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Maximizing the Impact of Cervical Cancer Prevention

The Open Society Institute, New York & PATH, Seattle, USA The Open Society Foundation for Albania & The Open Society Fund-Lithuania Cervical Cancer Prevention in Eastern-Europe & C-Asia Durres, Albania, March 11-13, 2004. Maximizing the Impact of Cervical Cancer Prevention.

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Maximizing the Impact of Cervical Cancer Prevention

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  1. TheOpen Society Institute, New York & PATH, Seattle, USA The Open Society Foundation for Albania & The Open Society Fund-LithuaniaCervical Cancer Prevention in Eastern-Europe & C-AsiaDurres, Albania, March 11-13, 2004 Maximizing the Impact of Cervical Cancer Prevention M. ARBYN 1,2 1European Network for Cervical Cancer Screening 2Scientific Institute of Public Health, Brussels

  2. Contents • Natural history of the disease, risk factors • Coverage and frequency of screening • Cost-effectiveness of screening using cytology • Cost-effectiveness of other screenng strategies • Brussels trial • Screening in the European Union

  3. Natural history of cervical cancer

  4. Natural history: conceptual model (1)

  5. Natural evolution ~ severity of CIN(Östör, Int J Gyn Pathol, 1993)

  6. Rationale for screening policy definition • Effect: reduction incidence invasive cancer & cause-specific mortality ~ back ground risk ~ participation of the target population ~ chosen screen test: sensitivity for progressive precursors lesions + QA ~ compliance with & efficicay of follow-up of screen-positives • Interval: ~ sensitivity ~ sojourn time of precursors • Start age: ~ age-specific incidence of cancer & sojourn time of precursors

  7. Costs of screening • Cost price of the screen-test (investment and recurrent costs); fees of health professionals logistical costs (transport, processing, storage); administrative costs (invitation, registration and analysis of data). • Specificity of the screen test: cost of follow-up and treatment of women with false-positive results or having non-progressive screen-detected lesions (over-diagnosis). • Sensitivity of the screen test: cost for follow-up and treatment of true positives; to be off-set by cost savings in avoided treatment of advanced disease. • Human costs: time spent by women to be screened, anxiety and discomfort for follow-up and/or treatment of women with true and false-positive results and consequences of delay in detection of cancer in false-negative women. • Specificity of quality control, triage and diagnostic follow-up procedures, contributing to increased positive predictive value and savings by avoiding treatment of false-positive women. • Quality of screen test, influencing the need for repeat tests.

  8. Costs-effect estimation of European screening strategies

  9. Costs-effect diagram V Ballegooijen, Eu J Cancer, 2000

  10. Cost-effectiveness of HPV DNA detection in addition to or as alternative for cytological screening for cervical cancer(Brussels trial)

  11. Background • Pap smear: standard cervical cancer screening test [Boyle, Ann Oncol, 2003] • hrHPV DNA detection: • recommended as a strategy allowing more optimal management of cases showing equivocal cytological findings [JNCI, 2004] • Several randomised trials are running opposing cytological screening versus HPV detection as primary screening test [Franco, JNCI Monographs, 2003].

  12. HPV triagecompared withprimaryHPV screening both in combination with liquid based cytology. Funded by Europe Against Cancer, W. Geps Fund Brussels trial, 2000 & 2003 13 BrusselsEORTC2003.ppt

  13. Study Population • 3000 women • Gynaecology polyclinic VUB-Brussels in 2000/2003 • Age: • median: 39.8 Y • range: 15-94 Y • 82.8% between 25-64Y • Randomised in 2 groups: A & B

  14. Experimental groups • Group A: (n=1500) • Pap smear • HPV test (all) • Group B: (n=1500) • Pap smear • HPV test (if ASCUS/LSIL)

  15. Screening tests • Smear: • Cervex-Brush sample rinsed in a vial with preservation liquid • Processed with AUTOCYTE • Interpreted ~ Bethesda 1991 • HPV-test: • Hybrid Capture II on residual fluid • Using probe for high risk HPV types

