Cancer prevention and early detection strategies Summit of the Future 2006 Mercedes Lassus, MD

1. Cancer prevention and early detection strategiesSummit of the Future 2006Mercedes Lassus, MD

2. The Burden of Cancer Worldwide Estimates for the year 2000* • Ten million new cases • 6.2 million deaths • 22.4 million living with cancer • The estimates indicate a 23% increase in cancer incidence with respect to 1990 * Parkin DM. Eur J Cancer 37: S4-S66, 2001

3. Number of new cases and deaths worldwide for the 15 most common cancers, 2000 European Journal of Cancer 37 (2001) S4-S66

4. The Burden of Cancer Worldwide Although mortality from individual cancers is decreasing in high income countries, mortality continues to increase in developing economies

5. Reducing the world cancer burden • Better therapies • Screening for earlier detection: Smaller, “younger” tumors have better prognosis and may be curable • Preventing malignancies

6. Cancer Screening World Wide: Status • High resource countries: evidence-based guidelines recommend optimal approaches to early detection, diagnosis and treatment. • But! These guidelines have limited application in resource-limited, culturally diverse, populations within the countries,

7. Cancer Screening World Wide: Status • And! These guidelines have limited application in resource-limited, culturally diverse, countries (WHO Executive Summary, Geneva, 2000) • The definition of evidence-based, economically feasible, culturally adequte “best practices with limited resources” is an urgent need. Several initiatives are ongoing

8. Uterine Cervix Cancer

9. Cervical Cancer Burden • Most common cause of cancer deaths in women in developing countries, despite being preventable. • Year incidence ww is approx. 500 000 • Sequela of a sexually transmitted infection with HPV • Year number of deaths ww: 230 000 • 83% of deaths occur in low-resource countries, that have access to <5% global cancer treatment resources. In high resource countries, the majority of cervical cancer cases and deaths occur in disadvantaged groups. • Cervical Cancer is a disease of Inequality

10. Cervical cancer is highly preventable • There is an easily identifiable precancerous lesion • Transition from precancer to cancer occurs over an extended period (average 10 years) • Acceptable screening tests for early detection of precancerous lesions are available • Outpatients therapies of precancerous lesions are available, safe, effective and relatively inexpensive • Cervical Cancer is a failure of screening

11. Cervical Cancer and HPV infection • HPV DNA is detected in about 100% of invasive squamous cell cancers. • HPV is the most common sexually transmitted disease, with prevalence rates of 19% - 46%. • Major risk factors are early age at onset of sexual activity, multiple partners, failure to use barrier contraception, and coinfection with other sexually transmitted disease. • Most HPV infections are transient. But women with chronic HPV tend to develop cervical abnormalities

12. Precancerous cervical lesions • HSIL: significant precancerous lesion, high risk • LSIL: low risk precancerous lesion. Most regress spontaneously in adolescents and in 50% - 80% in adults. • ASC-US: atypical squamous cells of undeterminate significance

13. A comparision of deaths from cervical cancer and maternal mortality in selected developing countries in 2000.

14. Cervical Cancer Burden: the good news • The effectiveness of cervical screening programs has been demonstrated in several countries, despite the absence of randomized trials. • It is estimated that screening with cervical smears every 3 years can prevent 90% of cervical cancers if all women participate in a screening program and all detected lesions are adequately followed-up*. • National screening programs exist in several EU countries *IARC working group on evaluation of of Cervical Cancer Screening Programes,Br. Med J 1986, 293, 659-654

15. Methods for cervix cancer screening Established, standard in high resource environments: • Pap smear New methods, subject of completed or ongoing studies: • Liquid-based Pap technology (2 approved by FDA and EU as equivalent to conventional Pap smear) • Automated methods • HPV testing as screening method and/or supplementary method in follow-up of cervical abnormalities (approved by FDA and EU) • Visual tests: Visual Inspection with Acetic Acid or with Lugol’s iodine. By staining the cervix precancerous lesions can be identified

16. European Union Recommendations • Pap smears should be the method used • Screening should start at age <30 and >20 • Upper age limit should depend on available resources and be > 60 • Screening intervals between 3 and 5 years • Performed only in organised screening programs with QA at all levels • Programs should be organised in accordance with the European guidelines

17. American Cancer Society Recommendations* • Pap smears should be the method used • Screening should start 3 years after onset of vaginal intercourse and <21 years. All adolescents should receive appropriate helath care, and prevention counseling. • Women > 70 yo with 3 consecutive normal smears and no abnormal tests in the last 10 years may elect to cease screening • Performed initially annually OR biannually if liqui-based cytology is used. At > 30 years, women with 3 conseutive normal results may be screened every 2-3 years *Saslow D, CA Cancer J Clin 2002;52;342-362

18. Performance of the Pap Test • It is not perfect • Sensitivity for CIN: 70% - 80%. Sensitivity depends on size of the lesion, accessibility, presence of only few abnormal cells on the slide, presence of inflammation and/or blood.

