dual Stain (5%) Concealed Dual Stain Other oncogenic positive 16/18 ± 45 positive Concealed Dual Stain Repeat in 6-12 weeks Repeat cytology in 12 months (LBC) 3 Repeat test in 12 months 3 Colposcopy 2 12 months Negative cytology p/d LSIL p/d HSIL+ Concealed Dual Stain (5%) Negative 5 Positive oncogenic Concealed Dual Stain Repeat cytology in 12 months (LBC) 3 Colposcopy 2 Repeat test in 12 months 3 Colposcopy 2 12 months Negative cytology p/d LSIL p/d HSIL+ Concealed Dual Stain (5%) Negative Positive oncogenic Concealed Dual Stain Routine screening in 2.5 years (LBC) Colposcopy 2 Routine screening in 2.5 years (LBC) Colposcopy 2 Footnotes: Study arm A 1) Includes any glandular abnormality, possible HG endocervical glandular lesions and atypical glandular cells of uncertain significance. 2) If results at colposcopy are negative/cin 1/, women require two negative follow-up tests at 12 months and 24 months, using index test, before returning to routine screening (return to original study arm). If CIN 2+/AIS: treatment and follow-up according to NHMRC guidelines. Colposcopy unsatisfactory: managed by the individual specialist, informed by NHMRC 2005 guidelines (see detailed management flow charts). 3) Unless the National Cervical Screening renewal states otherwise. 4) AIS annual cytology for the life of the trial Version 1.2_DRAFT_2September2014
Study Arm B Oncogenic DNA Testing Randomisation 1:2 (LBC:) Unsatisfactory Negative Other hr Positive 16/18 ± 45 Positive Repeat test in 6-12 weeks Routine screening in 5 years 5% return in 2.5 years for LBC Safety Monitoring Image read LBC Colposcopy 2 Image read LBC Unsat cytology Negative cytology p/d LSIL p/d HSIL 1 Repeat LBC test in 6-12 weeks Repeat test in 12 months Repeat test in 12 months Colposcopy 2 12 months Negative Positive oncogenic Image read LBC 12 months Repeat test in 12 months Colposcopy 2 Negative Positive oncogenic Routine screening in 5 years Colposcopy 2 Footnotes: Study arm B 1) Includes any glandular abnormality, possible HG endocervical glandular lesions and atypical cells of uncertain significance. 2) If results at colposcopy are negative/cin1/, women require two negative follow-up tests at 12 months and 24 months, using index test, before returning to routine screening (return to original study arm). If CIN 2+/AIS: treatment and follow-up according to 2005 NHMRC guidelines (see detailed management flow charts). Colposcopy unsatisfactory: managed by the individual specialist, informed by NHMRC 2005 guidelines (see detailed management flow charts). 3) AIS will have test of cure until returned to routinely 5 yrly screening. Management will be similar to proposed NCSP management guidelines Version 1.2_DRAFT_2September2014
Study Arm B Oncogenic DNA Testing Randomisation 1:2 (LBC:) Unsatisfactory Concealed Dual Stain (5%) Negative Concealed Dual Stain Other hr Positive Concealed Dual Stain 16/18 ± 45 Positive Repeat test in 6-12 weeks Routine screening in 5 years 5% return in 2.5 years for LBC Safety Monitoring Randomisation 1:1 Image read LBC Colposcopy 2 Dual Stained Image read LBC Unsat DS Negative DS Positive DS Unsat cytology Negative cytology p/d LSIL p/d HSIL 1 Repeat DS test in 6-12 weeks Repeat test in 12 months Image read LBC Colposcopy 2 12 months Repeat LBC test in 6-12 weeks Repeat test in 12 months Repeat test in 12 months Colposcopy 2 Concealed Dual Stain (5%) Negative Positive oncogenic Concealed Dual Stain Concealed Dual Stain (5%) Negative Positive oncogenic Concealed Dual Stain Image read LBC Image read LBC Repeat test in 12 months Colposcopy 2 12 months Repeat test in 12 months Colposcopy 2 Concealed Dual Stain (5%) Negative Positive oncogenic Concealed Dual Stain Concealed Dual Stain (5%) Negative Positive oncogenic Concealed Dual Stain Routine screening in 5 years Colposcopy 2 Routine screening in 5 years Colposcopy 2 Footnotes: Study arm B 1) Includes any glandular abnormality, possible HG endocervical glandular lesions and atypical cells of uncertain significance. 