  16. Follow-up • All HPV+, HSIL+ or glandular abnormalities (AGUS+) or worse, were called for further diagnostic exploration and treatment: • Colposcopy/biopsy • Excision, conisation • Further follow-up • Outcome: detection of histologically confirmed CIN2+

  17. [+] [+] [+] [+] Decision tree (DataPro, Treeage, MA, US) Detection of CIN2+ per 1 000 screened women Cytological screening 7.7 Cytological screening + HPV triage 12.4 HPV screening 14.7 Combined cytological + HPV screening 16.4

  18. Normal cytology CostPap / 0 # ASCUS CostPap / 0 pASCUS LSIL Cytological CostPap / 0 screening pLSIL Colpo/hist HSIL+ (CostPap+Cost_Colpo_His) / 1 AGUSHSILCa pCIN2AGUSHSILCa Colpo/hist HSIL - pAGUSHSILCa (CostPap+Cost_Colpo_His) / 0 # Inadequate CostPap / 0 pInadequate Colpo/hist HSIL+ (CostHPV+Cost_Colpo_His) / 1 HPV+ pCIN2HPV HPV Colpo/hist HSIL - pHPV (CostHPV+Cost_Colpo_His) / 0 screening # HPV- CostHPV / 0 # Normal cytology CostPap / 0 # Colpo/hist HSIL+ (CostPap+CostHPV+Cost_Colpo_His) / 1 HPV+ pCIN2ASCUSHPV Colpo/hist HSIL - pHPVASCUS ASCUS (CostPap+CostHPV+Cost_Colpo_His) / 0 # pASCUS HPV- (CostPap+CostHPV) / 0 # Colpo/hist HSIL+ Cytological screening (CostPap+CostHPV+Cost_Colpo_His) / 1 HPV+ + HPV triage pCIN2LSILHPV Colpo/hist HSIL - pHPVLSIL LSIL (CostPap+CostHPV+Cost_Colpo_His) / 0 # pLSIL HPV- (CostPap+CostHPV) / 0 # Colpo/hist HSIL+ (CostPap+Cost_Colpo_His) / 1 AGUSHSILCa pCIN2AGUSHSILCa Colpo/hist HSIL - pAGUSHSILCa (CostPap+Cost_Colpo_His) / 0 # Inadequate CostPap / 0 pInadequate Colpo/hist HSIL+ (CostHPV+CostPap+Cost_Colpo_His) / 1 HPV+ pCIN2HPV Colpo/hist HSIL - pHPV (CostHPV+Costpap+Cost_Colpo_His) / 0 # Combined Normal cytology Cytological + (CostHPV+CostPap) / 0 # HP screening ASCUS (CostHPV+CostPap) / 0 pASCUSHPVn LSIL (CostHPV+CostPap) / 0 HPV- pLSILHPVn Colpo/hist HSIL+ # (CostHPV+CostPap+Cost_Colpo_His) / 1 AGUSHSILCa pCIN2HPVnAGUSHSILCa Colpo/hist HSIL - pAGUSHSILCaHPVn (CostHPV+CostPap+Cost_Colpo_His) / 0 # Inadequate (CostHPV+CostPap) / 0 pInadHPVn

  19. Outcome of economical analysis • Costs per detected CIN2+ • Cost per screened women • Incremental cost per additional CIN2+

  20. Costs (€) for detection of CIN2+

  21. Cost-effectiveness of 4 strategies Compared with baseline strategy Incr. Incr. Cost- Incr. cost- Strategy Cost Cost Effect effect effect effect ratio (detected (detected (€) (€) cin2+) cin2+) (€/cin2+) (€/cin2+) Cytological screening 37.9 0.0077 4892 Cytological screening + HPV triage 43.4 5.5 0.0124 0.0047 3499 1170 HPV screening 104.1 66.2 0.0147 0.0070 7055 9457 Combined cytological + HPV screening 141.4 103.5 0.0164 0.0087 8617 11897

