HPV vakcina a gyakorló nőgyógyász szemével Ungár László 2006

HPV Konszenzus Konferencia, 2006. Október 20. A HPV epidemiológia HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Cumulative HPV Positivity for Infection Over Time Among Women Who Were HPV Negative for that Group at Enrollment: Ludwig-McGill Cohort*,1 Months Cumulative probability of HPV detection 0.25 0.20 0.15 0.10 0.05 0.00 4 8 12 16 Any types Non-oncogenic types Oncogenic HPV 16 1/Franco/p. 1419/Figure 1; p.1415/abstract Key Point HPV infection is widespread. However, because there are many types of HPV, the cumulative probability of HPV infection of a single type over time differs from the one with many types. Background In the Ludwig-McGill Cohort Study, a cohort of 1425 low-income women in Brazil, 18–60 years of age, was followed for up to 5 years to analyze the natural history of HPV infection and cervical neoplasia in these women. Specimens were collected every four months and were tested by a PCR protocol.1 Overall, there were 1.3% new infections per month, with 38% cumulative positivity over 18 months.1 The cumulative probability of HPV detection over time for infection of any time, for non-oncogenic and oncogenic types, and for HPV 16 among women who were HPV-negative for that type(s) at enrollment are shown in the figure.1 Among women who were negative at enrollment, the cumulative rates of infection for any types were 7.3%, 13.6%, and 23.6% at 6, 12, and 18 months, respectively. The cumulative probability of acquiring infections with a non-oncogenic type at 18 months was twice that of acquiring an oncogenic type (22.4% vs 11.2%, respectively). Among women who were HPV-16 negative at enrollment, the cumulative proportion testing positive for HPV 16 was 1.5% at 12 months and 4.0% at 18 months.1 Reference 1. Franco EL, Villa LL, Sobrinho JP, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis. 1999;180:1415–1423. 1/Franco/p. 1415/abstract; p. 1416/col 1/¶1,2 1/Franco/p. 1415/abstract *In a cohort of Brazilian women (n=1425), 18–60 years of age 1. Adapted with permission from The University of Chicago Press, from Franco EL, Villa LL, Sobrinho JP, et al. J Infect Dis. 1999;180:1415-1423. 1/Franco/p.1419/Figure 1 HPV Konszenzus Konferencia, 2006. Október 20. 1/Franco/p. 1418/col 2/¶1; p.1419/col 1/¶ 1

Determinants of HPV Infection 1/Insinga/ p. 1397/abstract 2/ Burk/p. 679/Abstract Women Young age (peak age group 20–24 years of age)1 Lifetime and recent number of sex partners2 Early age of first sexual intercourse*,3 Male partner sexual behavior3 Smoking*,4 Oral contraceptive use*,4 Uncircumcised male partners5,6 Men Young age (peak age group 25–29 years of age)1 Lifetime number of sex partners7 Being uncircumcised6,7 Sexual partner with CIN8 3/ Murthy/ p. 9/col 1/¶ 2; col 2/¶2 4/ Winer/ p. 223/Table 3 5/ Schiffman. p. 932/col 1/ ¶2 6/Castellsague/ p. 1105/abstract 7/ Svare/ p. 215/abstract; p. 216/ Table 1 8/Bleeker/ p. 36/abstract 1/ Burk/ p. 679/Abstract. 2/ Murthy p. 9/col 1/¶2 Key Point Though less documented, risk factors for HPV infection in males seem similar to those in females. Background A number of factors directly or indirectly related to sexual behavior have been associated with increased risk for HPV infection in both men and women. Those consistently relating to infection in women are young age, intercourse at an early age, and sexual behavior, particularly with a higher number of partners.1,2 The sexual behavior of male partners,2 smoking,3 oral contraceptive use,3 and lack of circumcision of male partners4 also appear to increase risk. Risk factors for HPV infection among men are similar to those in women and include young age, number of sex partners, and being uncircumcised.5 HPV infections and HPV-associated penile lesions are frequently found in male sexual partners of women with cervical intraepithelial neoplasia (CIN).6 References 1. Burk RD, Ho GY, Beardsley L, Lempa M, Peters M, Bierman R. Sexual behavior and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young women. J Infect Dis. 1996;174:679–689. 2. Murthy NS, Mathew A. Risk factors for pre-cancerous lesions of the cervix. Eur J Cancer Prev. 2000;9:5–14. 3. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226. 4. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med. 2003;127:930–934. 5. Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJ, van den Brule AJ. Risk factors for genital HPV DNA in men resemble those found in women: A study of male attendees at a Danish STD clinic. Sex Transm Infect. 2002;78:215–218. 6. Bleeker MC, Hogewoning CJ, Voorhorst FJ, van den Brule AJ, Berkhof J, Hesselink AT, Lettink M, Starink TM, Stoof TJ, Snijders PJ, Meijer CJ. HPV-associated flat penile lesions in men of a non-STD hospital population: less frequent and smaller in size than in male sexual partners of women with CIN. Int J Cancer. 2005;113:36-41. 2/ Murthy/ p. 9/col 2/¶2 3/ Winer/p. 223/Table 3 *Findings not consistent across studies 1. Insinga RP, Dasbach EF, Myers ER. Clin Infect Dis. 2003;36:1397–1403. 2. Burk RD, Ho GY, Beardsley L, Lempa M, Peters M, Bierman R. J Infect Dis. 1996;174:679–689. 3. Murthy NS, Mathew A. Eur J Cancer Prev. 2000;9:5–14. 4. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218–226. 5. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 6. Castellsagué X, Bosch FX, Muñoz N, et al. N Engl J Med. 2002;346:1105–1112. 7. Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJ, van den Brule AJ. Sex Transm Infect. 2002;78:215–218. 8. Bleeker MC, Hogewoning CJ, Voorhorst FJ, et al. Int J Cancer. 2005;113:36-41. 4/Schiffman/ p. 932/ col 1/ ¶2 5/ Svare/ p. 215/Abstract HPV Konszenzus Konferencia, 2006. Október 20. 6/Bleeker/ p. 36/abstract