2) If results at colposcopy are negative/cin1/, women require two negative follow-up tests at 12 months and 24 months, using index test, before returning to routine screening (return to original study arm). If CIN 2+/AIS: treatment and follow-up according to 2005 NHMRC guidelines (see detailed management flow charts). Colposcopy unsatisfactory: managed by the individual specialist, informed by NHMRC 2005 guidelines (see detailed management flow charts). 3) AIS will have test of cure until returned to routinely 5 yrly screening. Management will be similar to proposed NCSP management guidelines Version 1.2_DRAFT_2September2014
Adjustments to protocol Include all women who are presenting for screening or in follow up Women in follow up after previous LSIL would be managed as if they had a previous intermediate risk cervical screening result Women being followed after treatment for HSIL would undergo test of cure with LBC instead of conventional Pap
Adjustments to protocol Extend the upper age for recruitment to 69 years Reflecting an Exit test at 70 to 74 years as proposed for the renewed NCSP
The main trial challenges To have funding and ethics approval in place To complete recruitment before the Renewal is implemented
Lessons learned so far Need to keep the complexity within the labs and register(s) Need to continue to generate screening reports that clearly convey overall risk for cervical cancer precursors and that contain a single clinical recommendation Need to develop a language for the NCSP centred on risk The renewed programme will need a transition plan for women in follow for previous screen detected abnormalities
Conclusion This is a very exciting time to be involved in cervical screening We have the opportunity to have a renewed NCSP that is even more effective than our very successful current program, is less expensive and asks less of women and GPs Following the conclusion of phase 1 of Renewal we know where we are going. We still have to work out how we are going to get there, phase 2 of Renewal It is going to be enormously challenging to change the practice of the thousands of GPs around Australia and to communicate these changes to women given the high level of community understanding of Pap smears every two years message. We need to continue to learn from each other throughout this process.
Co-Principal Investigators A/Prof Karen Canfell A/Prof Marion Saville Chief Investigators Dr. Phil Castle Prof Ruth Salom A/Prof. Dorota Gertig (VCS) Dr. Julia Brotherton (VCS) Dr. David Wrede (RWH) Dr. Jeffery Tan (RWH) Dr. Sally Lord (CTC) Key Responsibilities Protocol development, review and revision. Associate Investigators Dr. Stella Heley Dr. Lara Roeske Ms Gillian Phillips Dr. Jane Collins Ms Sandy Anderson Miss Jessica Darlington-Brown Dr. Andrew Martin (CTC) Dr Michael Caruana Others to be determined Key Responsibilities Give advice on protocol and operational aspects of trial Quality Assurance Panel Histopathology Chair: A/Prof. Annabelle Farnsworth Key Responsibilities Review histopathology slides in a blinded manner Data Safety Monitoring Board (Chair: Prof. Michael Quinn) Key Responsibilities Regularly review safety data in a blinded manner Recommend study termination if pre specified stopping criteria are met Make safety or monitoring recommendations as appropriate Scientific Advisory Committee (Chair: Prof. Bruce Armstrong) Prof Jonathan Carter A/Prof Rachel Skinner Prof Suzanne Garland Prof Andrew Grulich Prof Annabelle Farnsworth Dr Deborah Bateson Dr Eduardo Franco Ms Bridget Whelan Key Responsibilities Advise on study protocol development Annual progress meetings (more frequent if required) Review pilot and main trial analysis NHMRC Clinical Trials centre Key Responsibilities Provision of randomisation mechanism Contribute to statistical aspects of protocol design Key Responsibilities Laboratory Management GP Recruitment Participant recruitment Implement linkage to VCCR & NVPR Key Responsibilities Lead protocol design Data management Lead data analysis and write-up