  22. Influential variables • C/E most affected by: • Cost of HPV testing • Prevalence of high-risk HPV types in screened population (~ age) • Specificity of HPV tests

  23. Conclusions • Cytology followed by HPV triage increases sensitivity for CIN2+ substantially at a rather limited extra cost (ICER<1200 €/case) • Ancillary HPV testing still increases the yield of CIN2+ but at a very high cost (ICER almost 12 000€/case) • Extra cost by adding HPV testing must be balanced by the possibility of increasing the screening-interval for HPV-negative women • ! Longitudinal dimension needed

  24. Cancer Screening Policy in the EU(Council recommendation)

  25. Conference on Screening and Early Detection of CancerNovember 18-19th, 1999, Vienna • Development of a European Strategy • Consensus reached: Advisory Commitee on Cancer Prevention: Eur J Cancer 2000; 36: 1473-8 • Evidence:organised screening can reduce cause-specific mortality from 3 cancers

  26. EU Screening policies • Evidence: organised screening can reduce cause-specific mortality from: • Breast cancer: • mammography, women 50-69 years, 2-year interval • Cervical cancer: • Pap smear, women from 20  30 to60 years, 3-5 year interval • Colo-rectal cancer: • FOBT, men & women 50-74 years, 1-2 year interval

  27. Council recommendation on cancer screening(a long way …) • Delay in translation of consensus into regulating texts. • European consensus should be applied urgently by health ministers. Arbyn M, Lynge E, Micksche M, BMJ 2001; 323: 396. • Commission’s Proposal for a Council Recommendation Brussels, 5th May 2003 (Ref 2003/0093 (CNS). • Consultation of member states and EU Parliament (May-Nov 2003). • 2nd December 2003: endorsement of the Council ecommendation. • Meanwhile: 3th Update “European Code Against Cancer” • Boyle P et al, Ann Oncol 2003; 14: 973-1005.

  28. Summary of the Council recommendation • Based on the Vienna consensus • Argumentation updated • Screening policy less detailed • Mammography for women 50-69 years • Pap test for women starting at 20-30 years • Colo-rectal cancer screening for man & women 50-74 years • Screening only offered in organised programmes: • Monitoring & QA at all levels: invitation, participation, screen test, follow-up of screen+, treatment, after-care, registration, data-linkage (privacy!)

  29. Summary of the Council recommendation (2) • Screening in accordance with evidence-based guidelines • Research on new screening methods (RCT, public health relevant outcomes: mortality or established surrogate endpoints) • Assessment of level of evidence concerning effects of new methods by pooling results of trials • Note: European guidelines • Cervix Network: 2nd update in 2004 • Note: industrial lobbying! • Question: screening in new MS of the EU?

  30. Council recommendation but … • European Cancer Networks (EBCSN, ECCSN, ECSN) not supported anymore in 2004 • Only marginal attention for cancer in the 2004 call for proposals • Nevertheless: last article of the recommendation: “to encourage co-operation between MS in research & exchange of best practices & evaluating new methods …”

  31. References • Advisory Committee on Cancer Prevention. Recommendations on cancer screening in the European Union. Eur J Cancer 2000; 36: 1473-78. • Arbyn M, Van Oyen H, Lynge E, Mickshe M. European consensus on cancer screening should be applied urgently by health ministers. BMJ 2001; 323: 396. • Arbyn M, Van Oyen H, Lynge E, Micksche M, Faivre J, Jordan J. European Commission's proposal for a Council recommendation on cancer screening. BMJ 2003; 327: 289-290. • Boyle P, Autier P, Bartelink H et al. European Code Against Cancer and scientific justification: third version (2003). Ann Oncol 2003; 14: 973-1005. • Council of the European Union. Council Recommendation of 2 December 2003 on cancer screening (2003/878/EC). Official J Eur Union 2003; L327: 34-38. • Coleman D, Day N, Douglas G, Farmery E, Lynge E, Philip J, Segnan N. European Guidelines for Quality Assurance in Cervical Cancer Screening. Europe against cancer programme. Eur J Cancer 1993; 29A Suppl 4: 1-S38. • Commission of the European Communities. Proposal for a Council Recommendation on Cancer Screening. 2003/0093 (CNS). Brussels, 5th of May, 2003. • Perry N, Broeders M, de Wolf C, Törnberg S, Schouten J. European Guidelines for Quality Assurance in Mammographic Screening, 3rd edition. Office for Official Publications of the European Communities, Luxembourg, 2001.