Current Approaches to Prevention of HPV Infections 1/Dailard/p. 5/col 2 ¶3. 2/Anhang/p.253/Table 3 Total abstinence from all genital contact is the most effective HPV prevention method.1,2 Lifetime mutual monogamy2,3 However, if one partner has not been monogamous, both are at risk.3 Condom use may help reduce risk, but is not fully protective.4,5 Risk of HPV infection is reduced among circumcised men.6 2/Anhang/p.253/Table 3. 3/Bosch/p. S332/col 1/¶3-4/Figure 5; col 2/¶1. 4/Winer/p. 224/col 1/¶5. 5/Manhart/p. 725/abstract. 6/Castellsagué/p. 1105/abstract Key Point Options currently available for preventing HPV infection are inadequate. Background There are a limited number of options currently available that provide optimal protection from HPV infection. Total abstinence from all genital contact is the most effective method for preventing HPV infection.1,2 However, common sense suggests that in the real world, the practice of abstinence is not always perfect.1 Lifetime mutual monogamy is an effective HPV prevention strategy2; however, a monogamous person may be at risk if his/her partner has had previous partners.3 For example, in a study of monogamous female adolescents, the risk of acquiring HPV was 46% within 3 years of her first sexual experience.4 Condom use may help reduce the risk of acquiring or transmitting HPV infection, but it is not fully protective.5 In a retrospective meta-analysis, Manhart and Koutsky reported that condoms may protect against anogenital warts, CIN 2 and 3, and invasive cervical carcinoma, but they do not prevent HPV infection.6 Male circumcision is also associated with a reduced risk of penile HPV infection in men and a reduced risk of cancer in their female partners.7 References 1. Dailard C. Understanding ‘abstinence’: Implications for individuals, programs and policies. Guttmacher Rep Public Policy. 2003;6:4–6. 2. Anhang R, Goodman A, Goldie SJ. HPV communication: Review of existing research and recommendations for patient education. CA Cancer J Clin. 2004;54:248–259. 3. Bosch FX. Epidemiology of human papillomavirus infections: New options for cervical cancer prevention. Salud Publica Mex. 2003;45(suppl 3):S326–S339. 4. Collins S, Mazloomzadeh S, Winter H, et al. High incidence of cervical human papillomavirus infection in women during their first sexual relationship. BJOG. 2002;109:96–98. 5. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226. 6. Manhart LE, Koutsky LA. Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis. Sex Transm Dis. 2002;29:725–735. 7. Castellsagué X, Bosch FX, Muñoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002;346:1105–1112. 1/Dailard/p. 5/col 2/¶3. 2/Anhang/p.253/Table 3. 3/Bosch/p. S332/col 1/¶3-4; col 2/¶1. 1. Dailard C. Guttmacher Rep Public Policy. 2003;6:4–6. 2. Anhang R, Goodman A, Goldie SJ. CA Cancer J Clin. 2004;54:248–259. 3. Bosch FX. Salud Publica Mex. 2003;45(suppl 3):S326–S339. 4. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218–226. 5. Manhart LE, Koutsky LA. Sex Transm Dis. 2002;29:725–735. 6. Castellsagué X, Bosch FX, Muñoz N, et al. N Engl J Med. 2002;346:1105–1112. 4/Collins/p. 96/abstract. 5/Winer/p. 224/col 1/¶5. HPV Konszenzus Konferencia, 2006. Október 20. 6/Manhart/p. 725/abstract. 7/Castellsagué p. 1105/ abstract/¶4

HPV Konszenzus Konferencia, 2006. Október 20. Összegzés Az adatok arra utalnak: HPV infekció kockázata jelentős. Új fertőzés kockázata az életkor előrehaladásával csökken. Az infekciók leggyakrabban nem onkogén típussal jönnek létre. Az újonnan fertőzöttek jelentős hányada onkogén, kisebb hányada16-os típussal fertőződik. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. HPV és méhnyakrák HPV Konszenzus Konferencia, 2006. Október 20.

Worldwide Prevalence of HPV Types in Cervical Cancer*,1 69.7 14.6 1/Munoz/p. 282/Table III HPV Type 16 52.5 25.7 18 45 67.6 17 31 North America/ Europe 33 57 12.6 52 South Asia 58 Key Point Most cases of invasive cervical cancer are associated with HPV 16 or 18, but approximately one quarter to one third of all cases are associated with other HPV types, the distribution of which varies by region. Background In a pooled analysis from an international survey of HPV types in cervical cancer and from a multicenter, case-control study (N = 3607), both co-coordinated by the International Agency for Research on Cancer (IARC) and with HPV DNA detection and polymerase chain reaction (PCR) done centrally, Muñoz and colleagues investigated geographic variations in the contribution made by different HPV types to invasive cervical cancer.1 HPV DNA was detected in 96% of specimens from women with incident, histologically confirmed cervical cancer. Thirty different HPV types were identified. The 15 most common types (in descending order of frequency) were 16, 18, 45, 31, 33, 52, 58, 35, 59, 56, 39, 51, 73, 68, and 66.1 Reference 1. Muñoz N, Bosch FX, Castellsagué X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer. 2004;111:278–285. Others Northern Africa 1/Munoz/p. 278/abstract. Central/South America *A pooled analysis and multicenter case control study (N = 3607) 1. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285. 1/Munoz/p. 278/abstract. HPV Konszenzus Konferencia, 2006. Október 20.

