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  1. 1. CERVICAL CANCER & OTHER HUMAN PAPILLOMAVIRUS- RELATED DISEASES Dr.Ahmed Eltigani Elmahdi Hussain Consultant Obstetrician & Gynaecologist, IRELAND
  2. 2. Incidence of Cervical Cancer In Europe Globocan 2002: ASR (World) < 1.5 < 0.4 <16.6 < 4.4 Age-adjusted incidence rates per 100,000 women per year < 7.9 38 countries: European Union except Cyprus (24 countries) + Iceland, Norway, Switzerland, Belarus, Bulgaria, Moldova, Romania, Russian Federation, Ukraine, Albania, Bosnia Herzegovina, Croatia, Macedonia, Serbia and Montenegro. 27 countries: European Union except Cyprus (24 countries) + Iceland, Norway, & Switzerland (3 countries). EUROPE (38 COUNTRIES): 60,000 new cases per year EUROPE (27 COUNTRIES): 33,386 new cases per year
  3. 3. * Ovary, Fallopian tube, broad ligament, round ligament, parametrium, and uterine adnexa. European Union except Cyprus (24 countries) + Iceland, Norway, & Switzerland (3 countries). Age-standardized (World) incidence & mortality rates EUROPE INCIDENCE MORTALITY 4.9 5.4 7.5 34.0 10.4 0 10 20 30 40 Thyroid Ovary &…* Melanoma of skin Cervix uteri Breast Number of cases per 100,000 women per year 1.3 1.3 1.7 2.0 5.7 0 2 4 6 Colon and rectum Brain, nervous system Lung Cervix uteri Breast SOURCE: GLOBOCAN 2002.
  4. 4. Cervical cancer is the second most frequent cancer in young women (15-44 years) in Europe 1 1. Ferlay et al. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancer-Base No.5, version 2. Lyon. IARC Press, 2004. 2. Cancer Research UK, Cancer Mortality Figures 2004 http://info.cancerresearchuk.org/images/excel/cs_mort_t6.2.xls Breakdown of cancers in the young European female population (15-44 years) in 2002 21 women die each week on average in the UK 2
  5. 5. National cervical screening programme <ul><li>The NHS cervical screening programme is recognised as world leading 1 </li></ul><ul><li>Cervical cancer incidence fell by 42% between 1988 and 1997 (England and Wales). This fall is believed to be directly related to an organised cervical screening programme 2 which was introduced in 1988 </li></ul>1. http://cancerscreening.org.uk/cervical/publications/cervical-annual-review-2004.pdf Accessed 12/10/05 2. NHS. Cervical Screening pocket guide. 2004.
  6. 6. <ul><li>Clinical studies have shown that in 99.7% of cases, cervical cancer is caused by a virus: human papillomavirus (HPV) 1, 2 </li></ul><ul><li>Mucosal HPV infection can also cause vulval and vaginal pre-cancerous lesions and genital warts 3 </li></ul>Human papillomavirus infection - the link to cervical cancer & other diseases 1. Munoz N. Human papillomavirus and cancer : The epidemiological evidence. J Clin Virol 2000;19:1–5. 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. 3 . Zur Hausen H. Papillomavirus and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2:342-350.
  7. 7. HPV <ul><li>It is the most common ST infection among women, an estimated 291 million women harbour an HPV worldwide. </li></ul><ul><li>Indeed all women who are, or have been, sexually active are at risk of HPV infection. </li></ul><ul><li>80% of the infections are thought to be transient, other lead to CIN, which may or may not then progress to CA. </li></ul><ul><li>Most early lesions will regress spontaneously. </li></ul><ul><li>Cervical CA is a late & rare complications of persistent infection and is the end result of a chain of events that take usually in excess of 10 years to unfold </li></ul>
  8. 8. Human papillomavirus types 6,11,16 & 18 are four common types affecting women’s health 1.Clifford, GM et al. Br J Cancer 2003; 88: 63-73. 2.Daling JR, et al. Gynecol Oncol 2002; 84: 263-270 3.Madeleine et al. J Natl Cancer Inst 1997;89:1516–1523. 4.Clifford GM, et al. Br J Cancer 2003; 89: 101–105 5.Sotlar K, et al. J Clin Microbiol 2004; 42: 3176-3184. 6.van Beurden M, et al. Cancer 1995; 75: 2879-2884. 7.Hording U, et al. Gynecol Oncol 1995; 56: 276–279. 8.Clifford GM, et al. Cancer Epidemiol Biomarkers Prev 2005; 14:1157-1164. 9.von Krogh G. Eur J Dermatol 2001; 11: 598-603. 10.Wieland U, Pfister H. Human Papilloma Virus: A clinical atlas. Ullstein Mosby; 1997. p1-18.