19. Strategies for Reducing Cancer Disparities • Improve knowledge on cancer screening, attitudes and behaviour among underserved populations • Increase physician compliance with the recommendations • Improve quality standard for laboratories • Decrease the need for follow up: See-and-Treat approach to manage cervical displasia

20. Usual Approach to Screening (1/2) • First visit: a vaginal examination with speculum is performed to collect cervical cells (Pap smear). • Slides are sent to a lab to be processed and examined under the microcope by a trained cytology technician. Selected results are verified by a physician cytologist. • Women with abnormal Pap are called for a 2nd visit to perform colposcopy and eventually have a biopsy. • A third visit takes place where treatment is initiated if the biopsty is abnormal

21. Usual Approach to Screening (2/2) • Colposcopy: high-powered illuminated magnification of the cervi • It allows to determine the extent of lesions and to take biopsies • It allows to provide directed treatment with cryotherapy or loop electrosurgical excision procedure (LEEP) • Performed as outpatient procedure • Non invasive (as opposed to cold knife conization requiring anesthesia) • Costly equipment (up to $13.000) and training

22. Less complex screening strategies (1/3) Two-visit approach • Pap smear in the first visit • Women with patological results undergo treatment in the second visit • Colposcopy is not performed

23. Less complex screening strategies (2/3) See and Treat approach • Pap smear and Colposcopy are substituted by direct visual examination of the cervix after application of an acetic acid solution or lugol iodine. • Screening and treatment can be performed in only one visit, decreasing the risk of losses to follow up.

24. Less complex screening strategies (3/3) Two-test approach • Direct visual inspection (DVI) and cytology, or DVI and HPV, or HPV and cytology. • An abnormal result in either test is considered a positive screen Sequential two tests • Only women with a positive results in one test undergo a second test, and if both are positive, the patient is treated.

25. Cost effect Analysis* • Use of a mathematical model and a hypothetical cohort of previously unscreened 30-yo black South African women • Results indicated that a single-lifetime screen with DVI or HPV DNA testing coupled with immediate cryotherapy for those with positive results, compared to no screening reduced the inidence of cervical cancer by 26% - 32% and cost <$50 per woman *Goldie SJ, JAMA 2001;285:3107-3115

26. Screening for Breast Cancer

27. Breast Cancer Burden • 1.1 million new cases diagnosed worldwide per year representing 10% of all new cancer cases. Approx 1 in 8.2 women will have a diagnosis of breast cancer in her lifetime • First cause of cancer death in women worldwide • Incidence is increasing 0.5% - 3% per year, expected new cases diagnosed in 2010 = 1.4 – 1.5 million. • Incidence tends to be higher in high resource countries but fatality rates tend to be higher in low-resource countries • Incidence increases with age • > 50% of cases occur in women without major predictors.

28. Breast Cancer Burden: the good news • Mortality rates have started to decrease in high-resource countries likely due to the combined effect of early diagnosis through Screening and more effective therapy • Only in the USA mortality in 2000 has decresed by 24% compared to 1990

29. Evolution of rates cancer of death from breast cancer 1975-2000, women 30-79 years old – Deaths / 105 women SEER Cancer Statistic Review 1975-2001 (2004)

30. Survival rates for women diagnosed with breast cancer in England and Wales aged 20-49 years, and 70-79 years during 1971-93 Survival rates are adjusted for mortality rates in the general in the General population andstandarised to the age distribution of women Diagnosed of breast cancer during 1986-90. Incidence (1971-96) and Mortality (1971-99) rates are standareised to the European population; mortality rates are also adjusted to take account of changes In death registration (1979-92) and in coding if the underlying cause of death (1984-92). The Lancet 356. August 12,2000

31. Methods for breast cancer screening • Mammography • Clinical breast examination • Breast self-examination Newer screening modalities: • Digital mammoraphy • Ultrasound • MRI • Computer-aided detection programs for mammography

32. Efficacy of Mammography • Evaluated in several randomized clinical trials. Endpoint: long-term breast cancer mortality • Efficacy demonstrated in several of those trials and in two metaanalysis.

33. Randomized trials evaluating 500.000 women by mammographic screening • Malmo - Andersson I et al. BMJ 1988; 297: 943-48 • Canada - Miller AB et al. Can Med Assoc J 192; 147: 1459-76 & 1477-88 • Kopparberg - Tabar L et al. Cancer 1995; 75: 2507-17 • Ostergotland - Tabar L et al. Cancer 1995; 75: 2507-17 • Stockholm - Frissel J et al. Breast Cancer Res Treat 1997; 45: 263-70 • Goteborg – Bjurstam N et al. Cancer 1997; 80: 2091-99 • New York - Chu KC et al. J Natl Cancer Inst 1988;80:1125-32 • Edinburgh - Alexander FE et al. Lancet 1999; 353:1903-08