Natural History from HPV Infection to Cervical Cancer1 Median Age of Event: Early 20s Early to mid 20s Mid to late 20s 40s to 50s Oncogenic HPV Infection of the Cervix LSIL & HSIL HSIL Cervical Cancer LSIL Undetected Cellular Changes 1/Baseman/ p.S21/Figure 2 Key Point Most HPV infections will typically clear, but some infections with high-risk HPV types may ultimately lead to cervical cancer via a number of intermediate steps. Most low-grade lesions do not lead to cancer. Some subjects progress directly to high-grade lesions.   Background Squamous intraepithelial lesions (SILs) are subdivided into low-grade squamous intraepithelial lesions (LSIL) and high-grade intraepithelial lesions (HSIL), based on cytology results. LSIL often are the marker of CIN 1, and HSIL of CIN 2/3.1 Incident HPV infection is the new detection of HPV infection in women who were previously HPV-negative. Although common in sexually active persons, more than 90% of infections are spontaneously cleared by the immune system within approximately 1 year without treatment.2 Persistent HPV infection is the detection of the same HPV type in follow-up visits 6–12 months apart in women who were naive for that particular HPV type at baseline.2 The schematic shows the progression from oncogenic HPV infection to cervical cancer. The known steps from HPV infection to cervical cancer include oncogenic HPV infection of the cervix; development of undetected cellular changes, LSIL or HSIL; development of HSIL; and progression to cervical cancer. The sequential steps of progression include: LSIL and undetected cellular changes to HSIL to cervical cancer. However, some LSIL may progress directly to cervical cancer, and some initial HPV infection may progress directly to HSIL. The literature suggests that between one-third and two-thirds of women with HSIL will progress to cervical cancer if left untreated.3 Approximately 60% of CIN 1 lesions (or low-grade dysplasia), the most common clinical manifestation of cervical HPV infections, regress without treatment, and about 10% can progress to CIN 2 and CIN 3.2,4 CIN 2 (moderate-grade dysplasia) also can regress; however women with CIN 2 are still at risk for developing invasive cervical cancer. In a meta-analysis of studies on the natural history of CIN, it was estimated that 22% of CIN 2 lesions that were not treated will progress.2,4 CIN 3 lesions (high-grade precancerous lesions and carcinoma in situ) are more likely to progress to cancer, with regression being less common.2 The mean age of invasive cervical cancer is approximately 50 years. The mean age of women with HSIL is approximately 28 years of age.3 References 1. Solomon D, Davey D, Kurman R, et al, for the Forum Group Members and the Bethesda 2001 Workshop. The 2001 Bethesda System: Terminology for reporting results of cervical cytology. JAMA. 2002;287:2114–2119. 2. Pagliusi SR, Aguado MT. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine. 2004;23:569–578. 3. Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol. 2005;32S:S16-S24. 4. Ostor AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol. 1993;12:186–192. * 1/Solomon/p 2116/box 2 ** 2/Pagliusi/p. 571/col 1/¶6/col 2/¶2,5 3/Baseman/ p.S21/col 2/¶ 2 and Figure 2 *LSIL = low-grade squamous intraepithelial lesion **HSIL = high-grade squamous intraepithelial lesion 1. Adapted from Baseman JG, Koutsky LA. J Clin Virol. 2005;32S:S16-S24, with permission from Elsevier. 2/Pagliusi/p. 571/col 1/¶6/col 2/¶2,5 4/Ostor/p. 186/abstract HPV Konszenzus Konferencia, 2006. Október 20. 2/Pagliusi/p. 571/col 2/¶5; p. 572/col 1/¶1 4/Ostor/p.190/ Table 7 2/Pagliusi/p. 572/col 1/¶1 3/Baseman/ p.S21/col 2/¶ 2 and Figure 2

