Prospektiv observasjonsstudie ved bruk av Kreftregisteret Langtidseffekter av HPV-vaksinen. dr. med. Mari Nygård Kreftregistert, Oslo

Transkript

1 Prospektiv observasjonsstudie ved bruk av Kreftregisteret Langtidseffekter av HPV-vaksinen dr. med. Mari Nygård Kreftregistert, Oslo

2 Disposisjon Generelt om livmorhalskreft forebygning i Norge humant papillomavirus (HPV) og HPV vaksine Long term follow-up study: LTFU study Vaccine impact in population study VIP study Konklusjoner

3 Natural history of the cervical cancer TID Uker, måneder Inntil 20 år Normal epithelium HPV infeksjon CIN I CIN II CIN III Invasive Carcinoma Spontaneous regression Treatment

4 The Norwegian Cervical Cancer Screening Programme since 1995 One national program (1995) National databases, The Cytology Register Mandatory reporting system One coding system (SNOMED) One cytology form Reminders to women years of age who do not have smear opportunistically Pap smear every three year Standardised follow-up routines Treatment of the confirmed CIN lesions National advisory group National QA Manual (January 2005)

5 Registries at the Cancer Registry The Cancer Registry of Norway (1951) Nationwide - population-based Compulsory reporting on all cancers Complete on all cancers The Cytology Registry (1992) Includes all smears from all labs (also private) all age groups CIN Registry in Norway (Nationwide 1999) An uniform CRF for all follow-up/treatment of abnormal pap-smears All treatments of premalignant lesions in hospitals Preoperative work-out (cytology/histology) Earlier treatment Histology Registry in Norway (2002) All cervical histology reports, including normals ID of women and specimens Morphology Date of smear report

6 HPV vaksine 16/18(6/11) FUTURE II 8,550 fikk placebo og 8,579 fikk vaksine 85 lesjoner i placebo og 1 lesjon i vaksine gruppen Efficacy 99% (93 100%) HPV vaksine 16/18 PATRICIA 7,312 fikk placebo og 7,344 fikk vaksine 56 lesjoner i placebo og 4 i vaksine gruppen Efficacy 92.9% ( %) Ault, et al. Lancet, 369: , Paavonen et al. Lancet, 374: , 2009.

7 Forebygning av livmorhalskreft Primærprofylakse Profylaktisk vaksinering mot HPV 16/18/6/11 Sekundærprofylakse screening Massevaksinering per årskull fra 2009 alder 12 år Masseundersøkelse celleprøver årlig alder år Behandling av preinvasive kreft Kvinner med påvist prestadier behandles 3000 behandlinger registrert årlig alder nye tilfeller årlig alder år

8 Ubesvarte spørsmålene Hvor lenge varer beskyttelse Revaksinering? Når? Forekommer langtidsbivirkninger? Vaksinering mot seksuelt overførbar sykdom: promotering av promiskuitet? Hva med andre onkogeniske HPV typer?

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10 Complete Ascertainment Program (CAP) FUTURE II participants, 1698 in Norway Scanning was performed monthly 258 ( 15%) protocol violators were identified Biopsies identified from the local labs and were sent to USA The subjects in FUTURE II were not invited to screening to avoid protocol violations From MSD all cytology and histology results were reported to the Cytology/Histology register By now, all subjects are included in the screening program

11 Practical conclusions from CAP study Register follow-up was doable Tracing the biopsies was doable Sending, receiving and returning biopsies between USA CRN and local labs was doable LTFU is doable in practical terms given existing infrastructure

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14 Prospektiv observasjonsstudie PROLOG FUTURE II: participants, >50% enrolled in Nordic countries 2004 simultaneous registry studies in Denmark, Iceland, Norway and Sweden Complete ascertainment study CAP 2006 FDA and EMEA: post-licensure regulatory commitment Efficacy, immunogenicity and safety data for 9-14 years post-dose 3 EMEA included a request to evaluate the impact of GARDASIL on infections present at vaccination onset 2007 Long Term Follow-Up (LTFU) study 2008 Gardasil Vaccine Impact in Population (VIP) study

15 Hvorfor i Norden Folkeregistre Personnumre Kreftregistre Organiserte screening program Dødårsaksregistre Lovpålagt melding Fødselsregistre HPV vaksineregistre

16 Interval of Screening and Starting Age for Cervical Cancer Screening Country Age at Start of Organized Mass Screening Interval for Organized Mass Screening Denmark 23 Every 3 years Iceland 20 Every 2 years Norway 25 Every 3 years Sweden 23 Every 3 years

17 Age of the study participants Age at start FUTURE II (2002) Age at start LTFU (2007-8)

18 Samarbeidsprosjekt Danish Cancer Society, Copenhagen, Denmark University of Lund, Malmo, Sweden Karolinska Institute, Stockholm, Sweden The Icelandic Cancer Registry, Reykjavík, Iceland The Cancer Registry of Norway, Oslo, Norway Merck Research Laboratories, USA and MSD i de respective land

19 Nordisk Patologi Panel HPV testing Behandles etter nasjonale retningslinjer Registrering i KRG Nordisk koordineeringssenter i Oslo, KRG -informasjon fra registre -samler biologisk materiale, videresender til HPV lab -Diagnose settes av Nordisk Patologi Panel -materialet returneres til lokale laboratorier Pasienter utredes etter nasjonale retningslinjer Allmennleger/gynekologer Nordisk Patologi Panel

20 Outcome FUTURE II participants will be followed for PAP CIN Cervical cancer Cancer in vulva and vagina Preinvasive lesions in vulva and vagina Tested for HPV types Nordic Patologi Panel confirms histology diagnose

21 Expanded scope Collection of the serum for HPV type specific antibodies, 2011 and 2017 Long-term side effects Patient administrative registries

22 Comparability Register quality extent to which coding and classification procedures the Registry adhere to the agreed international standards Completeness The extent to which all of the incident cases occurring in the population are included in the registry database Validity or accuracy the proportion of cases in the CRN with a given characteristic which truly have this attribute Timeliness the time from diagnosis to registration, and the time from registration to the reporting of incidence via the annual report

23 Challenges Registeroppfølgning: forskjellig kompetanse enn å gjennomføre en klinisk Phase III Lovverk, samtykke Data i registre: Data kvalitet kvalitet ved uttrekk Censoring: emigrasjon Biologisk material Innhenting, analyse, returnering

24 Documentations Quality check when receiving the tissue block back from study lab Quality check when receiving the local slides

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26 Vaccine Impact in Population VIP study Introduction of Gardasil in Denmark, Sweden, Norway Occurrence of cancer and preinvasive lesion in cervix, vulva, vagina Follow-up to estimate changes: expected and unexpected FDA and EMEA 2008 : massvaccination Denmark 2009: massvaccination Norway

27 Vaccine Impact in Population VIP study Introduction of Gardasil in Denmark, Sweden, Norway HPV type distribution in CIN cancer general population Follow-up to estimate changes: expected and unexpected FDA and EMEA 2008 : massvaccination Denmark 2009: massvaccination Norway

28 Vaccine Impact in Population VIP study Introduction of Gardasil in Denmark, Sweden, Norway Side effects: congenital anomalies Sexual behaviour Follow-up to estimate changes: expected and unexpected FDA and EMEA 2008 : massvaccination Denmark 2009: massvaccination Norway

29 Oppsummering Det er viktig å evaluere vaksineeffekten over lang tid Infrastruktur i de Nordiske land gjør det mulig at langtidseffekt av vaksine og bivirkninger kan dokumenteres Samarbeid mellom flere land kan gir bedre/tidligere resultater