34. Effectiveness of mammography in reducing breast cancer mortality • Individual trials: 4/7showed reductions between 9% - 32%. One was statistically significant (RR: 0.68, 95% CI 0.59 – 0.80) • Metaanalysis by the US Preventive Services Task Force (USPSTF, 2002): • Summary RR = 0.84 (CI:0-77 – 0.91) equivalent to 1224 women screened for each death saved, an average of 14 years after study entry • Women >50 yo, RR= 0.78 (0.70-0.87) with 838 needed to screen. RR increases with time • Women 40-49 yo, RR=0.85 (CI:0.73-0.99) with 1792 needed to screen to prevent one death. RR decreases with time

35. Randomized trials of mammographic screening • Another review by the International Agency for Research on Cancer (IARC) and the World Health Organization in May 2002, concluded that mammographic screening in women 50-69 years did reduce mortality from breast cancer by 39% (IARC handbooks of Cancer Prevention, vol 7, 2002) • Several national programs in high-resource countries have confirmed the contribution of screening.

36. Current Guidelines in North America • ACS 2003, USPSTF 2002*, NCCN 2006* For women at average risk: • At age 20: Start CBE and information on benefits/limitations of CBE & BSE within period health examination at least every 3y • At age 40: Start annual mammographic screening For women at increased risk • Start mammography at age 30 or earlier • Shorter mammography intervals, e.g. every 6 months • Addition of MRI screening • Addition of ultrasound screening * American Cancer Society, US Preventive Services Task Force, National Compreensive Cancer Network

37. Current Guidelines in Europe • European breast cancer screening network* For women 50 -69 years old: • Invitation to mammography to women age 50-69 yo. • Screening is repeated every 2-3 years For women 40-49 years old: • Screening may be offered in some centers or regions • Women should be clearly informed about possible benefits and adverse effects of screening • Organized programs should be set up, so that spontaneous screening in units without adequate control systems is discouraged • Two-view mammography with double reading • 12-18 months interval • Data monitoring and prper evaluation should be mandatory * Advisory Committe on Cancer prevention, Eur J of Cancer 2000, 36: 1473 - 1478

38. Factors of increased risk of breast cancer • Age • Personal history of prior thoracic RT, atypical hyperplasia or lobular carcinoma in situ (LCIS) • Family history of breast and/or ovarian cancer, with number, type and age of onset being important. • Presence of mutated BRCA1 or BRCA2 documented by genetic evaluation, or suspected by evidence of autosomal dominant inheritance

39. Autosomal Dominant inherance • > 2 relatives with breast or ovarian cancer • breast cancer in relatives < 50 yo • Relatives with both breast and ovarian cancer or two independent breast cancers • Male relatives with breast cancer • Family history of breast or ovarian cancer and Askenazi Jewish heritage

40. Teasing out the relative contribution of screening, and newer therapies: the CISNET* breast cancer working group • Randomized Clinical trials in patients with breast cancer have shown that adjuvant therapy following surgery for early disease and newer therapies for metastatic disease prolongs survival * Cancer Intervention and Surveillance Modeling Network

41. CISNET • CISNET is a consorcium of investigators sponsored by NCI (Bethesda, Md) to measure the effect of cancer-control interventions on the incidence of and risk of death from caner in the general population. • Seven independent teams developed statistical models to assess the relative and absolute contributions of screening mammography and adjuvant therapies to the reduction in breast cancer mortality in the US from 1975 to 2000. • The models showed that both screening mammography and treatment have helped reduce the rate of breast cancer death in the US New England Journal of Medicine; 353, 17, 2005

42. Estimate in actual rates of death from breast cancer among women 30-79 years of age from 1975-2000 (Panel A) and under hypothetical assumptions about the use of screening mammographies and adjuvant treatment (Panel B) New England Journal of Medicine 353; 2005

43. Low- resource countries • Have not always identified cancer as a health care priority (infectious diseases are the main health care issue) • However, resources are spent on cancer treatment, typically in advanced-stage disease

44. The Breast Health Global Initiative (BHGI) • Objective: to establish breast health guidelines for optimal care in countries with limited health care resources. • Sponsors: Fred Hutchinsons Cancer Research Center and the Susan G Komen Breast Cancer Foundation • Collaborating Organizations: 12 national and international groups from areas with high and low level of resources • Affiliations with 3 WHO programs • Two Global Summit Consensus Conferences (2002, 2005)

45. 2005 BHGI Global Summit Recommendations • Care Resources were stratified in 4 defined levels: basic, limited, enhanced and maximal • Recommendations were stratified by care resources level, for: • Diagnostic tools • Pathology method • Treatment and allocation of resources • Health care Systems and Public Policy

46. Basic Level: Indispensable Core Resources The Breast Journal 12; Suppl. 1, 2006

47. Limited Level: 2nd Tier resources The Breast Journal 12; Suppl. 1, 2006

48. Extended Level: Third Tier resources The Breast Journal 12; Suppl. 1, 2006

49. Maximal Level The Breast Journal 12; Suppl. 1, 2006

50. Early Detection The Breast Journal 12; Suppl. 1, 2006