  9. 9. Relationship of HPV infection with genital neoplasia <ul><li>Cervical cancer- third most common gynaecological malignancy </li></ul><ul><li>All cervical cancers contain HPV DNA- an estimated 99.7% prevalence </li></ul><ul><li>Significant fraction of vaginal, vulvar, penile and anal cancers </li></ul><ul><li>Oncogenic HPV types 16 and 18 cumulatively account for ~70% of all cervical cancers </li></ul><ul><li>HPV types most commonly results in sub clinical infections </li></ul><ul><li>Most infected women harbour HPV DNA without showing cytological or histological changes </li></ul>
  10. 10. Risk factors <ul><li>Sexual activity- number of current and previous partners </li></ul><ul><li>In men- circumcision reduces risk of the acquisition and transmission of HPV </li></ul><ul><li>Use of latex condoms reduces the risk of HPV infection </li></ul><ul><li>Co infection with Chlamydia trachomatis or Herpes simplex virus </li></ul><ul><li>A grater rate and incidence of infection has been observed imunocompromissed renal transplant patients and HIV infected patients </li></ul><ul><li>High parity (5 or more pregnancies) </li></ul><ul><li>Active and passive cigarette smoking </li></ul><ul><li>Long term use of oral contraceptives </li></ul>
  11. 11. Transmission <ul><li>HPV is transmitted by genital contact </li></ul><ul><li>Virus must have access to the basal epithelial cells, either in epithelium that is naturally thin & immature: </li></ul><ul><ul><li>TZ of the cervix </li></ul></ul><ul><ul><li>or the anal verge </li></ul></ul><ul><ul><li>microscopic tears or abrasions in the external genital skin or the introital or vaginal mucosa </li></ul></ul><ul><li>Genital-oral transmission-may be possible </li></ul><ul><li>Recurrent papillomatosis in young children can occur from the transmission of HPV 6 or 11 from a mother to a newborn baby </li></ul>
  12. 12. Circumcision Castellsagué et al, NEJM 2002 Male circumcision reduces the risk of HPV infection in men and of cervical cancer in the female partner
  13. 13. DISEASE CAUSED BY HPV 6/11 Causative agent of genital warts Causative agent of JORRP
  14. 14. Genital warts <ul><li>Genital warts, also referred to as condyloma acuminata. </li></ul><ul><li>They are soft growths that are typically found on the skin or mucous membranes </li></ul><ul><li>Benign, very rarely become malignant. </li></ul><ul><li>More than 90% of genital wart cases are caused by HPV types 6 and 11 2, 3 </li></ul>Genital warts on male subject Genital warts on female subject
  15. 15. P revalence <ul><li>HPV infection typically asymptomatic in men </li></ul><ul><li>prevalence rates of HPV in men range 16-45% </li></ul><ul><li>prevalence is similar in both sexes (both men and women develop genital warts-1%sexual active adults) </li></ul>
  16. 16. Prevalence <ul><li>HPV infection most prevalent in young woman and adolescents: </li></ul><ul><li>As a result of increased transmission during the early </li></ul><ul><li>years of sexual activity </li></ul><ul><li>A lack of previous exposure that might generate a protective immune response </li></ul><ul><li>The transformation zone of cervical epithelium undergoes a process of squamosus metaplasia during puberty that exposes normally protected basal cells to infection </li></ul><ul><li>In one study using PCR-based DNA amplification systems to detect HPV DNA 32% of women 16-24 years old tested positive for HPV DNA, compared with 4% of women aged >45 years </li></ul>
  17. 17. In women, peak exposure to human papillomavirus occurs in late teens and early twenties Sanofi Pasteur MSD Data on File 2006 06/004
  18. 18. Percentage of 15 year old girls who have had sexual intercourse by country Adapted from Ross J, Godeau E, Dias S. Sexual health. In: Currie et al. Eds. Young people’s health in context. Health behaviour in school-aged children study : international report from the 2001/2002 survey. WHO Europe;2004.p. 153-160.
