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PREVENTING CERVICAL CANCER BRYANSTON COUNTRY CLUB 4 th September 2010 Dr Peter C Koll.

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Presentation on theme: "PREVENTING CERVICAL CANCER BRYANSTON COUNTRY CLUB 4 th September 2010 Dr Peter C Koll."— Presentation transcript:

1 PREVENTING CERVICAL CANCER BRYANSTON COUNTRY CLUB 4 th September 2010 Dr Peter C Koll

2 CERVICAL CANCER To create the awareness To find the resources To stimulate the political will All we need to do is : Medical breakthroughs have occured Cervical cancer should not happen

3 1. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004. Global mortality per annum Cervical cancer mortality rates worldwide Cases per 100,000 women per year North America 14,500 new cases 6,000 deaths Latin America 72,000 new cases 33,000 deaths Africa 79,000 new cases 62,000 deaths Asia 266,000 new cases 143,000 deaths Europe 60,000 new cases 30,000 deaths Worldwide, every 2 minutes a woman dies of cervical cancer 1 Worldwide, every 2 minutes a woman dies of cervical cancer 1 The highest burden of disease (up to 80%) occurs in less developed regions 1 where there is a lack of effective screening programmes The highest burden of disease (up to 80%) occurs in less developed regions 1 where there is a lack of effective screening programmes This demonstrates a clear medical need for new cervical cancer interventions This demonstrates a clear medical need for new cervical cancer interventions < 7.9 < 7.9 < 23.8 < 23.8 < 14.0 < 14.0 < 55.6 < 3.9 < 3.9

4 Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004. The most frequent cancers in women: incidence and mortality Global data IncidenceMortality Age-standardized rate per 100,000 Breast Cervix Colon/ Rectum Lung Stomach Ovary Corpus 0510152025303540 37.4 16.2 14.6 12.1 10.3 6.6 6.5 Breast Lung Cervix Stomach Colon/ Rectum Liver Ovary 02468101214 13.2 10.3 9.0 7.9 7.6 5.7 4.0 Age-standardized rate per 100,000

5 The most frequent cancers in women: incidence and mortality Africa IncidenceMortality Cervix Breast Liver Stomach Kaposi’s sarcoma Ovary Colon/ Rectum 05101520253035 29.3 23.4 6.2 4.9 4.6 4.3 4.2 Cervix Breast Liver Stomach Kaposi’s sarcoma Colon/ Rectum Oesophagus 0510152025 23.1 16.2 6.2 4.6 4.3 3.7 3.2 Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon; 2004. Age-standardized rate per 100,000

6 The transformation zone (squamous metaplasia) Squamous epithelium Columnar epithelium ANATOMY

7 Pre-Cancerous lesions

8 Cervical cancer

9 HISTORY OF Ca Cx PREVENTION - 1928 George Papanicolaou first described the PAP test --- 81 years ago

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11 Limitations of PAP smear - Only prevents 70% of cancers - May miss adenocarcinoma Endometrium Uterine cavity Cervix Myometrium Adenocarcinoma Squamous cell carcinoma Adenocarcinoma: may be inaccessible to the cervical smear brush Squamous cell carcinoma: usually accessible to the cervical smear brush Adenocarcinoma Squamous cell carcinoma

12 Limitations of PAP smear - May miss adenocarcinoma - Only prevents 70% of cancers -Logistics -Cost -Treatment -Recall

13 HISTORY OF Ca Cx PREVENTION - 1928 George Papanicolaou first described the PAP test --- 81 years ago - 1983 Harald zur Hausen linked HPV to Ca Cx - IARC identified HPV DNA in 99.8% of cervical cancer specimens from 25 countries - Late 1990’s Carcinogenic subtypes of HPV identified - HPV VACCINES HPV vaccines, the first vaccines specifically developed to prevent a cancer

14 HPV >100 types identified 2 ~30–40 anogenital 2,3 ~15–20 oncogenic*, 2,3 HPV 16 and HPV 18 types account for the majority of worldwide cervical cancers. 4 Nononcogenic** types HPV 6 and 11 are most often associated with external anogenital warts. 3 These two types are responsible for >90% of genital warts. 5 Nonenveloped double- stranded DNA virus 1 *High risk; ** Low risk 1. Howley PM, Lowy DR. In: Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285. 5. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319–331. 2

