“A European network on cervical cancer surveillance and control in the new Member States - AURORA”

1. “A European network on cervical cancer surveillance and control in the new Member States - AURORA” 1st Module: Scientific Background for Advocacy Leaders

2. www.aurora-project.eu This publication arises from the project «AURORA» which has received funding from the European Union in the Framework of the Health Programme.

3. Index 1. Cervical cancer epidemiology. Risk factors 2. Introductory issues about STIsand HPV infection – transmission 3. Diagnosis of HPV infection. 4. How to organise a population based screening programme 5. Prevention of infection: vaccination 6. Diagnosis and treatment of cervical cancer disease

4. CERVICAL CANCER EPIDEMIOLOGY

5. 1. Cervical cancer epidemiology • Rates are lower in Western Asia, Northern America and Australia/New Zealand (ASRs less than 6 per 100.000). Cervical cancer remains the most common cancer in women only in Eastern Africa, South-Central Asia and Melanesia. • Using crude incidence rates, cervical cancer ranks as the 2nd most frequent cancer among women between 15 and 44 years of age. http://globocan.iarc.fr/factsheet.asp: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 International Agency for Research on Cancer; 2010. Bray F, Ren JS, Masuyer E, Ferlay J. Estimates of global cancer prevalence in 2008 for 27 sites in the adult population, submitted. • Cervical cancer is the third most common cancer in women with an estimated 530 000 new cases in 2008. More than 85% of the global burden occurs in developing countries, where it accounts for 13% of all female cancers. • High-risk regions are Eastern and Western Africa (ASR-age standardised rate /incidence per 100000 women greater then 30 per 100,000), Southern Africa (26,8 per 100000), South-Central Asia (24,6 per 100000), South America and Middle Africa (ASRs 23,9 and 23,0 per 100000 respectively).

6. Mortality http://globocan.iarc.fr/factsheet.asp: Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 International Agency for Research on Cancer; 2010. Bray F, Ren JS, Masuyer E, Ferlay J. Estimates of global cancer prevalence in 2008 for 27 sites in the adult population, submitted. Overall, the mortality incidence ratio is 52%, and cervical cancer is responsible for 275.000 deaths in 2008, about 88% of which occur in developing countries: 53.000 in Africa, 31.700 in Latin America and the Caribbean, and 159.800 in Asia.

7. Cervical cancer incidence Worldwide Estimated incidence from Cervix uteri cancer in 2008 ; Age Standardised Rate (European) per 100,000 Europe European Cancer Observatory http://eu-cancer.iarc.fr/cancer-14-cervix-uteri.html,en

8. Cervical cancer mortality Worldwide Estimated mortality from Cervix uteri cancer in 2008 ; Age Standardised Rate (European) per 100,000 Europe European Cancer Observatory http://eu-cancer.iarc.fr/cancer-14-cervix-uteri.html,en

9. HPV INFECTIONAND TRANSMISSION

10. HPV Transmission ● Through sexual intercourse ● Without sexual intercourse – through genital contact with an infected person ● In rare cases - from mother to baby during vaginal delivery ● HPV can be passed even when the infected partner has no signs or symptoms • Not all HPV infections will lead to cervical cancer. Most of the HPV infection will clear spontaneously or after treatment. Cytologic screening will allow early detection and effective intervention, but cervical cancer can not develop without a persistent HPV infection! • (http://www.cdc.gov/std/hpv/commonclinicians/ClinicianBro.txt). ◄ Schiffman & Castle, 2005 HPV Related Cervical Disease by Age

11. Risk Factors • HPV infection is the necessary cause of cervical cancer, but HPV infection is not sufficient to cause cervical cancer. Most of women infected with an oncogenic HPV type never develop cervical cancer, therefore additional factors contribute to cervical cancer development. • Age of sexual debut, lifetime number of sexual partners, history of sexually transmitted infections, and other characteristics of sexual activity are linked to the likelihood of HPV infection, but are not cofactors for the progression from HPV infection to cervical cancer. • Parity, use of oral contraceptives, tobacco smoking, immunosuppression (particularly related to HIV), infection with other sexually transmitted diseases, and poor nutrition, have been associated, to various extents, with the development of invasive cervical cancer. http://screening.iarc.fr/doc/RH_fs_risk_factors.pdf

12. ◄ The key events that occur following infection. This patterns of gene expression is apparent in low-grade squamous intraepithelial neoplasia (LSIL). Doorbar J. Clinical Science (2006)110, 525-541 HPV infection Transient infection - asymptomatic, subclinical • no clinical consequences in immunocompetent individuals. • incubation period – unclear, probably weeks to months for genital warts, several months to years for cervical cellular abnormalities. • Persistent infection - is not cleared by the immune system - persistently detectable HPV DNA. • factors: • older age, • high-risk HPV types, • immunodeficiency.

