The Compass trial: Informing changes to the National Cervical Screening Program

Transcription

1 The Compass trial: Informing changes to the National Cervical Screening Program Marion Saville I am Co-Principal Investigator on the Compass trial which has received equipment and funding contribution from Roche Molecular Systems. Research Predicts Outcomes Empirical Evidence Modelling

2 Why another primary HPV RCT? Evaluate primary HPV in partially vaccinated population using updated testing technology More focus on optimal management of HPV positive women Specific evaluation of safety, effectiveness and costs in Australian context Pragmatic trial/demonstration of concept Methods Large scale RCT of 5-yearly HPV vs. 2.5 yearly liquid-based cytology (LBC) screening in Victoria, Australia Designed as sentinel experience of Australia s renewed National Cervical Screening Program Women presenting for screening consented by primary practitioner LBC sample taken, Randomisation on receipt of first sample in the lab in lab.

3 Methods Phase I (pilot) of 5,000 women aged 25 to 64 Recruitment from Oct Nov 2014 Three arms: women randomised 1:2:2 to cytology: HPV: HPV screening Baseline screening round completed, including 6 month follow-up for histology outcomes These results reported here. Methods Phase 2 (main trial) of 121,000 women aged 25 to 69 Recruitment commenced Jan 2015 As at October 2016 a total of 56,414 women recruited Primary endpoint based on CIN3+ detection at 5 year exit testing.

4 Methods LBC screening COMPASS PILOT ARM 1 Women randomised to cytology screening ASCUS/LSIL Reflex HPV ASC-H/HSIL Routine screening in 2.5 years 12 month cyto FU Refer to colposcopy if any abnormality Otherwise repeat cyto in 12 months HPV -ve Other onco HPV HPV16/18 12 month HPV FU Refer to colposcopy if HPV +ve Otherwise repeat HPV in 12 months Methods HPV screening COMPASS PILOT ARM 2 Women randomised to HPV screening Other onco HPV HPV16/18 Routine screening in 5 years* LBC Neg or ASCUS/LSIL LBC ASC-H/HSIL Triage option A 12 month HPV FU Refer to colposcopy if any HPV +ve Otherwise repeat HPV in 12 months *In pilot, 6-yearly HPV specified initially This is the preferred pathway for the renewed NCSP downstream management to be finalised via a current process of clinical guidelines development

5 p16/ki-67 Dual Stained Cytology Methods Results HPV screening COMPASS PILOT ARM 3 Women randomised to HPV screening Other onco HPV HPV16/18 Routine screening in 5 years* p16/ki67 -ve p16/ki67 +ve Triage option B 12 month HPV FU Refer to colposcopy if any HPV +ve Otherwise repeat HPV in 12 months *In pilot, 6-yearly HPV specified initially

6 Pilot Results: Participants 47 clinics, 247 clinicians 5,001 eligible participants recruited Cobas 4800 (Roche) was used for 3,104 (78%) of the total 4,003 HPV-screened women; HC2 (Qiagen) for remainder. CINTech Plus (Ventana) used for p16/ki67 dual-stained cytology Recruitment rate 57% (range 25% - 95% across centres) Pilot Results: Participants Randomisation outcomes Offered HPV vaccination ( 33 years in 2014) Not offered HPV vaccination (34+ years in 2014) ARM 1 LBC screening ARM 2 HPV with LBC triage of OHR ARM 3 HPV with p16/ki67 triage of OHR TOTAL (%) (22%) (78%) Total

7 Pilot Results: Participants Age distribution Demographic information Australianborn Speak English at home All women screened in Victoria, % (of 17% with status recorded) 84% (of 18% with status recorded) Compass Pilot 80% (of 53% with status recorded) 91% (of 54% with status recorded) Data on women attending screening in Victoria from AIHW Cervical screening in Australia Data from pathology request form returned by providers and based on self-reported information. Compared to Victorian data, see VCCR Annual Report, 2013 (and subsequent analysis). Pilot Results (1): HPV Prevalence Australia, pre-vaccination (2005-8) 1 HPV 16/18 HPV OHR 20% 20% 15% 15% Prevalence (% HPV positive) 10% Prevalence (% HPV positive) 10% 5% 5% 0% Age group (years) 0% Age group (years) WHINURS HPV16/18 WHINURS OHRHPV Preliminary, not for citation or publication 1 Reanalysis of data from Garland et al. BMC Medicine 2011 [Testing with LA] Note: Data adjusted for women with both HPV16and/or18 and OHR infections