Cervical Cancer Is Essentially Caused by Oncogenic HPV Infection with oncogenic HPV types is the most significant risk factor in cervical cancer etiology.1 HPV is a main cause of cervical cancer.2 Analysis of 932 specimens from women in 22 countries indicated prevalence of HPV DNA in cervical cancers worldwide = 99.7%.2 Tissue samples were analyzed for HPV DNA by 3 different polymerase chain reaction (PCR)–based assays, and the presence of malignant cells was confirmed in adjacent tissue sections.2 1/Muñoz/ p. 519/col 1/¶1. 2/Walboomers/p. 12/title; abstract. 2/Walboomers/ p. 12/abstract; col 1 /¶1; col 2/ ¶2; p. 13 /col 2 /¶7; p. 18/col 1 /¶1. Key Point Oncogenic HPV types are the core cause of cervical cancer. Background In a meta-analysis, specific oncogenic HPV types have been identified in 63%–97% of invasive cervical cancer cases worldwide.1 Among 85 studies measuring HPV prevalence in invasive cervical cancer by polymerase chain reaction (PCR)–based assays (N=10,058), HPV 16 was the predominant type in squamous cell carcinoma cases (46%–63%), followed by HPV 18 (10%–14%), 45 (2%–8%), 31 (2%–7%), and 33 (3%–5%), except in Asia, where HPV 58 and 52 were found in 6% and 4% of cases, respectively. In adenocarcinoma and adenosquamous-carcinoma cases, HPV 18 was predominant (37%–41%), followed by type 16 (26%–36%) and type 45 (5%–7%). The overall detection of HPV DNA in invasive cervical cancer was similar in different regions worldwide.1 Due to sample inadequacy or integration events effecting the HPV L1 gene, the target of the PCR-based assay, some projected prevalences may actually be underestimated. Walboomers and colleagues conducted a study to more accurately assess the prevalence of HPV DNA.2 A PCR-based test was used; however, in HPV-negative cases, the biopsy was reanalyzed by a sandwich procedure, in which the inner sections of a series of tissue sections were assayed by 3 different HPV PCR assays targeting different open reading frames, while the outer sections were reviewed to verify the presence of malignant cells. Analysis of 932 specimens from women with cervical cancer in 22 countries indicated that worldwide HPV prevalence in cervical carcinomas is 99.7%.2 References 1. Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: A meta-analysis. Br J Cancer. 2003;88:63–73. 2. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19. 1/Clifford/p. 63/abstract/ calculation 1. Muñoz N, Bosch FX, de Sanjosé, et al. N Engl J Med. 2003;348:518–527. 2. Walboomers JM, Jacobs MV, Manos MM, et al. J Pathol. 1999;189:12–19. 2/Walboomers/p. 12/ abstract/ col 1 /¶1; col 2/¶2; p. 13/col 2 /¶7; p. 18/col 1 /¶1. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Összegzés Feltételezhető, hogy: A méhnyak rák kialakulásában a legfontosabb faktor az onkogén HPV. A méhnyak rák esetek 75-85%-ának kialakulásában a HPV 16 és 18 típusnak szerepe van. Lényeges eltérést ebben a vonatkozásban az egyes földrészek lakossága nem mutat. HPV Konszenzus Konferencia, 2006. Október 20.

A méhnyakrák társadalmi hatása HPV Konszenzus Konferencia, 2006. Október 20.

Impact of Cervical Cancer 1/WHO/p. 40/ ¶3,4. 1/WHO/p. 40/ ¶3,4. 2/Ferlay/GLOBOCAN/ Report 1/p. 4 Morbidity Global prevalence: ~2.3 million1 Global incidence: ~500,0001,2 Globally, cervical cancer is second to breast cancer as the leading cause of cancer in women.2 2nd leading female cancer in women less than 45 years of age in developed countries2 Mortality 3rd most common cause of overall female cancer-related mortality worldwide2 Burden Estimated individual loss of life = 25.9 years in the United States (2002)3 In comparison, women who die of breast cancer or ovarian cancer lose an estimated 19.0 and 17.4 years of life, respectively.3 2/Ferlay/GLOBOCAN /Table 1/p. 3 2/Ferlay/GLOBOCAN /Table 10 2/Ferlay/GLOBOCAN /Table 11 3/Ries/Figure I-19. 1/FerlayGLOBOCAN /Table 1/p. 3 Key Point Globally, cervical cancer is the second leading cause of cancer in women. Background Globally, cervical cancer is second to breast cancer as the leading cause of cancer in women,1 with a global prevalence of 2.3 million.2 It accounts for nearly 10% of all cancers (excluding non-melanoma skin cancers).3 In developed countries, cervical cancer is the second leading female cancer in women less than 45 years of age.1 In the absence of screening programs, cervical cancer is detected too late and leads to death in almost all cases. Cervical cancer is the third most common cause of female cancer-related mortality worldwide.1 According to data from the SEER Cancer Statistics Review (1975–2002), women who die from cervical cancer in the United States lose 25.9 years of life on average (2002). In comparison, women who die from breast cancer lose an average of 19.0 years of life, and women who die from ovarian cancer lose an average of 17.4 years of life (2002).4 References 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide, version 2.0. IARC CancerBase No. 5. Lyon, France: IARC Press; 2004. 2. World Health Organization. State of the art of new vaccines research and development: Initiative for vaccine research. Geneva, Switzerland: World Health Organization; 2003:1–74. 3. Franco EL, Harper DM. Vaccination against human papillomavirus infection: A new paradigm in cervical cancer control. Vaccine. 2005;23:2388–2394. 4. Ries LAG, Eisner MP, Kosary CL, et al. (eds). SEER Cancer Statistics Review, 1975–2002, National Cancer Institute. Bethesda, MD, http://see.cancer.gov/csr/1975_2002/. Based on November 2004 SEER data submission; posted to the SEER Web site 2005. 2/WHO/p. 40/ ¶4. 3/Franco/p. 2389/col 1/¶4. 1/FerlayGLOBOCAN /Table 10 1/Ferlay/GLOBOCAN/Table 11 1. World Health Organization. Geneva, Switzerland: World Health Organization; 2003:1–74. 2. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004. 3. Ries LAG, Eisner MP, Kosary CL, et al. (eds). SEER Cancer Statistics Review, 1975–2002, National Cancer Institute. Bethesda, MD; 2005. 4/Ries/ Figure I-19 HPV Konszenzus Konferencia, 2006. Október 20.