15 HPV Infection and Life Cycle NormalEpithelium Cervical Surface Basement Membrane Basal (Stem) Cells ParabasalCells SquamousLayer MatureSquamousLayer. . . .    ..    ..        InfectedEpithelium Adapted from Frazer IH. Nature Rev Immunol. 2004;4:46–54. Shedding of Virus- Laden Epithelial Cells Infection of Basal Cells (E1 and E2) Episomal Viral DNA in Cell Nucleus (E1 and E2, E6 and E7) Viral DNA Replication (E6 and E7) Viral Assembly (L1 and L2)

16 Why are antibody responses so poor in natural HPV infections? No viraemia HPV does not kill keratinocytes no inflammation no pro-inflammatory cytokines poor activation of epithelial antigen presenting cells Free virus particles are shed from mucosal surfaces with poor exposure to antigen presenting cell (APC)

17 What are the consequences of this? Natural infection dose not necessarily confer protection against future disease. Women remain at risk of persistent HPV infection, throughout their lives. Persistent HPV infection is the cause of Cervical Cancer

18 Vaccine HPV type HPV Types in Cervical Cancer Worldwide Cancer cases attributed to the most frequent HPV genotypes (%) HPV genotype 2.3 2.2 1.4 1.3 1.2 1.0 0.7 0.6 0.5 0.3 4.4 53.5 2.6 17.2 6.7 2.9 0102030405060708090 100 X Other 82 73 68 39 51 56 59 35 58 52 33 31 45 18 16 53.5 % 70.7 % 77.4 % 80.3 % Munoz N et al. Int J Cancer 2004;111:278–85.

19 Central/South America Northern Africa North America/ Europe South Asia 16 18 45 31 33 HPV Type 52 Others *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. Worldwide Prevalence of HPV Types in Cervical Cancer *,1 58 57 12.6 69.7 14.6 67.6 17 52.5 25.7

20 2.0 HPV 59 1.1 HPV 35 3.1 1.9 2.2 HPV 56 2.7 2.2 3.0 HPV 58 3.2 1.1 HPV 52 3.6 3.1 2.2 HPV 33 4.2 4.0 3.2 2.3 HPV 31 3.4 4.5 7.4 6.8 HPV 45 9.0 7.9 5.6 15.0 14.6 HPV 18 25.7 12.6 17.0 19.1 % HPV type % % %69.752.557.067.647.7 HPV 16 HPV type Europe & North America South Asia Central-South America Northern Africa Sub-Saharan Africa Adapted from Munoz N et al Int J Cancer 2004;111: 278-85 In 2855 HPV Positive Cervical Cancer Cases & Rank By Region Prevalence of the 10 most common oncogenic HPV types worldwide

21 Global burden of HPV - Carcinoma of the cervix -2002 - 493000 diagnosed -274000 died - Other HPV Carcinomas -Anal -Vulvo/vaginal -Penile -Oral -Nasopharangeal -Abnormal PAP smear -Repeat visits -Colpomicroscopy -Biopsy -Laser/Cone/LEEP/LLETZ -Financial -Emotional -Physical Morbidity

22 The most common STD 50% young females aquire it within 3 yrs of sexual debut Cumulative detection is 59-82% Majority transient in young women – only 10-20% persist for 24 mts Peak at 20 sharp decline by 30 If present after 30 – more likely to be persistent ONLY PERSISTENT HIGH RISK HPV CONSTITUTES RISK FOR CIN2 OR 3

23 Estimated World Burden of HPV-Related Diagnoses Focus on Cervical Disease and Genital Warts Cervical Cancer: 0.5 million cases/year 1 High-grade precancerous lesions: 10 million 2 Low-grade cervical lesions: 30 million 2 Genital warts: 30 million 3 Attributable to oncogenic HPV types HPV infection: 660 million 1 1. World Health Organization, Geneva, Switzerland: World Health Organization; 2005:1–38. 2. World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1–22. 3. World Health Organization. WHO Office of Information. WHO Features. 1990;152:1–6. Attributable to nononcogenic HPV types 2

24 HPV Infection and Risk of Invasive Cervical Cancer in Selected Countries *,1 *Assays used varied by site. **CI = confidence interval 1. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 0.110100100010,000 Brazil Mali Morocco Paraguay Philippines Thailand Peru Spain Colombia Overall Odds Ratio (95% CI**) % HPV Prevalence cases/contro 97.0/17.3 96.9/33.3 97.1/21.6 98.1/19.8 96.4/9.2 96.5/15.7 95.3/17.7 82.4/5.9 78.4/17.5 96.6/15.6 7

25 Human papillomavirus structure HPV is a relatively small virus containing double-stranded DNA within a spherical shell (capsid) 1 The capsid is composed of two proteins, the ‘late’ or structural proteins L1 and L2 1 L1 protein pentamer L2 supporting protein Circular DNA 55 nm 1. Burd EM. Clin Microbiol Rev 2003; 16:1–17.