  19. 19. Estimated HPV DNA prevalence in the world (Meta-analysis of 67 studies involving 139,777 cytologically normal women) GLOBAL 10.2% (10.0-10.5) AFRICA 23.4% (22.0 - 24.8) AMERICA 12.8% (12.1 - 13.5) EUROPE 8.2% (7.9 - 8.6) ASIA 7.6% (7.2 - 8.1)
  20. 20. Which specific HPV types are important in cervical cancer?
  21. 21. <ul><li>HPV types 16,18,31,33,35,45,52 are </li></ul><ul><li>responsible for >90%of all high grade CIN </li></ul><ul><li>grades CIN 11-111 </li></ul><ul><li>Just 2 types- 16,18 account for >70% of all </li></ul><ul><li>cervical cancers. </li></ul><ul><li>HPV 16 alone is responsible for 52% of all </li></ul><ul><li>cervical cancers) </li></ul>
  23. 23. Cervical Intraepithelial neoplasia (CIN1) 1 Vulval Intraepithelial neoplasia (VIN) 4 Cervical Intraepithelial neoplasia (CIN 2/3) 2,3 Genital warts 6,7 Vaginal Intraepithelial neoplasia (ValN) 5 1.Clifford GM etal. Cancer Epidemiol Biomarkers Prev 2005; 14:1157 – 1164 2. Clifford GM, Smith JS, Aguado T et al. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: A meta-analysis. Br J Cancer 2003; 89: 101–105 3. Sotlar K, Diemer D, Dethleffs A et al. Detection and typing of human papillomavirus by E6 nested multiplex PCR. J Clin Microbiol 2004; 42: 3176-3184. 4.Madeleine MM, Daling JR, Carter JJ et al. Cofactors with human papillomavirus in a population-based study of vulvar cancer.J Natl Cancer Inst 1997;89:1516–1523. 5. Daling JR, Madeleine MM, Schwartz SM et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002; 84: 263-270.6.Von Krogh G. Eur J Dermatol 2001;11:598-603. 7. Wieland U., Pfister H. In:Gross, Barrasso eds Human papillomavirus: A clinical atlas.Ullstein Mosby; 1997.p1-18
  24. 24. <ul><li>Oncogenic (High risk) </li></ul><ul><li>There are seven genotypes that account for 85-90% of cervical cancers worldwide 1 </li></ul><ul><li>Types 16 & 18 account for ~75% of cervical cancers in Europe 2 </li></ul><ul><li>Non-oncogenic (Low risk) </li></ul><ul><li>Types 6 & 11 account for 90% of genital warts 3,4 </li></ul>Common human papillomavirus types affecting women’s health <ul><li>Munoz et al. Int J Cancer 2004;111: 278-285. </li></ul><ul><li>Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 2003 </li></ul><ul><li>Von Krogh G. Eur J Dermatol 2001;11:598–603. </li></ul><ul><li>Wieland U,& Pfister H. Human Papilloma Virus Infection, A Clinical Atlas. Gross/Barrasso; 2005. </li></ul>Images courtesy of Dr J. Monsonego Genital Warts Cervical Lesions
  25. 25. Infection with human papillomavirus can lead to genital warts 4,174 people in Ireland were diagnosed in 2004 with genital warts which is an increase of 4.8% compared with 2003 1
  26. 26. ??? The economic burden of HPV infection ??? <ul><li>Cervical cancer screening </li></ul><ul><li>Follow- up of abnormal Pap test results </li></ul><ul><li>Treatment of invasive cancer </li></ul><ul><li>Only 10% is attributed to the treatment of invasive cervical cancer </li></ul><ul><li>Other 90% is for cervical cancer prevention </li></ul><ul><li>Diagnosis and treatment of genital warts alone also very expensive </li></ul><ul><li>Cervical cancer screening programs are not accessible to women of all social and ethnic backgrounds </li></ul>
