Cervical Cancer Prevention in CEE and the NIS: The Way Forward

1. Cervical Cancer Prevention in CEE and the NIS:The Way Forward John Sellors, MD PATH (Program for Appropriate Technology in Health) Seattle, USA

2. Overview of Presentation • Global burden of disease • Regional statistics and challenges • Overview of screening technologies and programmatic issues • Goals and objectives of the Albania Meeting

3. Cervical Cancer – A Global Problem • Over 230,000 women die from cervical cancer worldwide per year. • 470,000 new cases per year. • 80% are in poor countries. • A leading cause of cancer death in poor countries.

4. Cervical Cancer Incidence (ASR) • Worldwide, cervical cancer is the second most common cancer in women - in many developing countries it remains the most common. • Hardest hit regions include • Latin America and Caribbean, 33.5 per 100,000 • sub-Saharan Africa, 31 per 100,000 • South Central Asia, 26.5 per 100,000 • Melanesia, 43.8 per 100,000

5. Cervical Cancer Incidence Age standardized rates per 100,000 (based on world population)

6. Cervical Cancer’s Impact on Women in CEE/NIS • Incidence rates in Eastern Europe tend to range from 15-35 per 100,000 (ASR). • Hardest hit countries include • Poland, Hungary, Bulgaria (ASRs 20.1 - 30 per 100,000), and • Romania, 31.5 per 100,000 • Remaining countries typically have ASRs between 10-20 per 100,000.

7. Mortality from Cervical Cancer in CEE/NIS • Cervical cancer is a leading cause of death from cancer for women in the region (breast cancer is #1). • In developed countries, ASR for mortality is approx 4 per 100,000. In developing countries, the rate is more than twice as high, 9.8 per 100,000. • Mortality in several CEE/NIS countries exceeds 9.8

8. South Central and West Asia

9. EasternEurope

10. Northern & Southern Eastern Europe

11. Opportunities for Advances in Health Services in CEE/NIS • Empower providers, improve clinical training and standards. • Implement evidence-based guidelines and practices (effectiveness and efficiency). • Implement quality improvement methods. • Empower communities to participate. • Encourage increased investment in public health services, including health promotion (shift: cure to prevention). • Understand country contexts (social, political, economic/CEA, cultural).

12. Cervical Cancer Prevention Strategies:An Overview

13. Cervical Cancer Risk Factors • Human papillomavirus (HPV) is the sexually transmitted cause of precancerous lesions and cervical cancer (Wallboomers et al., ’99). • Over a lifetime, 80 percent sexually active women will be infected with a cancer-causing type of HPV(Koutsky, ’97). • So…why don’t all women get cancer?

14. HPV Prevalence in Ontario Women (Carcinogenic Types) (Sellors et al., CMAJ 2000)

15. Natural History: • Cervical cancer develops from an abnormal area - usually present for 15 to 20 years. • Precursor lesion does not cause symptoms but can be detected with various tests. • Screening = detection of the precancerous lesion in asymptomatic women. • Outpatient treatment of precancerous lesions is very effective.

16. ~20% within 10 years HPV Infection Low- grade (CIN 1) High- grade (CIN 2/3) Invasive Cancer 60% 15% 10% in 2 years Natural History of Cervical Cancer Screening strategies are intended to identify these abnormalities.

17. Successful Cervical Cancer Prevention Programs: It’s not just about the test… • The screening test is just one of the key components in an effective cervical cancer prevention program. Treatment Education Coverage Screening Test Follow up

18. Methods of Prevention—Vaccines? • The most effective prevention would be a protectivevaccine, given at an early age before sexual activity begins. • Vaccine programs have a high cost. • An HPV vaccine probably will provide excellent protection** but the impact on population health will not seen for 20-30 years. • Screening and management would still be necessary, at least until unvaccinated women had grown older. **Koutsky et al., NEJM, ‘02

19. Effect of age at vaccination on CC Incidence Barnabas and Garnett, ’02, unpublished

20. Key considerations for successful programs • Policy and political will. • Infrastructure development. • Integration of testing, investigation/treatment, and follow-up care in health services. • Evaluation of effectiveness to reduce disease burden.

21. Screening Tests for Cervical Neoplasia • Cytology • Conventional • Liquid based • Automated • Non-cytology methods • Visual inspection with acetic acid (VIA) • Visual inspection with Lugol’s iodine (VILI) • HPV-DNA testing

22. Cytology

23. Cytology • Time tested method. • Moderately accurate. • Unable to achieve concurrently high. sensitivity and specificity in many settings. • Resource intensive: laboratory, consumables, personnel, quality assurance. • Programmatic issues.

