PREVENTING CERVICAL CANCER

BRYANSTON COUNTRY CLUB

4th September 2010

Dr Peter C Koll

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

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 America14,500 new cases

6,000 deaths

Latin America72,000 new cases

33,000 deaths

Africa79,000 new cases

62,000 deaths

Asia266,000 new cases

143,000 deaths

Europe60,000 new cases

30,000 deaths

• Worldwide, every 2 minutes a woman dies of cervical cancer1

• The highest burden of disease (up to 80%) occurs in less developed regions1 where there is a lack of effective screening programmes

• This demonstrates a clear medical need for new cervical cancer interventions

< 7.9

< 23.8

< 14.0

< 55.6 < 3.9

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

Incidence Mortality

Age-standardized rate per 100,000

Breast

Cervix

Colon/Rectum

Lung

Stomach

Ovary

Corpus

0 5 10 15 20 25 30 35 40

37.4

16.2

14.6

12.1

10.3

6.6

6.5

Breast

Lung

Cervix

Stomach

Colon/Rectum

Liver

Ovary

0 2 4 6 8 10 12 14

13.2

10.3

9.0

7.9

7.6

5.7

4.0

Age-standardized rate per 100,000

The most frequent cancers in women: incidence and mortality

AfricaIncidence Mortality

Cervix

Breast

Liver

Stomach

Kaposi’ssarcoma

Ovary

Colon/Rectum

0 5 10 15 20 25 30 35

29.3

23.4

6.2

4.9

4.6

4.3

4.2

Cervix

Breast

Liver

Stomach

Kaposi’ssarcoma

Colon/Rectum

Oesophagus

0 5 10 15 20 25

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 Age-standardized rate per 100,000

The transformation zone

The transformation zone (squamous metaplasia)

Squamous epithelium

Columnar epithelium

ANATOMY

Pre-Cancerous lesions

Cervical cancer

HISTORY OF Ca Cx PREVENTION

- 1928 George Papanicolaou first described the PAP test --- 81 years ago

Limitations of PAP smear

- Only prevents 70% of cancers

- May miss adenocarcinoma

Endometrium

Uterine cavity

Cervix

Myometrium

Adenocarcinoma

Squamous cell carcinoma

Adenocarcinoma: may beinaccessible to the cervical

smear brush

Squamous cell carcinoma:usually accessible to the cervical

smear brush

AdenocarcinomaSquamous cell carcinoma

Limitations of PAP smear

- May miss adenocarcinoma

- Only prevents 70% of cancers

-Logistics

-Cost

-Treatment

-Recall

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

HPV>100 types identified2

~30–40 anogenital2,3

~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 virus1

*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

HPV Infection and Life Cycle

Normal Epithelium

Cervical Surface

Basement Membrane

Basal (Stem) Cells

Parabasal Cells

Squamous Layer

Mature Squamous

Layer

. .

. .

.

.

.

Infected Epithelium

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)

Why are antibody responses so poor innatural 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)

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

Vaccine HPV type

HPV Types in Cervical Cancer Worldwide

Cancer cases attributed to the most frequent HPV genotypes (%)

HPV genotype

2.32.21.41.31.21.00.70.60.50.3

4.4

53.5

2.6

17.26.7

2.9

0 10 20 30 40 50 60 70 80 90 100

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.

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

1752.5

25.7

2.0HPV 591.1HPV 35 3.1HPV 351.9HPV 35

2.2HPV 562.7HPV 56

2.2HPV 56 3.0HPV 583.2HPV 58

1.1HPV 52 3.6HPV 52

3.1HPV 52

2.2HPV 33

4.2HPV 33

4.0HPV 333.2HPV 33

2.3HPV 31

3.4HPV 31

4.5HPV 31

7.4HPV 31

6.8HPV 45

9.0HPV 45 7.9HPV 455.6HPV 4515.0HPV 45

14.6HPV 18 25.7HPV 1812.6HPV 1817.0HPV 1819.1HPV 18

% HPV type% HPV type% %HPV typeHPV type

%

69.7 52.557.067.647.7HPV 16 HPV 16HPV 16HPV 16HPV 16

HPV type

Europe & North America South AsiaCentral-South

AmericaNorthern AfricaSub-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

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

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

Estimated World Burden of HPV-Related Diagnoses Focus on Cervical Disease and Genital Warts

Cervical Cancer: 0.5 million cases/year1

High-grade precancerous lesions: 10 million2

Low-grade cervical lesions: 30 million2

Genital warts: 30 million3

Att

ribu

tabl

e to

onc

ogen

ic H

PV ty

pes

HPV infection: 660 million1

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.

Att

ribu

tabl

e to

non

onco

geni

c H

PV ty

pes

Att

ribu

tabl

e to

non

onco

geni

c H

PV ty

pes

2

HPV Infection and Risk of Invasive Cervical Cancer in Selected Countries*,1

*Assays used varied by site.**CI = confidence interval1. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527.

