CERVICAL CANCER & OTHER HUMAN CERVICAL CANCER & OTHER HUMAN PAPILLOMAVIRUS- RELATED DISEASESPAPILLOMAVIRUS- RELATED DISEASES

Dr.Ahmed Eltigani Elmahdi HussainDr.Ahmed Eltigani Elmahdi Hussain

Consultant Obstetrician & Gynaecologist, IRELANDConsultant Obstetrician & Gynaecologist, IRELAND

Globocan 2002: ASR (World)

< 1.5

< 0.4

<16.6

< 4.4

Age-adjusted incidence rates per 100,000 women per year

Incidence of Cervical Cancer In Europe

< 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

* 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 & Age-standardized (World) incidence & mortality rates mortality rates

EUROPEEUROPE

Age-standardized (World) incidence & Age-standardized (World) incidence & mortality rates mortality rates

EUROPEEUROPEINCIDENCEINCIDENCEINCIDENCEINCIDENCE MORTALITYMORTALITYMORTALITYMORTALITY

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

SO

UR

CE

: GLO

BO

CA

N 2

002.

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 Breakdown of cancers in the young European female population (15-44 years) in 2002female population (15-44 years) in 2002

21 women die each week

on average in the UK2

Cervical cancer is the second most frequent cancer in Cervical cancer is the second most frequent cancer in young women (15-44 years) in Europeyoung women (15-44 years) in Europe11

National cervical screening programmeNational cervical screening programme

The NHS cervical screening programme is recognised as The NHS cervical screening programme is recognised as world leadingworld leading11

Cervical cancer incidence fell by 42% between 1988 and Cervical cancer incidence fell by 42% between 1988 and

1997 (England and Wales). This fall is believed to be directly 1997 (England and Wales). This fall is believed to be directly

related to an organised cervical screening programmerelated to an organised cervical screening programme22

which was introduced in 1988which was introduced in 1988

1. http://cancerscreening.org.uk/cervical/publications/cervical-annual-review-2004.pdf Accessed 12/10/052. NHS. Cervical Screening pocket guide. 2004.

Clinical studies have shown that in 99.7% of cases, cervical cancer is caused by a virus: human papillomavirus (HPV)1, 2

Mucosal HPV infection can also cause vulval and vaginal pre-cancerous lesions and genital warts3

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.

Human papillomavirus infection - the link to cervical cancer & other diseases

HPVHPV It is the most common ST infection among women, an It is the most common ST infection among women, an

estimated 291 million women harbour an HPV worldwide.estimated 291 million women harbour an HPV worldwide.

Indeed all women who are, or have been, sexually active Indeed all women who are, or have been, sexually active are at risk of HPV infection.are at risk of HPV infection.

80% of the infections are thought to be transient, other 80% of the infections are thought to be transient, other lead to CIN, which may or may not then progress to CA.lead to CIN, which may or may not then progress to CA.

Most early lesions will regress spontaneously.Most early lesions will regress spontaneously.

Cervical CA is a late & rare complications of persistent Cervical CA is a late & rare complications of persistent infection and is the end result of a chain of events that take infection and is the end result of a chain of events that take usually in excess of 10 years to unfold usually in excess of 10 years to unfold

Human papillomavirus types 6,11,16 & 18 areHuman papillomavirus types 6,11,16 & 18 arefour common types affecting women’s healthfour 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.

Relationship of HPV infection with genital neoplasiaRelationship of HPV infection with genital neoplasia Cervical cancer- third most common gynaecological malignancyCervical cancer- third most common gynaecological malignancy

All cervical cancers contain HPV DNA- an estimated 99.7% prevalence All cervical cancers contain HPV DNA- an estimated 99.7% prevalence

Significant fraction of vaginal, vulvar, penile and anal cancersSignificant fraction of vaginal, vulvar, penile and anal cancers

Oncogenic HPV types 16 and 18 cumulatively account for ~70% of all Oncogenic HPV types 16 and 18 cumulatively account for ~70% of all cervical cancerscervical cancers

HPV types most commonly results in sub clinical infectionsHPV types most commonly results in sub clinical infections

Most infected women harbour HPV DNA without showing cytological Most infected women harbour HPV DNA without showing cytological or histological changesor histological changes

Risk factorsRisk factors

Sexual activity- number of current and previous partners In men- circumcision reduces risk of the acquisition and

transmission of HPV Use of latex condoms reduces the risk of HPV infection Co infection with Chlamydia trachomatis or Herpes

simplex virus A grater rate and incidence of infection has been observed

imunocompromissed renal transplant patients and HIV infected patients

High parity (5 or more pregnancies) Active and passive cigarette smoking Long term use of oral contraceptives