24. Study Site No. Women Sensitivity (%) Specificity (%) PPV (%) Fahey et al. 10 295 58.0 69.0 - U. Harare/ JHPIEGO 2092 44.3 90.6 33.3 IARC-ACCP/ India 21 802 58.1 94.7 11.7 Accuracy of conventional cytology to detect HSIL

25. Conventional Pap test is still the only screening test ‘proven’ to reduce incidence and mortality rates of ICC. CIN is slow growing. Many low-grade CINs regress. Abnormalities missed by one screening will probably be detected in next interval. ICC usually due to lack of screening rather than cytologic errors. Pap Test Is Problematic But…

26. ThinPrep (Cytyc) automated LBC sample prep system ~60,000 selected cells distributed in a thin layer smaller area than conventional Pap specimens read optically or digitally *FDA approved for screening As of Sept. 2001 AutoPap 300 (Tripath) and Trac Cell 2000 (Accumed International) automated LBC sample prep visual intelligence computer technology sorts by probability of abnormality *FDA approved only for mandatory rescreening Liquid-Based Cytology (LBC) and Computerized Reading

27. Pros randomly selected cells in thin layer better quality fixation and less ‘debris’ quicker reading - 3.2 min (double for Pap) amenable to HPV testing and immunohistochem. for different antigens Cons costly equipment more costly than Pap - worse compliance? retraining needed for smear-takers and pathology lab morphology changes Liquid-based Cytology: Other Considerations

28. Cost-Effectiveness of Conventional Pap and LBC • Base case – Conventional Pap screen every 3 yrs compared with no screening is $4,096/life-year saved • If thin-layer cytology can decrease the FNR (by factor of 0.6) and incremental cost/slide is $10, the incremental cost is $22,010/life-year saved, if interval every 3 yrs • If computer allows 100% re-reading (decreasing FNR by 0.85) and incremental cost per slide is $10, incremental cost is $45,375/life-year saved, if every 3 yrs

29. HPV DNA Tests

30. HPV DNA Testing • Dependent on proprietary technology: HC IITM (Digene, Inc) is the only FDA approved, commercially available test. • Higher sensitivity but somewhat lower specificity than Pap. • Used in combination with Pap achieves high sensitivity and increases negative predictive value—allows for increase in screening intervals.

31. HPV Testing • Testing expensive currently • Sophisticated testing infrastructure • Higher sensitivity, but lower specificity than cytology • Range in sensitivity: 80-100% • Range in specificity: 61-95% • 61.2% sensitivity and 93.8% specificity in Indian studies • Currently being evaluated in cross-sectional studies and RCTs

32. SELF-SAMPLING: Vaginal swab

33. Sensitivity and specificity of HC II for the detection of CIN 2/3 infour specimen types n=200, colposcopy clinic Sellors et al, 2000

34. Visual Inspection with Acetic Acid or Lugol’s Iodine

35. Visual Inspection with Acetic Acid (VIA) • Promising low technology alternative to Pap smear. • Cervix is swabbed with 3-5% acetic acid and examined with a bright light to identify acetowhite lesions. • Results are immediate allowing for treatment and management decisions in the same session.

36. Visual Inspection with Lugol’s Iodine (VILI) • Normal squamous epithelial cells have substantial stores of glycogen. • Glycogen stains mahogany brown with iodine solution. • Abnormal areas of squamous epithelium (CIN or inflammation) do not contain glycogen to the same extent and do not stain brown.

37. a b • VIA-positive: A large acetowhite area • (b)VILI-positive: After Lugol’s iodine application, the lesion is iodine negative

38. Multi-Centered Study of VIA and VILI • 11 sites in Africa and India, N=55,000 Sens.*Spec.* VIA 77% 85% VILI 92% 85% *for high grade disease Sankaranarayanan et al, Int J Cancer 2004

39. Screening Tests: Summary • Given an adequate program with all necessary components, conventional cytology works when repeated at intervals. • Cytology not feasible in all settings. • Increasing evidence-base from a range of settings on cytology, VIA, VILI, and HPV. • Incremental life-year gains from newer cytology and HPV technologies are at considerable cost.

40. Programmatic Considerations

41. Key Components for Quality Assurance in CEE/NIS • Assess quality and effectiveness of current strategies • Identify common deficits & modify strategies as needed: • inadequate information systems • faulty transport mechanisms • poorly trained providers/laboratory specialists • poor quality of care • low participation rates

42. Key Components for Involving Women in CEE/NIS • Increase awareness of cervical cancer and preventive health seeking behavior among women ages 30-50. • Emphasize the need for screening in this age group. • Increase coverage first and add rescreening later. • Resources are always scarce – use CEA.

43. Key Components of Screening Strategies for CEE/NIS • Screen all women aged 30-50 at least once before expanding services to other age groups or decreasing the interval between screenings. • Refer screen-positive women for colposcopy. • Treat women with high-grade precancers, refer those with invasive disease, provide palliative care for women with advanced cancer.

44. Key Components for Monitoring Impact • Collect service delivery and quality control data that will facilitate ongoing monitoring and evaluation of program activities and outputs.

45. The Durres, Albania Conference on Cervical Cancer Prevention in CEE and the NISMarch 11-13, 2004

46. Objective of the Conference • Unique opportunity to bring together the most interested and involved professionals and key Ministry of Health staff to: • Share experiences of implementing cervical cancer programs in CEE/NIS countries. • Provide technical update about cervical cancer prevention practices. • Facilitate exchange of information about key recommendations and potential policy change at the national level.

47. Anticipated Success: • Important step in strengthening cervical cancer prevention efforts in the region. • Raising profile of cervical cancer prevention in CEE/NIS via unified messages. • Accelerating progress through sharing materials, experience, lessons learned. • Using evidence base to inform cervical cancer prevention work.

48. Thank you

49. EXTRA SLIDES

50. Screening & Management Strategies • Test in primary care and refer women screened positive for treatment • Test, investigate, and treat in the same session • Test and treat in the same session