Randomiserade vårdrpogram vid implementering av nya screeningstrategier

Transcription

1 Randomiserade vårdrpogram vid implementering av nya screeningstrategier Joakim Dillner Professor of Infectious Disease Epidemiology Director, Swedish Cervical Cancer Prevention Registry (NKCx/Analys) Director, Swedish National Biobanking Infrastructure (BBMRI.se) Karolinska Institute and Karolinska Hospital, Stockholm, Sweden

2 The making of new organised policies Basic research Cohort studies The Research Setting Randomised controlled trials Modelling and health economics studies The Real-Life Setting Randomised health care studies - implementation evaluation

3 Randomised Healthcare Studies Tests the situation where the effect and safety of a policy is in principle known from research studies in experimental settings. Evaluates the real-life policy in practise, including patient and payer acceptability. Uses no research grants. Extensively used in public health research. In screening, examples include the Finnish studies on mammography (Hakama et al), use of cytology or HPV testing in cervical screening (Kotaniemi-Talonen et al) and Swedish studies on HPV triaging (Lena Dillner et al).

4 Organised screening in Sweden Ages every 3rd year, every 5th year. In the greater Stockholm county about 60,000 women per year receive a letter of invitation to screening. 0.6% have ASCUS and 1.0% have CIN1. Formal exchange of reference slides has found that most slides diagnosed as ASCUS in USA or UK are diagnosed as Normal in Sweden and Norway (Scott et al, Cancer 96: 14-20, 2002). Cost-benefit of triaging different, e.g. because of different diagnostic practices.

5 Randomized health care study evaluation of Human Papillomavirus-based management of low-grade cytological abnormalities Lena Dillner 1, Levent Kemetli 2, Kristina Elfgren 3, Gordana Bogdanovic 4, Pia Andersson 4, Agneta Carlsten-Thor 2, Sonia Andersson 3, Elisabeth Persson 3, Eva Rylander 5, Lena Grillner 4, Joakim Dillner 1 and Sven Törnberg 2 International Journal of Cancer, ) WHO HPVLabNet Global Reference laboratory, Dept. of Clinical Microbiology, Lund University, Malmo University Hospital, SE Malmö, Sweden 2) Department of Cancer Screening, Regional Oncologic Centre, Stockholm, Sweden 3) Dept of Obstetrics & Gynecology, Karolinska University Hospital Huddinge and Solna, Stockholm, Sweden 4) Dept. of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden 5) Dept. of Obstetrics & Gynecology, Danderyd Hospital, Stockholm, Sweden,

6 Evaluation of HPV triaging in real-life study-flow ASCUS, CIN1 Established policy Colposcopy New policy HPV-test HPV+ Colposcopy HPV- Pap-smear 1 year

7 Randomized health-care study All 15 hospitals and outpatient clincis in the greater Stockholm county were randomized to either: Continue with the established policy (colposcopy of all women with ASCUS/CIN1) or New policy with HPV triaging by HCII and colposcopy only of HPV-positive women Hospitals/outpatient clinics were randomized pairwise with matching of catchment area population size and CIN2+ incidence in catchment area population Better statistical power by reducing variance in outcome

8 Randomized health care study Working group established 2001 Swedish association for Gynecology and Obstetrics and the Stockholm county expert group in gynecology issue statements that HPV triaging is an evidence-based policy Ethical Committee approval: Information about the randomized health care study included in all invitation letters for screening January 2003: All hospitals agree to randomization Policy switch for 7 hospitals in the HPV triaging arm: March 17, 2003

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10 CIN2+ yield in histopathology is the same, in spite of referring only 68% of women

11 Change of policy induces changes in management 72% of ASCUS/CIN1 women were HPV-positive. But some women did not do the HPV test: Only 68% out of all ASCUS/CIN1 women were referred. Higher attendance rate in the HPV triaging arm 73% as many colposcopies by HPV triaging. Increased number of colposcopies per woman in the HPV triaging arm 87% as many colposcopies total by HPV triaging Increased number of histopathologies per colposcopy in the HPV triaging arm 95% as many histopathologies by HPV triaging

12 HPV-positivity in ASCUS and LSIL by age (cost savings if less than 60%)

13 Evaluated policy not cost-effective below 35 years of age

14 Conclusions A real-life, randomised healthcare policy evaluation of HPV triaging of women with ASCUS/CIN1 demonstrated similar detection of CIN2+ if colposcopy of HPV-positive women only - as when using colposcopy of all women. Cost-effectiveness evaluation showed policy costeffective only for women <35 years of age at 50 euro/hpv test price. New tender 2011: 15 euro/hpv test price. HPV triaging previously found safe for all ages Now cost-effective for all ages and introduced for all ages in 2011.