Cervical Cancer Incidence and Mortality Estimates by Region 2002 estimated cervical cancer incidence and mortality by region1: 1/GLOBOCAN /Cervix Uteri Table /col 1; col 4: (US/Can)p.3/ (CentAmer)p. 2/ (S.Amer)p.2/ (Europe)p. 4/ (Africa)p. 1/ (Aust/New Z) p. 5/ (Asia)p. 3. 14,670 5796 United States/ Canada 59,929 29,814 Europe 61,132 31,314 Eastern Asia 157,759 86,708 Southcentral Asia 17,165 8124 Central America 42,538 22,594 Southeast Asia Key Point Worldwide cervical cancer rates are high, particularly in developing countries, and are still unacceptable in developed countries. Background According to data obtained from GLOBOCAN 2002, 82% of new cervical cancer cases occur in developing countries.1 As stated by WHO, “without screening programs (i.e., routine pap smears), cervical cancer is detected too late and leads to death in almost all cases.”2 However, even in Europe, the United States, or Canada, where most women have access to routine screening, approximately 30,000 women die each year.1 References Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide, version 2.0. IARC CancerBase No. 5. Lyon, France: IARC Press; 2004. World Health Organization. State of the art of new vaccines research and development: Initiative for vaccine research. Geneva, Switzerland: World Health Organization; 2003: 1–74. 78,896 61,670 Africa 1/GLOBO-CAN/World–Females Table/p.1/col 8; Cervix Uteri Table/p. 1/col 1; col 4. Table/p.3-4/col 4; Calculation Table/p.5. 48,328 21,402 South America 1,063 330 Australia/ New Zealand 1. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004. 2/WHO/p.40/¶3 HPV Konszenzus Konferencia, 2006. Október 20.

Cervical Cancer: Age-Adjusted Survival 2002 estimated age-adjusted survival by region1: 1/GLOBOCAN /Cervix Uteri Table /p. 1-5; calculations /p. 1. 51.0% Central/Eastern Europe 70.1% North America 66.0% Western Europe 65.0% Japan 1/GLOBOCAN /Age-adjusted Survival Table. 42.0% India 51.0% Central America 17.9% Middle Africa 57.6% Thailand Key Point Overall, age-adjusted survival rates are considerably lower in less developed regions than in developed regions. Background Data from GLOBOCAN 2002* indicate that age-adjusted survival rates are relatively high in more developed areas in the world, such as the United States, Canada, Western Europe, and Japan. In these regions, age-adjusted survival is 65%–~70%. Overall, the age-adjusted survival rate is 61.2% in more developed countries, compared with 41.4% in developing countries, although Thailand and some countries in Central and South America (such as Belize, Argentina, and Uruguay) have higher survival rates than some countries in Eastern Europe (such as Romania and the Russian Federation).1 However, in less developed regions, such as Middle Africa, age-adjusted survival rates can be as low as 17.9%. Reduced survival rates in these regions are likely due to inadequate screening practices.2 Without screening programs (i.e., routine Pap smears), cervical cancer is detected too late and leads to death in almost all cases.3 *GLOBOCAN 2002 is a project that aims to present estimates of the incidence and prevalence of and mortality from 27 cancers for all the countries in the world in 2002. References 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide, version 2.0. IARC CancerBase No. 5. Lyon, France: IARC Press; 2004. 2. Sankaranarayanan R, Budukh AM, Rajkumar R. Effective screening programs for cervical cancer in low- and middle-income developing countries. Bull World Health Org. 2001;79:954–962. 3. World Health Organization. State of the art of new vaccines: Research and development: Initiative for vaccine research. Geneva, Switzerland: World Health Organization; 2003:1–74. 54.9% South America 1/GLOBOCAN /Cervix Uteri Table /p. 1-5; calculations/p. 1; age-standardized rate survival table Age-adjusted survival: 61.2% in more developed countries; 41.4% in developing countries1 2/Sankaranarayanan /p. 40 /abstract. 3/WHO/p. 40/¶4. 1. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Kelet-Európa: Nők daganatos halálozási adatai Kelet Európában a méhnyak rák a 3. vezető halálok. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Kelet-Európa: A méhnyakrák mortalitása HPV Konszenzus Konferencia, 2006. Október 20.

Magyarország: A méhnyakrák mortalitása, 1955-2002 KSH 2002 HPV Konszenzus Konferencia, 2006. Október 20.

Age Distribution of New Cervical Cancer Cases1 1/GLOBOCAN/ Table 5,6 Key Point Whereas cervical cancer is more prevalent in women 45–54 years of age in the developing world, it is a disease of either elderly or young women in the developed world. Background Data from the GLOBOCAN 2002* database demonstrate that the incidence of new cervical cancer cases is considerably higher in developing countries compared with the incidence in developed countries. In less developed regions, the number of new cases per year is 409,269, compared with 83,437 in more developed regions. The age-standardized rate is 19.1 cases per 100,000 individuals in less developed regions and 10.3 cases per 100,000 individuals in more developed regions. Interestingly, the ratio of new cervical cancer cases in developed to developing countries is lowest in women >65 years of age.1 Prevalence is higher in young and older populations in the developed world, as screening may be less effective in these age groups.2 *GLOBOCAN 2002 is a project that aims to present estimates of the incidence and prevalence of and mortality from 27 cancers for all the countries in the world in 2002. References 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide, version 2.0. IARC CancerBase No. 5. Lyon, France: IARC Press; 2004. 2. Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: Evaluation based on routinely collected statistics. BMJ. 1999;318:904–908. Age Group 0–14 15–44 45–54 55–64 65+ Developing 133 117,242 125,040 93,485 73,369 Developed 27,828 18,513 14,021 23,075 1/GLOBO-CAN/ Table 2,3 2/Quinn/ p. 906/col 1/¶2; p. 907/col 2/¶3 1. Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Összegzés A méhnyak rák Magyarországon (Kelet-közép Európában) a fiatal nők második leggyakoribb rosszindulatú daganata harmadik leggyakoribb halálok. Átlagosan 30 évvel rövidíti meg a betegek várható élettartamát. Az elmúlt évtizedekben a szűrési erőfeszítések ellenére gyakorisága hazánkban lényegesen nem csökkent HPV Konszenzus Konferencia, 2006. Október 20.