13. Classification of Oncogenic Risk by HPV Genotype HR types cause cervical intraepithelial neoplasia (CIN) and invasive cancer. 99% of all cervical cancer cases are caused by HPV infection. Two HR types, HPV16 and 18, cause over 70% of cervical cancers, with type 16 having the greatest oncogenic potential. The LR types such as HPV6 and HPV11 are associated with condyloma acuminate and LSIL (Low-grade cervical lesions) The distribution of HPV types varies among geographical regions, but the dominant oncogenic type in all regions is HPV-16 There are over 100 different types of HPVs. Over 30 types are involved in genital infections. Based on their oncogenic power they are divided in “low risk” (LR) and “high risk”

14. Natural History of HPV infection Normal Infection Transient infection Clearance >90% HPV infection Within 1 year Progression 10% Regression 70% Persistent infection While persistent infection with high-risk types is considered necessary for the development of cervical cancer, it is not sufficient, as the vast majority of women with high-risk HPV infection do not develop cancer. Precancer (LSIL) Up to 5 years Progression 30% Regression 30 % Precancer (HSIL) Invasion >10 years Cervical Cancer LSIL - Low-grade cervical lesions (e.g. 6,11) HSIL – High- Low-grade cervical lesions (e.g. 16, 18) 1. Koutsky, Am J Med 1997. 2. Feoli-Fonseca et al. J med Virol 2001. 3. Liaw ET AL. JNCI 1999. 4. Clifford et al. IntPapillomvirus Conference 2004. 5. Globocan 2000. 6. Sawaya et al. NEJM 2003. 7. Mark Schiffman J Natl Cancer Inst Monogr 2003. 8. E.J. Mayeaux. Medscape 2005. 9. CDC EpidemiolPrev Vaccine PrevDis 2009. 10. Edward E. Partridge. Medscape 2006. 11. Kenneth A Alexander. Medscape 2007.

15. DIAGNOSIS

16. Sensitivity and specificity Test accuracy refers to: Sensitivity – proportion of truly ill people in the screened population who are identified as ill by the screening test Specificity – proportion of truly healthy people who are so identified by the screening test

17. Tests for CC screening As far as today there is sufficient evidence that screening for cancer precursors every 3-5 years between the ages 35 and 64 years by conventional cytology in a high-quality programme reduces the incidence of invasive cancer by 80% or more among the women screened. HPV molecular tests are very sensitive, but they do not discriminate between transient and persistent infection and this means less specificity. HPV test was accepted for the triage of equivocal cytology (ASCUS) and follow up of treated lesions. New strategies can simplify the screening process or reduce the cost of screening. Recently, many wide, randomized clinical trials show that carcinogenic HPV DNA screening is more sensitive than cytological screening for detecting histological CIN3. A negative HPV test provides long-term risk stratification; this high negative predictive value permits safe and cost-effective lengthening of the cervical screening interval when HPV testing is used. IARC Handbooks on Cancer Prevention 2005; www.ecca.info; Ronco G et al. Lancet Oncol. 2010; Mayrand MH et al. N Engl J Med. 2007; Bulk S et al. Int J Cancer. 2007; Naucler P et al. N Engl J Med. 2007; Sankaranarayanan R et al. N Engl J Med. 2009; Bulkmans NW et al. Lancet. 2007; Khan MJ et al. J Natl Cancer Inst. 2005; Dillner J et al. BMJ. 2008.

18. POPULATION BASED SCREENING

19. Definitionofoncological screening “Screening” is an organized, controlled, systematic, public health intervention actively and periodically proposed, that involves the application of a relatively simple, innocuous, acceptable, ripetible, and relative cheap (for the organization, free for the involved population) test, to an asymptomatic and well defined population, to obtain detection of cancer at an earlier stage or of a pre-cancerous lesion, with the goal to decrease the mortality and, if possible, the incidence of the tumor, with an effective and conservative treatment, possibly less aggressive than in clinically detected cases.