  27. 27. UK burden of disease – cervical cancer 17.9% 7.3% CC Cases * Management of abnormal findings CC Screening Hospital days for existing cervical cancer cases New cervical cancer cases £104.3 million £34.5 million £33.3 million £13.5 million 56.2% 18.6% 25.2% *No data for NI Brown RE et al. Curr Med Res Opin 2006; 22 : 663–670 Total estimated cost of cervical cancer from screening to management of the disease in the UK in 2003 is around £185.6 million Estimated cost of disease management
  28. 28. The Solution!!!!!! The Vaccine ????? <ul><li>Gardasil </li></ul><ul><li>Cervarix </li></ul>
  29. 29. Vaccines <ul><li>2 multivalent VLP vaccines: </li></ul><ul><li>Bivalent HPV 16 and 18 VLP- reduce cervical cancer rates(CERVARIX) </li></ul><ul><li>Quadrivalent HPV vaccine includes most common HPV disease causing types- 6,11,16,18- reduce the incidence of external genital warts in addition to preventing cervical cancer(GARDASIL) </li></ul><ul><li>In the per-protocol cohort, the vaccine was 89% effective in preventing persistent infection and 100% effective in preventing clinical disease (CIN 1/2/3) associated with the 4 HPV types </li></ul>
  30. 30. Vaccines- prepared from exogenously expressed HPV major L1 capsid proteins VLPs (virus-like particles) and have been induce HPV type-specific antibody responses
  31. 31. <ul><li>VLPs: </li></ul><ul><li>Do not contain genetic material </li></ul><ul><li>Are not infectious </li></ul><ul><li>Have no oncogenic potential </li></ul>
  32. 32. * CIN = Cervical intraepithelial neoplasia ** World Health Organisation *** Food and Drug Administration US Proven efficacy in the prevention of cervical cancer against a truly predictive clinical endpoint 0 years 10 + years 1. Adapted from Franco EL, Harper DM. Vaccine 2005; 23:2388-94 2. Sanofi Pasteur MSD Data on File 06/008 2
  33. 33. Rationale for designing a quadrivalent HPV vaccine 1. Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 2003 2. Von Krogh G. Eur J Dermat . 2001;11: 598-603. 3. Koutsky L. Am J Med. 1997; 102: 3-8. Reason for choice of the human papillomavirus types Anticipated benefits 41
  34. 34. HPV vaccines for prevention of infection <ul><li>Reduce the incidence of the majority of HPV- associated diseases </li></ul><ul><li>Vaccine induced immunity may reduce both horizontal (person-to-person) and vertical (mother-to-newborn) transmission </li></ul>
  35. 35. HPV VACCINE <ul><li>The vaccine was shown to be 100% effective in the short term at preventing type-specific premalignant disease of the cervix. </li></ul><ul><li>The potential of such a vaccine to reduce the worldwide incidence of cervical cancer is immediately apparent. </li></ul>
  36. 36. THEORETICAL IMPACT OF A VACCINE INCLUDING HPV Types 6, 11, 16 & 18 67-71% 52-60% ~35% ~20-30% ASCUS: Atypical Squamous Cell of Undetermined Significance L/HSIL: Low/High Grade Squamous Intraepithelial Lesion ICC: Invasive Cervical Cancer ICC ASCUS LSIL HSIL POTENTIAL REDUCTION Months Years Decade(s)
  37. 37. Potential benefits of HPV vaccines <ul><li>Vaccination of 12-year-old girls with an HPV 16/18 vaccine would reduce the number of cervical cancer cases by >95% </li></ul><ul><li>Vaccination both men and women was predicted to be more beneficial than vaccinating only women </li></ul><ul><li>Vaccines effectively reduce the incidence of HPV-associated clinical disease will also reduce the psychological morbidity associated with diagnosis and treatment </li></ul>