8 Pilot Results (1): HPV Prevalence WHINURS (2005-8) vs. Compass (2014) HPV 16/18 HPV OHR 25% 25% 20% 20% Prevalence (% HPV positive) 15% 10% 82% lower Prevalence (% HPV positive) 15% 10% 5% 5% 0% Age group (years) 0% Age group (years) COMPASS HPV16/18 WHINURS HPV16/18 COMPASS OHRHPV WHINURS OHRHPV Preliminary, not for citation or publication 1 Reanalysis of data from Garland et al. BMC Medicine 2011 [Testing with LA] Note: Data adjusted for women with both HPV16and/or18 and OHR infections Pilot Results (2): Overall colposcopy referrals Reference rate shown of 1.5%: observed in women years, Victoria % 3.5% 3.0% 2.5% 2.0% Referred on basis of primary screening test Referred as reflex triage positive Total referred 1.5% 1.0% 0.5% Preliminary, not for citation or publication Arm 1 Arm 2 Arm 3

9 Preliminary, not for citation or publication Pilot results: Study arm 1 (LBC) 998 women No HSIL or phsil results Rescreen Full manual rescreen of all 998 cases at VCS Image based rescreen at Douglas Hanly Moir Very high overall agreement 2 cases amended to ASC-H, biopsy follow-up not yet available Pilot Results (3): Detected CIN2+ & CIN3+ Arm 1 (N=998) Age-eligible for HPV vaccination (N=211) Not age-eligible for HPV vaccination (N=787) Total(N=998) Arm 2 (N=1994) Age-eligible for HPV vaccination (N=418) Not age-eligible for HPV vaccination (N=1576) Total(N=1994) Arm 3 (N=2009) Age-eligible for HPV vaccination (N=449) Not age-eligible for HPV vaccination (N=1560) Total(N=2009) CIN2+ rate (%) (95% CI) ( )* ( )* ( )* 2.2% ( ) 0.5% ( ) 0.9% ( ) 2.4% (1.2% - 4.3%) 0.5% ( ) %0.9 ( ) CIN3+ rate (%) (95% CI) ( )* ( )* ( )* 1.9% ( ) 0.3% ( ) 0.6% ( ) 1.6% (0.6% - 3.2%) 0.4% ( ) 0.6% ( ) Test for differences in detected CIN2+: Arm 1 vs. Combined Arms 2/3, p = Arm 2 vs. Arm 3: p = 0.75 Preliminary, not for citation or publication 102 women were referred to colposcopy; histological outcomes could be ascertained for 98 (96%) which are reported here.

10 Pilot Results (3): PPV for CIN2+* ARM 1 (N=998) ARM 2 (N=1994) ARM 3 (N=2009) Referred on basis of primary screening test 0/2 ( ) 10/25 4 ( ) 7/ % ( ) Referred as reflex triage positive 0/3 ( ) 7/ % ( ) 12/30 4 ( ) Referred overall 0/5 ( ) 17/ % ( ) 19/ % ( ) Rate of confirmed CIN2+ ( ) 0.9% ( ) 0.9% ( ) Preliminary, not for citation or publication *102 women were referred to colposcopy; histological outcomes could be ascertained for 98 (96%) which are reported here. Preliminary, not for citation or publication Conclusions (1) HPV PREVALENCE Rates of detected HPV16/18 in women years are low (1.8%) and reduced by >80% compared to pre-vaccination measurements This limits direct referrals to colposcopy in younger women (and thus overall) First evidence of vaccine impact in this age group. Shows capacity of primary HPV screening program to routinely monitor vaccine impact.

11 Preliminary, not for citation or publication Conclusions (2) FINDINGS FOR LBC vs. p16/ki67 TRIAGE OF HPV OHR p16/ki67 appears to have twice the referral rate, but a similar PPV for CIN2+ and CIN3+, when compared to cytology at an ASC-H threshold Leads to increase in colposcopy referrals compared to the program benchmark when OHR HPV women are triaged with p16/ki67. But potential for further increase in disease detection However in this analysis, no difference in overall disease detection rates was identified between the two HPV screening arms Statistical power to detect a difference is limited. Preliminary, not for citation or publication Conclusions (3) OVERALL FINDINGS FOR HPV-SCREENED WOMEN In the first round of screening referrals from HPV screened women are significantly higher than for cytology-screening women (2.0% and 2.8% vs. 0.5%) While modelling is suggesting an initial increase in colposcopy numbers, Compass data suggests that this is at least partially offset by vaccine effect. Because vaccine impact limits referrals for HPV16/18 positivity CIN2+ disease detection rates in HPV-screened women are increased compared to cytology-screened women.