TransmissionTransmission

HPV is transmitted by genital contact HPV is transmitted by genital contact Virus must have access to the basal epithelial cells, either in Virus must have access to the basal epithelial cells, either in epithelium that is naturally thin & immature: epithelium that is naturally thin & immature: TZ of the cervix TZ of the cervix or the anal vergeor the anal verge microscopic tears or abrasions in the external genital microscopic tears or abrasions in the external genital

skin or the introital or vaginal mucosaskin or the introital or vaginal mucosa

Genital-oral transmission-may be possibleGenital-oral transmission-may be possible

Recurrent papillomatosis in young children can occur from the Recurrent papillomatosis in young children can occur from the transmission of HPV 6 or 11 from a mother to a newborn babytransmission of HPV 6 or 11 from a mother to a newborn baby

Circumcision

Castellsagué et al, NEJM 2002

Male circumcision reduces the risk of Male circumcision reduces the risk of HPV infection in men and of cervical HPV infection in men and of cervical

cancer in the female partnercancer in the female partner

DISEASE CAUSED BY HPV 6/11

Causative agentof genital warts

Causative agentof JORRP

Genital warts

Genital warts, also referred to as Genital warts, also referred to as condyloma acuminata.condyloma acuminata.

They are soft growths that are typically They are soft growths that are typically found on the skin or mucous membranesfound on the skin or mucous membranes

Benign, very rarely become malignant.Benign, very rarely become malignant.

More than 90% of genital wart cases are More than 90% of genital wart cases are caused by HPV types 6 and 11caused by HPV types 6 and 112,2, 33

Genital warts on male subject

Genital warts on

female subject

Prevalence

HPV infection typically asymptomatic in men prevalence rates of HPV in men range 16-45% prevalence is similar in both sexes (both men and

women develop genital warts-1%sexual active adults)

Prevalence

HPV infection most prevalent in young woman and adolescents:

As a result of increased transmission during the early years of sexual activity A lack of previous exposure that might generate a

protective immune response The transformation zone of cervical epithelium undergoes

a process of squamosus metaplasia during puberty that exposes normally protected basal cells to infection

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

In women, peak exposure to human papillomavirus occurs In women, peak exposure to human papillomavirus occurs in late teens and early twenties in late teens and early twenties

Sanofi Pasteur MSD Data on File 2006 06/004

PercentagePercentage of 15 year old girls who have of 15 year old girls who have had sexual intercourse by countryhad 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.

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)

Which specific HPV Which specific HPV types are important types are important in cervical cancer?in cervical cancer?

•HPV types 16,18,31,33,35,45,52 are HPV types 16,18,31,33,35,45,52 are responsible for >90%of all high grade CIN responsible for >90%of all high grade CIN grades CIN 11-111grades CIN 11-111

•Just 2 types- 16,18 account for >70% of all Just 2 types- 16,18 account for >70% of all cervical cancers.cervical cancers.

•HPV 16 alone is responsible for 52% of all HPV 16 alone is responsible for 52% of all cervical cancers)cervical cancers)

HPV PREVALENCE IN THE CERVIX BY HPV PREVALENCE IN THE CERVIX BY CYTOLOGICAL / HISTOLOGICAL DIAGNOSISCYTOLOGICAL / HISTOLOGICAL DIAGNOSISHPV PREVALENCE IN THE CERVIX BY HPV PREVALENCE IN THE CERVIX BY CYTOLOGICAL / HISTOLOGICAL DIAGNOSISCYTOLOGICAL / HISTOLOGICAL DIAGNOSIS

WOMEN WITH N. CYTOLOGY 9-10 % (2-3%)

PRE-INVASIVE LESIONS 80-90 % (50%)

CERVICAL CANCER 95-100 % (70%)

DIAGNOSIS HPV-DNA HPV 16/18

DE SANJOSE ET AL IN PREPARATION;DE SANJOSE ET AL IN PREPARATION;CLIFFORD ET AL 2003; CLIFFORD ET AL 2003;

MUÑOZ ET AL 2003MUÑOZ ET AL 2003

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

Common human papillomavirus types affecting Common human papillomavirus types affecting women’s healthwomen’s health

1.Munoz et al. Int J Cancer 2004;111: 278-285.2.Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 20033.Von Krogh G. Eur J Dermatol 2001;11:598–603.4. Wieland U,& Pfister H. Human Papilloma Virus Infection, A Clinical Atlas. Gross/Barrasso; 2005.