  38. 38. INDICATION OF VACCINE <ul><li>Prevention of: </li></ul><ul><li>high-grade cervical dysplasia (CIN 2/3) </li></ul><ul><li>cervical carcinoma </li></ul><ul><li>high-grade vulvar dysplastic lesions (VIN 2/3) </li></ul><ul><li>external genital warts (condyloma acuminata ) </li></ul><ul><li>… . causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18 </li></ul><ul><li>in adult females 16 to 26 years of age and , 9- to 15-year old children and adolescents </li></ul>
  39. 39. Dosage and administration <ul><li>Primary vaccination series consist of 3 separate 0.5 ml doses, administrated IM injections </li></ul><ul><li>Following schedule : 0-2-6 month </li></ul><ul><li>Alternative schedule: 0-1-3 month </li></ul><ul><li>All 3 doses should be given within a 1 year period </li></ul><ul><li>The need for booster dose has not been established </li></ul><ul><li>Pregnancy- insufficient data- vaccinations should be postponed until after completion of pregnancy </li></ul><ul><li>Can be given breast feeding women </li></ul>
  40. 40. Vaccine Generally well-tolerated <ul><li>Most commonly reported adverse events were injection site reactions and mild fever </li></ul><ul><li>Fever >38.9°C (oral temperature) within 5 days of a vaccination visit, was reported in 1.5% of the GARDASIL ® vaccinated population (n=6,040) compared to 1.1% in the placebo population (n=3,981) 1 </li></ul>Sanofi Pasteur MSD Data on File 2006 06/007
  41. 41. SUMMARY <ul><li>HPV is an important health problem in Europe & worldwide </li></ul><ul><li>HPV is a common virus </li></ul><ul><li>(approximately 290 millions women are harboring HPV DNA, of whom 105 millions are positive for HPV 16/18) </li></ul><ul><li>An estimated 80% of sexually active women will be exposed to HPV in their lifetime </li></ul><ul><li>HPV types 16 & 18 have been found in > 75% cases of cervical cancer </li></ul><ul><li>HPV is casually related to: </li></ul><ul><ul><li>Benign conditions: genital warts, CIN1, RRP, </li></ul></ul><ul><ul><li>Pre-malignant conditions: CIN2/3, CIS, VaIN, VIN, AIN, PIN </li></ul></ul><ul><ul><li>Malignant conditions: cervix, vulva, vagina, penis, anus, tonsil and oropharynx </li></ul></ul>
  42. 42. <ul><li>benefits of the HPV vaccine </li></ul><ul><li>Before cervical cancer occurs </li></ul><ul><li>The vaccine can prevent high-grade cervical dysplasia (CIN 2/3) </li></ul><ul><li>The vaccine has demonstrated efficacy against low-grade cervical dysplasia (CIN 1) </li></ul><ul><li>Beyond the cervix </li></ul><ul><li>The vaccine can prevent vulval pre-cancers and reduces the incidence of vaginal pre-cancers compared with placebo (0 vs 5 women) </li></ul><ul><li>The vaccine can prevent external genital warts </li></ul>Summary
  43. 43. Should we offer Vaccine to boys? <ul><li>With the Rubella Vaccine they ended up having to vaccinate boys to eradicate Rubella. </li></ul><ul><li>If WE don’t vaccinate boys, Gay men are not going to be protected from HPV. </li></ul><ul><li>ARE WOMEN ALWAYS TO BE RESPONSIBLE FOR EVERYTHING TO DO WITH SEXUALLY TRANSMITTED INFECTIONS? </li></ul>
  44. 46. THANK YOU

Hinweis der Redaktion

  • Europe (27 countries): European Union except Cyprus (24 countries) + Iceland, Norway, Switzerland (3 countries)
  • N.B. MHRA request that you always have the actual numbers available when you present this slide
  • We can have an effect not only on cervical cancer but also precancerous lesions – a tremendous impact.