15 What about primary HPV screening? How to design the primary HPV screening policy? Can we implement and evaluate it using a randomised health care study?

16 Main finding of 20 years of research on HPV-based screening: HPV test protects against cancer for >6 years the Pap smear only for 3 years. Negligible extra protection by doing cytology among HPV-negative women (Dillner et al, BMJ 2008) 90 cyt- 80 Incidence of CIN 3+ per 10, hpv- cyt-/hpv Time in months since intake testing

17 HPV-based screening also provides better protection against invasive cervical cancer (Ronco et al Lancet 2014) Cytology-negative women are adequately protected for 3 years = No hurry to follow up HPV+/Cyt- women. Only when positive in the next screening round 3 years later.

18 Simplified approach to HPV screening: Using HPV screening only to select specimens for cytology Previous method Sampling Slides Cytology 2.5% Abnormal Referral Primary LBC reflex HPV Sampling Vial Robotic slide preparation Mildly abnormal HPV test 1.5% 1% HPV+ Referral HPV- No referral Primary HPV reflex LBC Sampling Vial HPV test of vial 10% HPV+:robotic slide prep & cytology Abnormal Referral

19 Preliminary calculation shows method development can save considerable cost Method Cost DTot DTot% DGyn DGyn% DLab DLab% Conventional 3.7 MEUR LBC with reflex HPV 3.5 MEUR % % % Ph Ia 12 check-ups 3.5 MEUR % % % Ph Ib 11 check-ups 3.2 MEUR % % % Ph II 10 check-ups 2.9 MEUR % % % Reduction in check-ups = cost saving 1. Assumptions: Each method is implemented in the whole Stockholm county council, i.e. comprises all 100,000 check-ups each year. The price for the HPV test with kit, machines and labor is similar to the price for a high-volume Chlamydia test. 19

20 Randomised Healthcare Study for primary HPV screening Randomisation done at lab: Smear taking stations no change. Invitations issued at organised screening center that reports to political level about program changes and program success. Other RHS ongoing on mammography & colorectal cancer screening. Invitations to all women in the population describe that a policy change is being piloted in a randomised manner. RHS plan supported by RCC advisory board, by national consensus conference 24/4 (organised together with RCC and Swedish Society for Ob/Gyn working party on cervical cancer) and by IRB.

21 Design and evaluation Check-out test at 60 years of age (2012). Randomisation 1:1 at lab on individual sample level of whether to do HPV or LBC first. Follow-up of HPV+/LBC- 60 year old women: Women not released from program until HPV-negative. Primary HPV screening at years of age (2014): HPV+/LBC- women: Not referred until HPV persistence also at next screening round. Stop/Go Evaluation before entirely switching: Primary: HPV - LBC at least equal yield of CIN2+ as LBC - HPV. Secondary: Equal yield of CIN3+ Cost - efficiency Acceptance and popularity among women and clinicians

22 Results of primary HPV screening RHS after 2 years About invitations were sent - only positive feedback. Similar attendance rates: In the HPV policy, 5979 women attended the HPV screen. In the cytology policy, 6087 women attended the cytology screen. 10 women took another test than invited to. Population HPV prevalence was 6.1% = 94% decline in number of cytologies. (HPV16 0.5%; HPV %). 10 cases of CIN2+ with HPV policy. 5 cases with cytology policy (difference not significant). Similar number of biopsies with benign histopathology (22 and 21 biopsies, respectively). Primary HPV screening: was acceptable to the population, resulted in similar attendance rates, reduced the screening costs had a tendency towards increased sensitivity for CIN2+.

23 Summary There is consistent evidence that HPV screening is more sensitive than cytology and has a longer duration of the protective effect. As costs of HPV tests are declining, HPV screening with reflex LBC is likely to replace LBC screening with reflex HPV. As cost-effectiveness gains are dependent on longer testing intervals, use of HPV screening is only recommended in well organised programs. Organised screening programs allow for cost-control and continuous improvement/evaluation using Randomised Healthcare Studies