Oncogenic (High risk)

There are seven genotypes that account for 85-90% of cervical cancers worldwide1

Types 16 & 18 account for ~75% of cervical cancers in Europe2

Non-oncogenic (Low risk)

Types 6 & 11 account for 90% of genital warts3,4

Images courtesy of Dr J. Monsonego

Genital Warts

Cervical Lesions

Infection with human papillomavirus can lead to genital warts 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 20031

??????The economic burden of HPV infectionThe economic burden of HPV infection??????

Cervical cancer screeningCervical cancer screening

Follow- up of abnormal Pap test resultsFollow- up of abnormal Pap test results

Treatment of invasive cancerTreatment of invasive cancer

Only 10% is attributed to the treatment of invasive cervical cancerOnly 10% is attributed to the treatment of invasive cervical cancer

Other 90% is for cervical cancer preventionOther 90% is for cervical cancer prevention

Diagnosis and treatment of genital warts alone also very expensiveDiagnosis and treatment of genital warts alone also very expensive

Cervical cancer screening programs are not accessible to women Cervical cancer screening programs are not accessible to women of all social and ethnic backgroundsof all social and ethnic backgrounds

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 NIBrown RE et al. Curr Med Res Opin 2006; 22 : 663–670

Total estimated cost of cervical cancer from screening to Total estimated cost of cervical cancer from screening to management of the disease in the UK in 2003 is around management of the disease in the UK in 2003 is around £185.6 million£185.6 million

Estimated cost of disease management

The Solution!!!!!! The Solution!!!!!! The Vaccine ?????The Vaccine ?????

GardasilGardasil

CervarixCervarix

VaccinesVaccines

2 multivalent VLP vaccines: Bivalent HPV 16 and 18 VLP- reduce cervical cancer

rates(CERVARIX) 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)

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

Vaccines- prepared from Vaccines- prepared from exogenously exogenously expressed HPV major L1 capsid proteins expressed HPV major L1 capsid proteins VLPs VLPs (virus-like particles)(virus-like particles) and have been and have been induce HPV type-specific antibody responsesinduce HPV type-specific antibody responses

VLPs:VLPs:

• Do not contain genetic materialDo not contain genetic material •Are not infectiousAre not infectious •Have no oncogenic potentialHave no oncogenic potential

* CIN = Cervical intraepithelial neoplasia** World Health Organisation*** Food and Drug Administration US

Proven efficacy in the prevention of cervical Proven efficacy in the prevention of cervical cancer against a truly predictive clinical endpointcancer 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

Rationale for designing a quadrivalent HPV vaccineRationale for designing a quadrivalent HPV vaccine

1. Clifford, G. M et al. British Journal of Cancer, 88, 63-73. 20032. 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 typesReason for choice of the human papillomavirus types

Anticipated benefits

41

HPV vaccines for prevention of infectionHPV vaccines for prevention of infection

Reduce the incidence of the majority of Reduce the incidence of the majority of HPV- associated diseasesHPV- associated diseases

Vaccine induced immunity may reduce Vaccine induced immunity may reduce both horizontal (person-to-person) and both horizontal (person-to-person) and vertical (mother-to-newborn) vertical (mother-to-newborn) transmissiontransmission

HPV VACCINEHPV VACCINE

The vaccine was shown to be 100% effective in the The vaccine was shown to be 100% effective in the short term at preventing type-specific short term at preventing type-specific premalignant disease of the cervix. premalignant disease of the cervix.

The potential of such a vaccine to reduce the The potential of such a vaccine to reduce the worldwide incidence of cervical cancer is worldwide incidence of cervical cancer is immediately apparent. immediately apparent.

