Cytologi, HPV infeksjon og vaksinasjon Hammerfest 2.11.12 OE Iversen Dept. of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway
Kasuistikk okt -10 Q 24 år: Frykt for cervixcancer pga familieanamnese. Cyt 20 år gml: N Cyt 23 år: N 24 år: blødningsforstyrrelse. Ville ha ny cyt fastlege avslo skiftet GU: suspekt tumor på cervix Biopsi: Adenocarcinom (I b) Lærdom/Poeng Screening <25 virker dårlig Adenocarcinom oversees Vaksinasjon? Kunne hun fått den?
Rate per 100,000 Age-specific incidence With/without screening 120 Age-specific incidence rates of cervical cancer in Brazil and the UK 100 80 Brazil UK 60 40 20 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+ Age Ferlay J et al. Globocan 2002. IARC 2004.
Early stop of FUTURE I and II Based on recommendations from the Data Safety Monitoring Board, it was decided for ethical reasons to stop the trials early in order to not delay vaccination of the placebo group. December 2005
Fra: Kampen mot cervix cancer: Utvikling Observasjon av naturlig forløp via Terapi og Sekundærprofylakse Til: Primærprofylakse HPV vaksinasjon
Milepeler i norsk screening Før 1995 1995-2005 2005- forts 2013/4??? 2023 Opportunistisk Organisert Organisert + HPV triage HPV primærscreening (Fase IV) Screening av vaksinerte
NRK 22.11.11 Relativ ja! Absolutt nei!
Best? Behandling eller forebygging? Dagbladet 11.1.12
Hva er målet med screeningprogrammene? (1995) Cervix 1. Redusere insidens - 2. Redusere dødelighet Mamma Redusere insidens Redusere dødelighet (målbar etter > 10 år) 3. Rasjonell bruk av prøver (ressurser) Nye tiltak (HPV) må dokumentere eller sannsynliggjøre bedret måloppnåelse!! Tidlig vurdering av surrogatmål ( downstaging, tumorstørrelse) Finne de 3000 blant >400.000 som må coniseres!
HPV - DNA virus Artspesifikk, infiserer plateepitel i hud og slimhinner Predeliksjonssted: transformasjonssonen akl 2004
Bethestad nomenklatur innført i Norge 2005 HPV test
HPV related resources - cervix Norway 2005 (pop. 4,5 mill) 450.000 gynecological exam. and smears 30-40.000 controls for abnormal smears 10.000 (?) biopsies 3000 conizations 300 cx cancers xxxxx exstra pregnancy visits because of conizations xxx extra late abortions and premature deliveries 10.000 treatments for condylomas
Resultater - cytologi (2005-6 n= 888.000) HPV triage av ASCUS/LSIL Normal 93,0 % Uegnet 2,5 % ASCUS 2,2 % LSIL 1,4 % HSIL 0,7 % Cancer 0,03 %* * = 3 pr 10.000
Screening in Norway Quality asurance manual 2005
Norwegian Cervical Cancer Screening Program from 1995 Every third year, ages 25-69 Standardised follow-up routines One cytology form One classification system (Bethesda from 2005) One coding system (SNOMED) One reporting system One national database Mandatory reporting system National advisory group National QA Manual
The co-ordinated screening program in Norway from 1995 has resulted in: Fewer Pap-smears (decreased expenses) Increased coverage (80 % 25-69 years) Decreased incidence of SCC (25-69 years) 65-69 years: Coverage increased from 43,5 to 67,5% and incidence rate decreased from 30,0 to 15,1
Incidence of SCC and ACC 1990-2001
Hva er potensialet for cervix cancer screening
Regression of LSIL in young women They are a minority, but...
Oppfølging av ASCUS + LSIL Vi skal finne de 3000 av > 400.000 som skal behandles for CIN 2+ Normal Ny cyt om 3 år ASCUS LSIL. HPV test 6 mnd - + HSIL Kolposkopibiopsi.
HPV testing brukes til kliniske veivalg Anbefalt fra 3/2005: Gyn.onk Veileder, Kreftregisteret 1.7.2005 Cytologi uegnet/normal høyrisiko HPV negativ Cytologi om 3 år Uegnet, uavklart og lavgradig cytologi Cytologi HPV-test 6 måneder Cytologi lavgradig/uavklart høyrisiko HPV negativ CIN2/3 behandling Normal/CIN 1 HPV 6 måneder Cytologisk høygradig HPV-test utgår Cytologi lavgradig/uavklart høyrisiko HPV positiv Cytologi uegnet/normal høyrisiko HPV positiv Kolposkopi umiddelbart HPV test 6 måneder Høyrisiko HPV positiv Høyrisiko HPV negativ. Vilkårlig valg av HPV test
IMPLEMENTERINGSSTUDIE I 4 FYLKER: HPV-TEST I PRIMÆRSCREENING MOT LIVMORHALSKREFT 2. desember 2010 Utvalgsmedlemmer: Olav K. Vintermyr Björn Hagmar Mari Nygård Ivar Sønbø Kristiansen Ole-Erik Iversen Bente Kristin Johansen Jannicke Berland Bjørn Hagen Christine M. Jonassen Kari Hilde Juvkam Tore Gutteberg (frem til aug 2010) Sveinung W. Sørbye (fra sep 2010) Trude Andreassen
Why do we still have a problem with Invasive Cervical Cancer in countries with organized screening programmes? 60 % of the cancers occur in the 15 % of the women who do not attend the programme!! (Cannot be reached by any screening test, but possibly by Primary prophylaxis) (Norwegian Cancer Registry - 2005) Adenocarcinoma unaffected by Screening Conlusion: Primary prophylaxis better than secondary!