A szűrés mint a megelőzés lehetősége HPV Konszenzus Konferencia, 2006. Október 20.

Cervical Cancer Screening Technologies Worldwide: IARC* Assessment1 Has reduced cervical cancer incidence and mortality rates Conventional cytology-based screening Can reduce cervical cancer incidence and mortality rates Liquid-based cytology Screening by automated cytology HPV DNA testing Limited evidence that screening by visual inspection of the cervix with acetic acid or iodine can reduce cervical cancer incidence and mortality rates. 1/IARC/Sec 8/p. 1/¶2 Key Point Organized cervical cancer screening programs with quality control using conventional cytology reduce cancer mortality. New technologies may be promising. Background The IARC (International Agency for Research on Cancer, World Health Organization) recently released an assessment of cervical cancer screening.1 The main conclusions are as follows: Cervical cancer screening is intended to reduce the incidence of, and mortality from, the disease. Cytology-based screening programs continue to be the mainstay of cervical cancer prevention worldwide. Adequate quality control and quality assurance measures are essential to these screening programs. Meta-analyses of studies of liquid-based cytology have shown that this technique is comparable to conventional cytology in terms of sensitivity and specificity. Sensitivity of visual inspection with acetic acid or iodine has been shown to be similar to cytology-based screening; however, specificity is lower. Its effect in reducing mortality from cervical cancer is unclear; however, visual inspection by application of acetic acid or iodine might be of “high-promise” in low-resource countries.2 HPV DNA testing, which has evolved considerably in the past 25 years, could be a potential screening and management tool. High cost, however, is an issue.1 References 1. International Agency for Research on Cancer. IARC Cervix Cancer Screening Meeting, 20–27 April 2004. Summary of data. Available at: http://www.iarc.fr/ENG/Press_Releases/Summary.pdf. Accessed July 9, 2005. 2. International Agency for Research on Cancer. IARC confirms efficacy of cervic cancer screening for women 25-65 in reducing mortality. Press release No. 151. Available at: http://www.iarc.fr/ENG/Press_Releases/archives/pr151a.html. Accessed November 29, 2005. 1/IARC/Sec 7/p. 7/¶2 1/IARC/Sec 7/p. 9/¶4; p. 10/¶4 1/IARC/Sec 7/p. 19/¶4 *IARC = International Agency for Research on Cancer 1. International Agency for Research on Cancer. Available at: http://www.iarc.fr/ENG/Press_Releases/Evaluation.pdf. Accessed November 29, 2005. 1/IARC/Sec 7/p. 11/¶1; 20/¶3,4 2/IARC/ Press release/p.1/¶5 HPV Konszenzus Konferencia, 2006. Október 20. 1/IARC/Sec 7/p. 11/¶5; p. 12/¶1,2,4

HPV Konszenzus Konferencia, 2006. Október 20. Improvements in Screening Coverage Can Reduce the Incidence of Cervical Cancer1 Age-standardized incidence of invasive cervical cancer and coverage of screening, England, 1971–1995 18 100 1/Quinn/p. 905 /Figure 3. 90 16 80 Coverage 70 14 60 Incidence Rate per 100,000 Invasive Cervical Cancer Percentage 50 12 40 30 Key Point Improvements in screening can lead to a decrease in incidence of invasive cervical cancer. Background Quinn and colleagues1 assessed the impact of screening on cervical cancer incidence and mortality in women >19 years of age in England. The overall incidence of invasive cervical cancer remained stable from 1971 to the mid-1980s (3,900 cases/year on average), when the cervical cancer screening program in England was largely ineffective because of problems with how it was organized. Upon instituting improvements in the screening program, including the introduction of the national call and recall system and incentive payments to general practitioners, screening coverage increased to around 85%. This resulted in a continuous decline in the incidence of invasive cervical cancer from 1990 onwards. In 1995, the incidence was 35% lower than in the mid-1980s.1 Reference 1. Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: Evaluation based on routinely collected statistics. BMJ. 1999;318:904–908. 10 20 National call-recall introduced 10 1/Quinn/p. 904 / abstract; p. 905/col 2/¶1; p. 907 col 1/¶2. 1971 1975 1980 1985 1987 1990 1995 Year 1. Quinn M, Babb P, Jones J, Allen E. BMJ. 1999;318:904–908. Adapted with permission from the BMJ Publishing Group. HPV Konszenzus Konferencia, 2006. Október 20.

Invasive Cancer Mortality/100,000 National Call-Recall Introduced In England, Organized Screening Has Impacted Cervical Cancer Mortality – But Less So in Young and Old Women1 Impact of systematic screening on cervical cancer mortality by age group 40 1975 1950 35 30 25 20 15 10 5 1955 1960 1965 1970 1980 1985 1990 1995 Invasive Cancer Mortality/100,000 National Call-Recall Introduced Year 1/Quinn/p. 906 /Figure 6. Key Point Pap smears are less effective in preventing cervical cancer mortality in younger and older populations. However, mortality in all of the other age groups has decreased. Background This study conducted in England on the impact of the screening program on the incidence and mortality of cervical cancer demonstrated that age-specific cervical cancer mortality has changed to differing degrees in the various age groups.1 In the youngest age group (25–34 years of age), the mortality rate tripled from the mid-1960s to the mid-1980s, and subsequently plateaued. In the older age group, the decrease in cervical cancer mortality was limited after the introduction of the National Health Service (NHS) screening program. Reference 1. Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: Evaluation based on routinely collected statistics. BMJ. 1999;318:904–908. Age Group ≥75 65–74 55–64 45–54 35–44 25–34 1/Quinn/p. 904/abstract; p.906/col 1/¶3. 1. Quinn M, Babb P, Jones J, Allen E. BMJ. 1999;318:904–908. Adapted with permission from the BMJ Publishing Group. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Összegzés A méhnyak rák szűrése: Jelentősen csökkentheti a betegség előfordulását A 35 évesnél fiatalabb és a 60 évesnél idősebb korosztályban a szűrés hatékonysága csekély A diszplázia 25-35, a méhnyak rák 45-55 éves korban a leggyakoribb. A szűrésen részesülő fiatalok közül minden 25-30. a citológiai eltéréssel kapcsolatos szorongásnak van kitéve. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Mindez mibe kerül? HPV Konszenzus Konferencia, 2006. Október 20.