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27 Virus Like Particle (VLP) L1 protein pentamer VLP Looks exactly like the virus but contains no viral DNA Thus elicits strong immune response without any risk of infection

28 Active protection via vaccination is mediated by neutralizing antibodies at the cervix HPV Cervical canal Neutralizing antibodies Blood vessel Epithelial tear Basement membrane Cervical epithelium 1. Stanley M. Vaccine 2006; 24:S16–S22; 2. Giannini S, et al. Vaccine 2006; 24:5937–5949; 3. Nardelli-Haefliger D, et al. J Natl Cancer Inst 2003; 95:1128–1137; 4. Poncelet S, et al. IPC 2007(poster).

29 GARDASIL™ (20/40/40/20 μg) Neutralizing Anti-HPV Immunogenicity In a double-blind, placebo-controlled, dose-ranging study of quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine. 1 10 100 1000 HPV 6 *** 1 10 100 1000 HPV 11 *** 712182430365460 Time Since Vaccination (Months) 10 100 1000 10,000 GMT with 95% CI mMU/mL (Log Scale) ** * 712182430365460 1 10 100 1000 HPV 18 *** HPV 16 Per-Protocol Subjects (GARDASIL) * vaccination GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Adapted from Olsson S-E et al. Vaccine. 2007;25:4931–4939. 712182430365460 712182430365460 10

30 CERVARIX

31 GARDASIL ™ [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL: FUTURE I-II End-of-Study Results Efficacy Against HPV 6/11/16/18-Related External Genital Lesions 1,2 EGL = external genital lesion; VaIN = vaginal intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia. 1. Haupt RM. ACIP. February 27, 2008. http://www.cdc.gov/vaccines/recs/ACIP/downloads/mtg-slides-feb08/14-3-hpv.pdf. Accessed July 11, 2008. 2. Data on file, MSD ______. 22 00 227 193 28 23 0 50 100 150 200 250 HPV 6/11/16/ 18-Related EGL Genital Warts VIN 1, VaIN 1 VIN 2/3, VaIN 2/3 99% Efficacy (97, 100) 99% Efficacy (96, 100) 100% Efficacy (86,100) 100% Efficacy (83,100) Related Cases GARDASILPlacebo n=7900n=7902 n=7900n=7902 n=7900 n=7902 n=7900n=7902 Per-protocol efficacy population, women 16–26 years of age followed up through 3–4 years

32 HPV 6, 11, 16, or 18-related GARDASILPlacebo NCasesNCasesEfficacy 95% CI PersistentInfection2352*2334596% (83, 100) Disease23502336100% (12, 100) CIN 1, 2, or 3 CIN 1, 2, or 323502333100% (<0, 100) Vulvar/vaginal neoplasias or genital warts 23502333100% (<0, 100) GARDASIL™: Durable Protection Through Five Years A total of 241 subjects were entered into the five-year extension phase of protocol 007. *One case of confirmed persistent infection: HPV 18 DNA detected at months 12 and 18 only (not a case in the five-year extension). *One case of HPV 16 DNA detected at the last visit (month 36); not a subject in the five-year extension phase. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Villa LL, Costa R, Petta R, et al. Br J Cancer. 2006;95:1459–1466. PPE population; subjects were naïve to HPV types 6, 11, 16, and/or 18 15

33 nn 87.9 - 100 100290 6 Month Persistence 72.3 - 100 100140 12 Month Persistence 32.7 - 100 10070CIN2+ 110 61.5 - 100 100CIN1+ 95% CI % Vaccine Efficacy Control HPV Vaccine Endpoints* *Combined analysis initial efficacy study and extended follow-up ATP analysis for virologic endpoints; ITT analysis for cytologic and CIN endpoints Presentation Gall S, AACR, Los Angeles, April 14-18, 2007 Up to 5.5 years Substantial Protection against HPV-16/18 infections and CIN outcomes