And for those who do not attend: self sampling for HPV testing «Quick and simple selfsample kit followed by DNA analysis that detects 13 highrisk strains of HPV. «
The Nobel Prize in Physiology or Medicine 2008 Harald zur Haussen "for his discovery of human papilloma viruses causing cervical cancer" October 6th 2008
HPV - Main areas of development 1983 Zur Haussen Diagnostics Prophyl. Vaccines Therapeutic Vaccines
Number of HPV related papers/5 y 1978-2007 (Total 23.846) > 20 fold increase! (The pill: ca 5000 in 50 years) 7000 6000 6497 5000 4000 3909 4568 3795 3000 2934 2000 1000 0 289 1978-82 1088 83-87 88-92 93-97 98-02 -03-07 -08-09 PubMed 16.5.2010
Cervix cancer by HPV type Munoz N: Int J Cancer 2004;111:278 16 +18 +45 +31 +33 +52 +58 +35 +59 +56 +51 +39 +68 +73 +82 +Other +X 0 20 40 60 80 100 6.7 Proportion of cancers associated with HPV types 70.7% 332,058 2.9 2.6 2.3 2.2 1.4 1.3 1.2 1.0 0.7 0.6 0.5 0.3 1.2 4.4
Rate per 100,000 Rates of Diagnoses of Genital Warts (U.K.) 300 CDR Weekly 2001; Vol 11(35) Samme for HPV 16/18 ++ som 6/11? 250 Males Females 200 150 100 50 0 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 oei 35
1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319 331. 2. Koutsky L. Am J Med. 1997;102:3 8. 3. Franco EL, Villa LL, Richardson H, Rohan TE, Ferenczy A. In: Franco EL, Monsonego J, eds. Oxford, UK: Blackwell Science; 1997:14 22. 4. Tortolero-Luna G. Hematol Oncol Clin North Am. 1999;13:245 257, x. HPV and Anogenital Warts Images top left and top right: Reprinted with permission from NZ DermNet (www.dermnetnz.org) HPV 6 and 11 responsible for >90% of anogenital warts 1 Clinically apparent in ~1% of sexually active US adult population 2 Estimated lifetime risk of developing genital warts ~10% 3,4
Stanley M, Lancet Conference: HPV and cancer Nov 12, 2010
Chaturvedi A, Lancet Conference: HPV and cancer Nov 12, 2010
Lassen P, Lancet Conference: HPV and cancer Nov 12, 2010
HPV vaccines - types: First published studies Monovalent (HPV 16) Koutsky NEJM 2002 Bivalent #(HPV 16/18) Harper Lancet 2004/6 Quadrivalent* (6, 11, 16, 18) Villa LL Lancet 2005 Polyvalent (8 and 9) in phase III trials from 2007 * Gardasil # Cervarix
Adult Women (24-45 years) negative to the relevant vaccine HPV type (P 019)
Young men (16-26 years) negative to the relevant Vaccine HPV type (P 026)
Donovan B et al. Lancet Infect Dis 2011, updated with person communication on Real-life of women of impact free vaccine - on eligible genital age warts (GW) ital warts, by resident status, 2004-2010 Proportion of women of free vaccine eligible age with new episodes of genital warts, by resident status, 2004-2010 p-trend=0.96 p-trend=0.84 Pre-vaccine period p-trend=0.06 p-trend<0.001 Vaccine period -25% -73%
Most Frequently Asked Questions about HPV- vaccines Are the vaccines safe and monitored? How long will the protection demonstrated by HPV vaccines last?
Post licensure: Health authorities reaffirm the positive safety profile of GARDASIL 1. EMEA statement on the safety of GARDASIL. EMEA/37479/2008. http://www.emea.eu/humandocs/pdfs/epar/gardasil/gardasil_press_release.pdf - last accessed on 04.09.08. 2. Centers for Disease control website. Available at: http://www.cdc.gov/vaccinesafety/vaers/gardasil.htm- last accessed on 24.04.09. 3. RELEVE EPIDEMIOLOGIQUE HEBDOMADAIRE, No 5, 30 JANVIER 2009. 4. Press release Spain MINISTERIO DE SANIDAD Y POLÍTICA SOCIAL 23.04.2009
Har vi valgt feil kjønn for vaksinasjon? Hva om bare gutter? Ville beskytte jenter Ville beskytte MSM Redusere mannlige HPV cancere Hva med lesbiske? OBS vaksinedekning
Hvor mye HPV vaksine tilbys i Skandinavia? (årskull): Norge: 11/12 år 1 Sverige*: 12-24 år 14 Danmark: 12-24 år 14 *+ Blå resept ordning UK: 6 Årskull
HPV morbiditet et årskull uvaksinerte kvinner (30.000) 3000 koniseringer (10%) 300 cx cancere (1 %) 100 cx cancer dødsfall XX Ekstra senaborter og premature fødsler 3000 condylomer (10 %)
Viktige spørsmål i debatten: Ikke testet på 12-åringer Ikke vist beskyttelse mot kreft Kjenner ikke varighet av vaksinen Andre HPV typer tar over
All 12 years old girls to be Research rabbits
20 girls died Re HPV vaccine
Assault on girls Professor in ethics Would not vaccinate my daughter + Editorial against vaccine Week before budget
HPV vaccine for the rich only!
Scenario when vaccination started 2009 of all girls at 12 years: cumulative proportion vaccinated Vaccinated cohort starts screening 2023 120 100 % 80 60 40 20 2023 0 2000 2010 2020 2030 2040 2050 2060 2070 % vaccinated 25-70 years % NOT vaccinated 25-70 years 2023: Vaccinated women needs new HPV based screening algorithm
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