3.6 million women screened Identifying Cervical Abnormalities: A Large Public Health Burden Example of the Cervical Screening Program in England, 2003–20041 3.6 million women screened 4.0 million Pap smears 1/NHS/p. 1/¶3; p. 2/Table 7/ calculations 83.6% negative Key Point Although screening programs have obvious benefits, the burden of inadequate Pap smears and the moderate number of cervical abnormalities is still evident. Background In the UK, 2003–2004, 3.6 million women were screened, and laboratories examined an estimated 4.0 million samples.1 Of the ~4 million Pap smears, 83.6% were negative; 9.1% were inadequate (thus women ultimately had to be rescreened); 7.3% were abnormal. Among the abnormal smears, 2.2% were classified as mild dyskaryosis; 1.2% were classified as moderate-to-severe dyskaryosis; and 0.08% were invasive carcinoma or glandular neoplasia.1 The high number of inadequate smears or false-positive results causes stress for the patient and is costly for the healthcare system.2 In England, the annual cost of the screening program is estimated to be £132 million (equivalent to ~$200 million).3 Data from the Population Based Screening Study Amsterdam (POBASCAM) in the Netherlands observed higher levels of cervical abnormalities in their study population. Approximately 2.5% of patients had borderline or mild dyskaryosis; 0.8% of patients had moderate dyskaryosis or worse; and <0.1% of patients had suspected invasive cancer.4 References National Health Service. Cervical cancer screening programme, England: 2003–04. Available at: http://www.dh.gov.uk/assetRoot/04/09/80/42/04098042.pdf. Accessed August 4, 2005. Raffle AE, Alden B, Quinn M, Babb PJ, Brett MT. Outcomes of screening to prevent cancer: Analysis of cumulative incidence of cervical abnormality and modelling of cases and deaths prevented. BMJ. 2003;326:901–905. Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: Evaluation based on routinely collected statistics. BMJ. 1999;318:904–908. Bulkmans NW, Rozendaal L, Snijders PJ, et al. POBASCAM, a population-based randomized controlled trial for implementation of high-risk HPV testing in cervical screening: Design, methods and baseline data of 44,102 women. Int J Cancer. 2004;110:94–101. 9.1% inadequate smears 1/NHS/p. 1/¶3; p. 2/ Table 7/ calculations. 2/Raffle/p. 1/ col 1/¶2;p. 3/ col 1/¶5 3.8% borderline changes 2.2% mild dyskaryosis 7.3% abnormal smears 1.2% moderate to severe dyskaryosis 0.08% invasive carcinoma + glandular neoplasia 3/Quinn/p.3/ col 2/¶6. 4/Bulkmans/p. 94/abstract. 1. National Health Service. Available at: http://www.dh.gov.uk/assetRoot/04/09/63/75/04096375.pdf. Accessed July 13, 2005. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Costs of Genital Warts, Cervical Cancer Screening, and Management in UK, 20031 Calculations: Total costs=208 million Management of genital warts=22.4/208= 10.8% New cervical cancer cases=33.3/208= 16.0% Hospital=13.5/208=6.5% Management of abnormal findings=34.5/208=16.6% Cervical cancer screening= 104.3/208=50.1% 1/Brown/ p.667/Table 2;p.668/Table 4 1/Brown/ p.668/col 1/¶ 3-4 Key Point The direct medical costs associated with detection and management of cervical cancer, cervical dysplasia, and treatment of genital warts in the UK are substantial. Background This burden of disease study uses data from the National Health Data and Statistics Services for England, Scotland, Wales, and Northern Ireland to estimate the direct medical costs for the screening and management of cervical dysplasia and cervical cancer, and the treatment of genital warts in the UK in 2003.1 In 2003, there were 4.8 million screening tests and an estimated 230,303 referrals for colposcopy procedures, resulting in a total of £138.8 million for cervical screening and management of the abnormal and inadequate findings.1 Annual management costs for incident and prevalent cervical cancer cases were £46.8 million.1 There were an estimated 76,457 incident genital warts cases, and 38,902 and 16,755 recurrent and persistent genital warts cases, respectively, in 2003.1 The costs for managing these cases were approximately £22.4 million.1 In the UK, the total annual estimated costs for cervical cancer care, screening, and management of cervical dysplasia and genital warts for 2003 was £208 million.1 Reference 1. Brown RE, Breugelmans JG, Theodoratou D, Bénard S. Costs of detection and treatment of cervical cancer, cervical dysplasia and genital warts in the UK. Curr Med Res Opin. 2006; 22:663–670. 1/Brown/ p.664/col 2/ ¶ 2-4 Direct medical costs associated with detection and management of cervical cancer, cervical dysplasia, and treatment of genital warts in the UK in 2003 was £208 million.1 1/Brown/ p.667/ Table 2 1. Brown RE, Breugelmans JG, Theodoratou D, Bénard S. Curr Med Res Opin. 2006; 22:663–670. HPV Konszenzus Konferencia, 2006. Október 20. 1/Brown/ p.666/col 2/ ¶ 2; p.663/abstract 1/Brown/ p.667/col 2/ ¶ 2; p.668/col 1/¶ 3-4 1/Brown/p. 663/ abstract

HPV Konszenzus Konferencia, 2006. Október 20. Összegzés A szűrés és kezelés költsége: Az adatot szolgáltató országok statisztikái jelentősen eltérnek egymástól. Szűrés és kezelés egyaránt jelentős anyagi teher. HPV Konszenzus Konferencia, 2006. Október 20.