34 Disease Cross-Protection Analysis: Efficacy Against CIN 2/3 or AIS in the Generally HPV-Naïve Population CIN 2/3 or AIS* # of cases GARDASIL n=4616 # of cases Placebo n=4675Efficacy 95% CI HPV 31/45 82162% 10, 85 HPV31/33/45/52/58 274843% 7, 66 HPV 31/33/35/39/45/5 1/52/56/58/59 386238% 6, 60 * Composite endpoints were analyzed (primary endpoints). In analyses for the individual components of the endpoints, efficacy was variable, and there was no evidence of efficacy with respect to HPV 35 and 45-related disease. Brown D; for the FUTURE Study Group. Poster presented at ICAAC; September 17-20, 2007; Chicago, IL.

35 Cross Protection Cervarix® showed significant type-specific efficacy against pre-cancers (CIN 2+) associated with HPV types beyond 16 and 18 Vaccine efficacy was : 100% for HPV 31/45 against CIN2+ 68.2% for the 5 most frequent oncogenic types (31,33,45,52,58) 68.4% for the 10 most frequent oncogenic types (31,33,35,39,45,51,52,56,58,59) Cervarix® showed vaccine efficacy of 77.7% for 14 oncogenic types, including HPV 16 and 18 measured as a composite endpoint

36 No clinically meaningful differences between study groups with respect to:  Medically significant conditions Serious Adverse Events New onset chronic disease and new onset autoimmune diseases Pregnancy outcomes SAFETY

37 WHICH ONE ? Both safe Both very effective Both equally effective in preventing Ca Cx Both equally effective in preventing Ca Cx Only two undisputed facts: 1) Gardasil protects against 6 and 11 2) Cervarix is cheaper

38 The Gardasil argument 1)Proven protection against vulval and vaginal carcinoma 2)Protection against 6 and 11

39 GARDASIL HPV 6 & 11 HPV Types 6 and 11 responsible for >90% of anogenital warts1 Estimated lifetime risk of developing genital warts ~10%2,3 Estimated lifetime risk of developing genital warts ~10%2,3 External genital warts are very contagious. Infectivity >75%

40 RRP Age distribution is bimodal with peaks at 1 : 2 to 4 years of age (childhood-onset) 20 to 40 years of age (adult-onset) HPV Types 6 and 11 cause ~100% of both juvenile- and adult-onset RRP. 2 Papillomas are stratified squamous epithelial masses that can obstruct the airway if not removed. 3 Although histologically benign, RRP causes significant morbidity and mortality due to recurrent nature. 3 Could require surgery under general anesthesia as frequently as every few weeks Possible causative role of RRP in head and neck cancers 3-5 RRP is rare. 6 GARDASIL™ is not indicated for RRP. 1. Derkay CS. Laryngoscope. 2001;111:57–69. 2. Lacey CJN, Lowndes CM, Shah KV. Vaccine. 2006;24S3:S3/35– S3/41. 3. Abramson AL, Nouri M, Mullooly V, Fisch G, Steinberg BM. J Med Virol. 2004;72:473–477. 4. Steinberg BM, DiLorenzo TP. Cancer Metastasis Rev. 1996;15:91–112. 5. Szentirmay Z, Pólus K, Tamás L, et al. Cancer and Metastasis Reviews. 2005;24:19–34. 6. Derkay CS, Darrow DH. Ann Otol Rhinol Laryngol. 2006;115:1–11.

41 The Cervarix argument 1.Higher antibody levels 2.Higher number of memory b cells 3.Higher antibody levels in cervical mucous 4.Better cross protection data

42 Cervarix ® Gardasi ™ p<0.0001 HPV-16 and 18 Neutralising antibody responses: Geometric Mean Titers TVC* = at least 1 dose received GMT (ED50) 31715 8682188613732 1:GSKBio_WWMA_DoF018_3_2009 3.7 -fold 7.3 -fold HPV 16** HPV 18**

43 Memory B cells The frequency of antigen-specific memory B-cells in responders was significantly higher (2.7-fold) in the Cervarix ® group than in the Gardasil ™ group for both HPV 16 and HPV 18 (women aged 18–45 years, p<0.0001).