20. Definitionofpopulationbased screening A screening programme with individual identification and personal invitation of the elegible population. An optimal program is a screening program with quality assured at every step in the process: identification and personal invitation of the target population, performance of the test, compliance, call/recall system, second level diagnosis and treatment of the lesions detected, data registration, communication and training. von Karsa et al., 2008, Antilla et al., 2009

21. Cervicalcancer screening Among all malignant tumours, cervical cancer is the one that can be most effectively controlled by screening. Detection of cytological abnormalities by microscopic examination of Pap smears, and subsequent treatment of women with high-grade cytological abnormalities avoids development of cancer. Miller, 1993

22. Impact • If an optimal CCS policy is implemented in their countries, with adequate funds and supports, the figures of cervical cancer cases and deaths could substantially decrease. • As far as today many European countries have developed population-based screening programs for cervical cancers, although they differ greatly in terms of organizational characteristics, implementation stage, coverage and quality assurance. von Karsa et al., 2008, Antilla et al., 2009

23. Finland • In Finland organised cervical screening was introduced in the early 1960s; from the early 1970s the screening invitational coverage has been almost complete. • During 1955–1964 the incidence of invasive cervical cancer in Finland was at a level of 15 cases per 100,000 woman-years age-adjusted to the world standard population; currently the age-adjusted rate is 4 cases per 100,000 woman-years. • The age-standardized mortality rates decreased over 80% from the level of 7.0 deaths per 100,000 in early 1960s to 1.2 deaths per 100,000 in the 1990’s (rates adjusted for age to the world standard population). Hristova & Hakama, 1997; Anttila & Laara,2000

24. Cervical cancer incidence and mortality rates in Finland Anttila A , Niemininen P, Cervical Cancer Screening Programme in Finland with an Example on Implementing Alternative Screening Methods. Coll. Antropol. 31 (2007) Suppl. 2: 17–22

25. Uk Cytological screening was introduced in the 1960s, but an organised programme including a call/recall system and quality assurance was not initiated until1988. In the preceding years, mortality and incidence decreased by 1-2% per year, whereas since 1988 the decrease has been about 7% per year, despite an increased underlying risk of disease inwomen born since 1940 Sasieni et al., 1995; Quinn et al., 1999; Sasieni & Adams, 1999; Peto et al., 2004; Bray et al., 2005; IARC, 2005

26. Effect of screening on incidence of cervical cancer in England Quinn M , Babb P, Jones J et al. Effect of screening on incidence of and mortality from cervical cancer of cervix in England: Evaluation based on routinely collected statistics. BMJ 1999;318:904–908.

27. Strategy • The strategy of a screening programme must clearly establish: • Who is the target population • general population • certain age groups / gender categories • certain geographic regions • those with a certain risk level • What detection tests shall be used, in what order and at what intervals they shall be applied • Who shall apply the tests and where they shall be carried out • A screening programme must have a quality assurance structure

28. Hard to reach population • Important problems are associated with conducting the screening on hard-to-reach population. • Definition of Hard to reach population (HTRP): those sections of the community that are difficult to involve in public participation. • The term can be used to refer to minority group such as ethnic group, sometimes to hidden populations such as illegal immigrants, sometimes to unserved groups (no services available for these groups) or service “resistants” (people failing to access the services that are available). • no homogeneity in the term • certain groups may be hard to reach in some contexts or locations and not in others • the term can bring some prejudices about the people “hard to reach” • paradoxically top business women, can be “hard to reach” for cervical cancer screening, because of lack of time

29. PREVENTION OF INFECTION: VACCINATION

30. Prevention Prevention activities aimed at reducing the incidence or spreading of disease, or at least minimizing the consequences of disease or health disorders There arethree levels of prevention: • Primary prevention – the aim is to prevent disease – as an example vaccination or provizion of drinking water.. • Secondary prevention – a number of measures to allow early detection and rapid intervention – ex. screening forcervical cancer • Tertiary prevention – reduces the number of complications and consequences of diseases and disorders of health, increasing the chance of extending life expectancy – ex. in oncology, follow-up of patients after therapy with the aim of early detection of relapse of disease.

31. The vaccination protects a person from future infection by the HPV high-risk types that can lead to cancer. A person receives a series of three shots over a 6-month period. Health professionals inject these virus-like particles (VLPs) into muscle tissue. Both available vaccines Gardasil/Silgard(quadrivalent – types 6, 11, 16 and 18) and Cervarix(bivalent – types 16 and 18)demonstrate also a certain degree of cross-protection towards HPV types genetically and antigenically related to those included in the vaccines, as follows: HPV 31, 33, 52, 58 similar with HPV 16; HPV 39, 45, 59 similar with HPV 18.