A vakcináció mint a megelőzés lehetősége HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Natural History of HPV Infection Drives the HPV Vaccine Demonstration for Cancer Prevention1,2 1/Franco/p. 2391/ col 2/¶3. 2/Pagliusi/p. 572/ col 1/Figure 2. Initial HPV Infection Continuing Infection CIN* 2/3 Cervical Cancer CIN* 1 Key Point The natural history of HPV infection has driven the design of the HPV vaccine clinical trial program: CIN 2/3 prevention is recommended as a surrogate of cancer prevention. Background HPV infections typically occur in women soon after the onset of sexual activity.1 Most HPV infections clear within 1 year.2 Cervical intraepithelial neoplasia (CIN) 1 is the most common clinical manifestation of cervical HPV infection. These lesions are low-grade abnormalities, and most CIN 1 lesions clear on their own.3,4 A small proportion of women will have persistent infections that may lead to CIN 2/3 or cervical cancer.4 Persistent infections with high-risk HPV types are powerful predictors for moderate or high-grade dysplasias and cancer.2 The efficacy of vaccines in preventing persistent HPV infection was used as an end point in the initial proof-of-principle studies.5,6 The prespecified end point for efficacy in ongoing population-based Phase III studies for GARDASIL™ includes CIN 2/3, an end point recommended by an expert committee convened by the World Health Organization, as well as by the US Food and Drug Administration.2 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. References Franco EL, Harper DM. Vaccination against human papillomavirus infection: A new paradigm in cervical cancer control. Vaccine. 2005;23:2388–2394. Pagliusi SR, Aguado T. Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine. 2004;23:569–578. Moscicki AB, Shiboski S, Hills NK, et al. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet. 2004;364:1678–1683. Östör AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol. 1993;12:186–192. Villa LL, Costa RLR, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6:271–278. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645–1651. 1/Franco/p. 2391/ col 1/¶2. Cleared HPV Infection 2/Pagliusi/p. 571/col 1/¶6; col 2/¶5. 3/Moscicki/p.1678/ abstract. 4/Östör/p.186/ abstract. 4/Östör/p.186/ abstract *CIN = cervical intraepithelial neoplasia 1. Franco EL, Harper DM. Vaccine. 2005;23:2388–2394. 2. Pagliusi SR, Aguado MT. Vaccine. 2004;23:569–578. 2/Pagliusi/p.571/ col 2/¶2. HPV Konszenzus Konferencia, 2006. Október 20. 5/Villa/p. 272/col 2/¶5;p. 273/col 1/¶1. 6/Koutsky/p.1645/ abstract 2/Pagliusi/p. 569/ abstract; p. 573/¶6

Ki a vakcináció célcsoportja Avegare age of sexual debut1 years Serdülők mivel: a szexuális élet megkezdése előtt szükséges a védettség kialakulása. Minden szexuálisan aktív nő a szexuálisan aktív nők több mit 50%-a megfertőződik HPV-vel élete során.3 a HPV fertőzés nem biztosít teljes védelmet egy későbbi újabb HPV fertőzés ellen.4 2 1. Durex Study, 2004; 2. Adapted from Collins S, Mazloomzadeh S, Winter H, et al. BJOG. 2002;109:96–98, with the permission of the Royal College of Obstetricians and Gynaecologists. 3. World Health Organization. R3232eport of the consultation on human papillomavirus vaccines. Geneva, Switzerland, April 2005.; 4. Carter JJ, Koutsky LA, Hughes JP, et al. J Infect Dis. 2000;181:1911–1999. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. Érvek ….. A méhnyak rák 75%-ért felelőssé tehető HPV 16,18 fertőzés a vaccinával kezelt populációban megelőzhető. A védettség évekig megmarad. A vakcinával kezelt népességben az összes CIN 2/3 eset előfordulása több mint 60%-al csökken a méhnyak rák megbetegedések többsége valószínűleg megelőzhető. HPV Konszenzus Konferencia, 2006. Október 20.

HPV Konszenzus Konferencia, 2006. Október 20. ….. és kérdőjelek A vakcina rákmegelőző hatását (10 éves korosztály oltása esetén) 30-50 év múlva igazolhatjuk. A védettség 20-30 éves fennmaradását még vizsgálni kell. Ha a 16,18-as HPV típusok eltűnnek, előtérbe kerülhetnek egyéb onkogén típusok. A védettség „biztonság tudata” csökkentheti a szűrővizsgálatokon való részvételi hajlandóságot. HPV Konszenzus Konferencia, 2006. Október 20.

Üzenet a jövő generációjának Bár nyitott kérdések miatt a vakcina rák-megelőző hatásáról egyelőre nem tudhatunk mindent, legjobb meggyőződésem szerint bevezetése mellett több érv szól, mint az alkalmazás halogatása mellett. A szűrés hatékonyságának javítása mellett ma Magyarországon ez kiemelten fontos kérdés. HPV Konszenzus Konferencia, 2006. Október 20.