  32. Burden of Cervical Cancer

  33. W-Age standardised mortality from and incidence of cervical cancer European Union, 2000 Ferlay J, et al. GLOBOCAN 2000: Cancer incidence, mortality and prevalence worldwide, Version 1.0. IARC CancerBases No. 5. Lyon, IARC, 2001.

  34. W-Age standardised mortality from and incidence of cervical cancer Acceding EU member states & Finland, 2000 Ferlay J, et al. GLOBOCAN 2000: Cancer incidence, mortality and prevalence worldwide, Version 1.0. IARC CancerBases No. 5. Lyon, IARC, 2001.

  35. Burden of cervical cancerEuropean Continent, 2000 • Estimated number of cases: 66,000 • Number of deaths: 29,000 Ferlay J, et al. GLOBOCAN 2000: Cancer incidence, mortality and prevalence worldwide, Version 1.0. IARC CancerBases No. 5. Lyon, IARC, 2001.

  36. Cervical cancer mortality in Europe Source: Globocan 2000, IARC Map produced by M. Arbyn

  37. IARC\iarc.do

  38. IARC\iarc.do

  39. IARC\iarc.do

  40. Number of deaths by cancer of the uterus(Belgium 1954-94) Arbyn M, Int J Cancer 2002

  41. Estimated number of deaths by cancer of cervix and corpus uteri (Belgium 1954-94) Arbyn M, Int J Cancer 2002

  42. Cervix uteri (corrected) Standarised mortality rate for cervical cancer (Belgium 1954-94, European reference population) 24 22 Cervix uteri (certified) 20 18 16 14 deaths/100 000 women/y Start screening 12 10 8 6 4 2 0 1955 1960 1965 1970 1975 1980 1985 1990 Year Arbyn M, Int J Cancer 2002

  43. Cervical cancer screening systems

  44. Screening systems • Organised screening: • more effective & cost-effective • Finland, UK >1990, Denmark, Sweden, Iceland, The Netherlands, Norway • Opportunistic screening: • overscreening • heterogenous quality • in most other European countries Miscan.xls

  45. Effectiveness opportunistic versus organised screening • Case-control study Finland (Nieminen, Int J Cancer, 1999) • History of previous Pap smears in 156 cancer cases, 1139 controls • OR for no screening (ref)= 1 • OR if organised screening: 0.25 (.13-.48) • OR if opport. screening: 0.57 (.30-1.06) • OR if org. & opp. screening: 0.27 (.15-.49) Miscan.xls

  46. National cervical cancer policies in EU countries Miscan.xls Van Ballegooijen M et al, Eur J Cancer 2000

  47. Screening coverage in EU countries (Having had at least 1Pap since screening interval) European Network Cervical Cancer Screening, Eur J Cancer, 2000 * Rousseau A, Bull épid hebd, 2002.

  48. Study: current status CC screening in Europe • Update of the descriptive studies in 15 EU countries (Eur Network for CC screening: Eu J Cancer, 2000) • Extension towards other countries of the European continent • In collaboration with: Miscan.xls

  49. Questionnaire • In collaboration with: • European Federation of Colposcopy • European Cervical Cancer Association • Developed by • M. Arbyn, J. Jordan, P. Nieminen, JJ. Baldauf Miscan.xls

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