12 Main trial update Changes from pilot protocol Age range now 25 to 69 years Not excluding women in follow-up of abnormalities Change to the randomisation structure following statistical advice Sample size 121,000 women 110,000 women presenting for routine screening 114,000 women to allow for inclusion of women in follow-up of previous screen detected abnormalities 121,000 to allow for early follow up of HPV negative women for safety monitoring

13 Study Arm A Image Read LBC Unsatisfactory cytology cytology p/d LSIL p/d HSIL Repeat LBC in 6-12 weeks Routine screening in 2.5 years-lbc Oncogenic HPV DNA testing Unsatisfactory HPV Other oncogenic HPV 16/18 ± 45 oncogenic HPV HPV positive positive Repeat HPV in 6-12 weeks Repeat cytology in 12 months (LBC) Repeat HPV test in 12 months Study Arm B Oncogenic HPV DNA Testing Unsatisfactory HPV HPV Other hr HPV Positive HPV Positive 16/18 ± 45 Repeat HPV test in 6-12 weeks Routine HPV screening in 5 years 5% return in 2.5 years for LBC Safety Monitoring Image read LBC Image read LBC Unsat cytology cytology p/d LSIL p/d HSIL Repeat LBC test in 6-12 weeks Repeat HPV test in 12 months Repeat HPV test in 12 months C

14 Study Arm B Oncogenic HPV DNA Testing Unsatisfactory HPV HPV Other hr HPV Positive HPV Positive 16/18 ± 45 Repeat HPV test in 6-12 weeks Routine HPV screening in 5 years 5% return in 2.5 years for LBC Safety Monitoring Randomisation 1:1 Image read LBC Dual Stained Image read LBC Unsat DS DS Positive DS Unsat cytology cytology p/d LSIL p/d HSIL Image read LBC Repeat LBC test in 6-12 weeks Repeat HPV test in 12 months Repeat HPV test in 12 months Repeat DS test in 6-12 weeks Repeat HPV test in 12 months 450 Clinics Recruiting across Victoria

15 Follow-up of women in Compass Management of follow-up via VCCR Collecting and storing addresses and mobile telephone numbers Active recall for rescreening three months prior to the due date for the next test Years Years 19,601 recruited women 450 Practitioners Actively Recruiting 36,300 target reached 84,700 target Total Recruitment as at 7 th October 2016 = 56,414

16 Like us on FaceBook! It s inspirational that so many Victorian women and health professionals are actively involved in this research and are contributing to our understanding of cancer screening Todd Harper CEO Cancer Council Victoria Acknowledgements PRINCIPAL INVESTIGATORS Prof Karen Canfell A/Prof Marion Saville OTHER CHIEF INVESTIGATORS (MAIN TRIAL) Dr. Philip Castle Prof Val Gebski Dr Michael Caruana Prof Dorota Gertig Dr Julia Brotherton Dr Stella Heley CYTOLOGY QC RE-READ Prof. Annabelle Farnsworth WHINURS DATA: Prof Suzanne Garland A/Prof Julia Brotherton ASSOCIATE INVESTIGATORS (MAIN TRIAL) Mr C. David H. Wrede, Clinical lead for the Dysplasia service, The Royal Women s Hospital, Melbourne Dr Jeff Tan, Obstetrics and Gynaecology, The Royal Women's Hospital, Melbourne Ms Jessica Darlington Brown, Compass Clinical Trial Coordinator Dr Siobhan Bourke, Sexual Health Physician and Liaison Physician at VCS Dr Lara Roeske, Sexual Health Physician and Liaison Physician at VCS Dr Jane Collins, co-owner and the Clinical Director of the Clifton Hill Medical Group and Vice President of the Board of VCS Sandy Anderson, Women's Health Nurse / Practice Nurse, Ballarat and District Aboriginal Cooperative A/Prof Sally Lord, Epidemiologist and Senior Research Fellow at the NHMRC Clinical Trials Centre OTHER INVESTIGATORS (PILOT) Ms. Gillian Philips Prof. Ruth Salmon SCIENTIFIC ADVISORY COMMITTEE (SAC) MEMBERS Prof Bruce Armstrong (Chair) Prof Jonathan Carter A/Prof Rachel Skinner Prof Suzanne Garland Dr Deborah Bateson Prof Andrew Grulich Dr Eduardo Franco Ms Bridget Whelan A/Prof Annabelle Farnsworth (Chair: Histopathology Review Board) INDEPENDENT DATA AND SAFETY MONITORING COMMITTEE (IDSMC) MEMBERS Prof Michael Quinn, Ramsay Health (Chair) A/Prof Penny Blomfield, Director of Gynaecologic Oncology Services Tasmania, Royal Hobart Hospital Prof Gordon Wright, Director of Anatomic Pathology Gold Coast Hospital Campus A/Prof Katrina Sharples, Biostatistician, Preventive & Social Medicine, Dunedin School of Medicine, Health Sciences Compass details: Website Pilot Study Registration ACTRN Main Trial Registration: Clinicaltrials.gov NCT

17

18

19 Australian Cervical Cancer Typing Study n = 800 HPV type , 11, 16, 18 31, 33, 45, 52, 58 39, 51, Neg and other type