44 Mucosal HPV antibody response in cervicovaginal secretion (CVS) Positivity rates for anti-HPV-16/18 neutralizing antibodies in CVS frequencies were higher for Cervarix ®. 81.3% vs 50.9% for HPV 16 33.3% vs 8.8% for HPV 18

45 Thus, we have two teams of international immunoligical heavyweights sending us different messages ! RESULT

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47 REMEMBER Both safe Both very effective Both equally effective in preventing Ca Cx Both equally effective in preventing Ca Cx Only two undisputed facts: 1) Gardasil protects against 6 and 11 2) Cervarix is cheaper

48 So, which one ? Short answer: -it doesn’t matter If can’t make up mind: -toss a coin -Either way, you won’t be wrong For goodness sake VACCINATE

49 WHO AND WHEN

50 Cumulative Risk of Any HPV Infection by Age in Women*,1 Cumulative Risk of HPV Infection (%) Age at Baseline N=1610 Years 0 10 20 30 40 50 012345 15–19 20–24 25–29 30–44 45+ *In a cohort of Colombian women 1. Adapted from Muñoz N, Méndez F, Posso H, et al. J Infect Dis. 2004;190:2077–2087. Reprinted with permission from The University of Chicago Press. Copyright © 2004 by the Infectious Diseases Society of America. All rights reserved. 8

51 WHO AND WHEN Before sexual debut ?9-13 “ screen yourselves-vaccinate your daughters ” BUT 20 years to see any impact 30-40 years to see benefit on Ca Cx THEREFORE May consider “catch up” vaccination for all sexually active women We know its effective and safe in older women (10-55) We know very few carry both 16 and 18 We know most HPV infections are transient SUGGESTS SIGNIFICANT BENEFIT FOR ALL SEXUALLY ACTIVE WOMEN

52 WHO AND WHEN In other words, vaccinating all sexually active women will probably : Reduce Ca Cx Reduce repeat visits and smears Reduce colposcopies Reduce destructive cervical procedures and the obstetric complications associated with them Reduce hysterectomies for pre- invasive cervical lesions And consequently reduce the - Psychological Physical Financial - Morbidity and mortality associated with them

53 WHO AND WHEN NOT only pre sexual debut NOT only up to 26 NOT only the promiscuous Current PAP status irrelevant Current HPV status irrelevant

54 WHO AND WHEN ? Males - Controvercial ? Pre vaccination HPV test - Not necessary ? Boosters - Not needed to 7.3 years trials ongoing but look promising for long term ? Prev abn PAP ? Pregnancy ? Lactation ? Current abn PAP - Vaccinate - Postpone - Benefit vs Risk

55 PSYCOLOGICAL ASPECTS Parents don’t mind Vaccination does not change sexual behavior (ie promiscuity) Vaccination does not change sexual practice (ie safe sex)

56 Screening to prevent Ca Cx PAP remains the mainstay of screening Importance of PAP even after vaccination What is the place of HPV testing?

57 SCREENING Potential use of HPV testing: 1) Primary screening 2) Triange of abn PAP 3) Test of cure

58 SCREENING How good are PAPs ? (Pooled European and Canadian studies) Sensitivity 53% Specificity 96% How good is HPV testing ? Sensitivity almost 100% Specificity very low Logic for primary HPV screen

59 HPV is common (80%) Only 10 to 20% persist Only some of the persistent HPV lead to High-Gr Sil Peak at 20 sharp decline by 30 Only persistent HPV is a problem but current tests only show presence HPV TESTING - Problems

60 TRIANGE OF ABN PAP ASCUS 43% HPV Positive LSil 76% HPV Positive Therefore only worthwhile in ASCUS Low-Gr Sil needs Colposcopy In ASCUS HC2 identifies 37% more CIN2 than repeat cytology

61 TEST OF CURE Sweedish study looked at longterm incidence/mortality following treatment for CIN3 Showed lifelong increased risk of invasive Ca that accelerated with age. We thus need better Risk stratification of these patients

62 TEST OF CURE 6 months post treatment HPV test showed 99% sensitivity Cytology + HPV 100% Good test of cure Longer follow up needed

63 LIQUID BASED CYTOLOGY No convincing evidence of better detection of High-Gr Sil Two advantages: 1) Reflex HPV test if ASCUS found 2) Better in automated screening What will it’s place be in future?

64 Take home message Vaccinate all women 10 to 50 Vaccinate boys on request Continue screening after vaccination


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