32. VLPs Preventive vaccines are based on virus-like particles (VLPs). The virus-like particles in the HPV vaccine(similar to the real human papillomavirus) have the same outer L1 protein coat, but they have no genetic material inside, so they are non infective VLPs enable the vaccine to induce a strong protective immune response. If an exposure to the virus occurs, the vaccinated person's antibodiesagainst the L1 protein coat covers the virus and prevents from releasing its genetic material.

33. Advantages and limits of CC vaccination • It has been proven high efficacy of both vaccines in prevention premalignant cervical lesions and cervical cancer (up to 70-82% of cases of cervical cancer) • They have notherapeutic effect • Vaccination prevents reinfection by vaccinal types but it cannot prevent already presentpersistent infection • There are also other types of cancer attributable to HPV (anal, vulvar, vaginal, penile, oral, laryngeal, tonsilar) • Silgard/Gardasil also preventcondyloma acuminata • Vaccines have good safety profile ; the most common adversereactions are fever and site reactions – pain, redness, swelling • Vaccines reduce the costs related to the diagnosis and treatment of precancerous lesions and cervical cancer

34. Screening vaccination • Vaccination does not replace CC screening • When girls vaccinated will reach the age of CC, screening, different screening strategies will be implemented (years of interval, algorithm). • The exchange of information (list of vaccinated women) between screening centers and vaccination centers is mandatory.

35. DIAGNOSIS AND TREATMENT OF CERVICAL PRE-CANCER LESIONS AND CANCER DISEASE

36. Treatment Different types of treatment are available depending on the staging of the disease. Cryotherapy - Eliminates small precancerous areas on the cervix by freezing them, can be performed on an outpatient basis. Loop electrosurgical excision procedure (LEEP) - Removal of abnormal areas from the cervix using a thin heated wire, it can be performed under local anaesthesia on an outpatient basis Hysterectomy - The uterus is surgically removed with or without other organs or tissues Radiation therapy - Uses high-energy x-rays – kills cancer cells or keeps them from growing Chemotherapy - Uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing http://www.cancer.umn.edu/cancerinfo/NCI/CDR62961.html

37. Resources • World Health Organization (http://www.who.int/reproductivehealth/topics/cancers/en/index.html) • Union for International Cancer Control (http://www.uicc.org/programmes/hpv-and-cervical-cancer-curriculum) • Merck manual (http://www.merckmanuals.com/professional/gynecology_and_obstetrics/gynecologic_tumors/cervical_cancer.html) • Center for Disease Control and Prevention (http://www.cdc.gov/cancer/cervical/) • National Cancer Institute (http://cancer.gov/cancertopics/types/cervical) • European guidelines for quality assurance in cervical cancer screening; Second Edition; International Agency for Research on Cancer • Cancer Research UK (http://cancerhelp.cancerresearchuk.org/type/cervical-cancer/) • RHO/PATH (http://www.rho.org/) • American Cancer Society (http://www.cancer.org/cancer/cervicalcancer/index) • Alliance for Cervical Cancer Prevention (http://www.alliance-cxca.org/ ) • Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2009. Atlanta: U.S. Department of Health and Human Services; 2010. • Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2010. MMWR 2010;59; 69 • WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in Europe. Summary Report 2010. Available at www. who. int/ hpvcentre • Human papillomavirus vaccines - WHO position paper , Weekly epidemiological record, WHO, 10 APRIL 2009, No. 15, 2009, 84, 118–131, (http://www.who.int/wer) • WHO HPV LabNet Newsletter No.8, 18 July 2011 • Shepherd JP, Frampton GK, Harris P, Interventions for encouraging sexual behaviours intended to prevent cervical cancer, Cochrane Database Syst Rev. 2011 Apr 13;(4):CD001035. • Weinstein LC, Buchanan EM, Hillson C, Chambers CV, Screening and prevention: cervical cancer, Prim Care. 2009 Sep;36(3):559-74. • Kasap B, Yetimalar H, Keklik A, Yildiz A, Cukurova K, Soylu F., Prevalence and risk factors for human papillomavirus DNA in cervical cytology, Eur J ObstetGynecolReprod Biol. 2011 Nov;159(1):168-71. • Gonzalez-Bosquet E, Selva L, Sabria J, Pallares L, Almeida L, Muñoz-Almagro C, Lailla JM, Predictive factors for the detection of CIN II-III in the follow-up of women with CIN I, Eur J Gynaecol Oncol. 2010;31(4):369-71.