THEORETICAL IMPACT OF A VACCINE INCLUDING HPV Types 6, 11, 16 & 18THEORETICAL IMPACT OF A VACCINE INCLUDING HPV Types 6, 11, 16 & 18

67-71%

52-60%

~35%

~20-30%

ASCUS: Atypical Squamous Cell of Undetermined SignificanceL/HSIL: Low/High Grade Squamous Intraepithelial LesionICC: Invasive Cervical Cancer

ICC

ASCUS

LSIL

HSIL

POTENTIAL

REDUCTION

Months

Years

Decade(s)

Potential benefits of HPV vaccinesPotential benefits of HPV vaccines

Vaccination of 12-year-old girls with an HPV 16/18 Vaccination of 12-year-old girls with an HPV 16/18 vaccine would reduce the number of cervical vaccine would reduce the number of cervical cancer cases by >95%cancer cases by >95%

Vaccination both men and women was predicted to Vaccination both men and women was predicted to be more beneficial than vaccinating only womenbe more beneficial than vaccinating only women

Vaccines effectively reduce the incidence of HPV-Vaccines effectively reduce the incidence of HPV-associated clinical disease will also reduce the associated clinical disease will also reduce the psychological morbidity associated with diagnosis psychological morbidity associated with diagnosis and treatmentand treatment

INDICATION OF VACCINEINDICATION OF VACCINE

Prevention of:Prevention of:

high-grade cervical dysplasia (CIN 2/3)high-grade cervical dysplasia (CIN 2/3)

cervical carcinomacervical carcinoma

high-grade vulvar dysplastic lesions (VIN 2/3)high-grade vulvar dysplastic lesions (VIN 2/3)

external genital warts (condyloma acuminataexternal genital warts (condyloma acuminata)

….causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18 causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18

in adult females 16 to 26 years of age and , 9- to 15-year old children and in adult females 16 to 26 years of age and , 9- to 15-year old children and

adolescentsadolescents

Dosage and administrationDosage and administration

Primary vaccination series consist of 3 separate 0.5 ml doses, Primary vaccination series consist of 3 separate 0.5 ml doses, administrated IM injectionsadministrated IM injections

Following schedule : 0-2-6 monthFollowing schedule : 0-2-6 month

Alternative schedule: 0-1-3 monthAlternative schedule: 0-1-3 month

All 3 doses should be given within a 1 year periodAll 3 doses should be given within a 1 year period

The need for booster dose has not been establishedThe need for booster dose has not been established

Pregnancy- insufficient data- vaccinations should be postponed Pregnancy- insufficient data- vaccinations should be postponed until after completion of pregnancyuntil after completion of pregnancy

Can be given breast feeding womenCan be given breast feeding women

VaccineVaccine Generally well-toleratedGenerally well-tolerated

Most commonly reported adverse events were Most commonly reported adverse events were

injection site reactions and mild feverinjection site reactions and mild fever

Fever >38.9°C (oral temperature) within 5 days of a Fever >38.9°C (oral temperature) within 5 days of a

vaccination visit, was reported in 1.5% of the vaccination visit, was reported in 1.5% of the

GARDASILGARDASIL®® vaccinated population (n=6,040) compared vaccinated population (n=6,040) compared

to 1.1% in the placebo population (n=3,981)to 1.1% in the placebo population (n=3,981)11

Sanofi Pasteur MSD Data on File 2006 06/007

SUMMARYSUMMARY

HPV is an important health problem in Europe & HPV is an important health problem in Europe & worldwideworldwide

HPV is a common virus HPV is a common virus (approximately 290 millions women are harboring HPV DNA, of

whom 105 millions are positive for HPV 16/18) An estimated 80% of sexually active women will be exposed to HPV in An estimated 80% of sexually active women will be exposed to HPV in

their lifetimetheir lifetime HPV types 16 & 18 have been found in > 75% cases of cervical cancerHPV types 16 & 18 have been found in > 75% cases of cervical cancer HPV is casually related to:HPV is casually related to:

Benign conditions: genital warts, CIN1, RRP, Pre-malignant conditions: CIN2/3, CIS, VaIN, VIN, AIN, PIN Malignant conditions: cervix, vulva, vagina, penis, anus, tonsil and

oropharynx

benefits of the HPV vaccinebenefits of the HPV vaccine

Before cervical cancer occursBefore cervical cancer occurs

The vaccine can prevent high-grade cervical dysplasia (CIN 2/3)The vaccine can prevent high-grade cervical dysplasia (CIN 2/3)

The vaccine has demonstrated efficacy against low-grade cervical The vaccine has demonstrated efficacy against low-grade cervical

dysplasia (CIN 1)dysplasia (CIN 1)

Beyond the cervixBeyond the cervix

The vaccine can prevent vulval pre-cancers and reduces the The vaccine can prevent vulval pre-cancers and reduces the

incidence of vaginal pre-cancers compared with placebo (0 vs 5 incidence of vaginal pre-cancers compared with placebo (0 vs 5

women)women)

The vaccine can prevent external genital warts The vaccine can prevent external genital warts

SummarySummary

THANK YOUTHANK YOU