0.1 10 100 1000 10,000

Brazil

Mali

Morocco

Paraguay

Philippines

Thailand

Peru

Spain

Colombia

Overall

Odds Ratio (95% CI**)

% HPVPrevalencecases/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

Human papillomavirus structureHPV 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 L21

L1 protein pentamer L2 supporting protein

Circular DNA

55 nm

1. Burd EM. Clin Microbiol Rev 2003; 16:1–17.

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

Active protection via vaccination is mediated by neutralizing antibodies at the cervix

HPV

Cervical canal

Neutralizing antibodies

Blood vessel

Epithelial tear

Basement membrane

Cervicalepithelium

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).

GARDASIL™ (20/40/40/20 μg) Neutralizing Anti-HPV Immunogenicity

In a double-blind, placebo-controlled, dose-ranging study ofquadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine.

1

10

100

1000HPV 6

** * 1

10

100

1000HPV 11

***

7 12 18 24 30 36 54 60

Time Since Vaccination (Months)

10

100

1000

10,000

GM

T w

ith

95

% C

Im

MU

/mL

(L

og

Sc

ale

)

*** 7 12 18 24 30 36 54 60

1

10

100

1000HPV 18

***

HPV 16

Per-Protocol Subjects (GARDASIL)

* vaccinationGARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.Adapted from Olsson S-E et al. Vaccine. 2007;25:4931–4939.

7 12 18 24 30 36 54 60 7 12 18 24 30 36 54 60

10

CERVARIX

GARDASIL™ [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

GARDASIL: FUTURE I-II End-of-Study ResultsEfficacy Against HPV 6/11/16/18-Related External Genital Lesions1,2

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 0 0

227

193

28 23

0

50

100

150

200

250

HPV 6/11/16/18-Related EGL

GenitalWarts

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)R

elat

ed C

ases

GARDASIL Placebo

n=7900 n=7902 n=7900 n=7902 n=7900 n=7902n=7900 n=7902

Per-protocol efficacy population, women 16–26 years of age followed up through 3–4 years

HPV 6, 11, 16, or 18-related

GARDASIL Placebo

N Cases N Cases Efficacy 95% CI

PersistentInfection

235 2* 233 45 96% (83, 100)

Disease 235 0 233 6 100% (12, 100)

CIN 1, 2, or 3 235 0 233 3 100% (<0, 100)

Vulvar/vaginal neoplasias or genital warts

235 0 233 3 100% (<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

nn

87.9 - 1001002906 Month Persistence

72.3 - 10010014012 Month Persistence

32.7 - 100 10070CIN2+

110 61.5 - 100 100CIN1+

95% CI%

Vaccine EfficacyControlHPV VaccineEndpoints*

*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

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

Placebon=4675

Efficacy 95% CI

HPV 31/45 8 21 62% 10, 85

HPV 31/33/45/52/58

27 48 43% 7, 66

HPV 31/33/35/39/45/51/5

2/56/58/5938 62 38% 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.

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

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

WHICH ONE ?

• Both safe• Both very effective• Both equally effective in preventing Ca Cx

• Only two undisputed facts: 1) Gardasil protects against 6 and 11 2) Cervarix is cheaper

The Gardasil argument

1) Proven protection against vulval and vaginal carcinoma

2) Protection against 6 and 11

GARDASILHPV 6 & 11

HPV Types 6 and 11 responsible for >90% of anogenital warts1

Estimated lifetime risk of developing genital warts ~10%2,3

External genital warts are very contagious.Infectivity >75%

RRP

Age distribution is bimodal with peaks at1: 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 cancers3-5

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.

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

Cervarix®

Gardasi™

p<0.0001

HPV-16 and 18 Neutralising antibody responses:

Geometric Mean Titers

TVC* = at least 1 dose received

GM

T (

ED

50

)

31715 8682 188613732

1:GSKBio_WWMA_DoF018_3_2009

3.7 -fold

7.3 -fold

HPV 16** HPV 18**

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).

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 1633.3% vs 8.8% for HPV 18

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

RESULT

REMEMBER

• Both safe• Both very effective• Both equally effective in preventing Ca Cx

• Only two undisputed facts: 1) Gardasil protects against 6 and 11 2) Cervarix is cheaper

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

WHO AND WHEN

Cumulative Risk of Any HPV Infection by Age in Women*,1

Cum

ulat

ive

Ris

k of

HP

V I

nfec

tion

(%

)Age at Baseline

N=1610

Years

0

10

20

30

40

50

0 1 2 3 4 5

15–1920–24

25–2930–4445+

*In a cohort of Colombian women1. 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

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

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

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

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

- Vaccinate

- Postpone

- Benefit vs Risk

PSYCOLOGICAL ASPECTS

Parents don’t mind

Vaccination does not change sexual behavior (ie promiscuity)

Vaccination does not change sexual practice (ie safe sex)

Screening to prevent Ca Cx

• PAP remains the mainstay of screening

• Importance of PAP even after vaccination

• What is the place of HPV testing?

SCREENING

Potential use of HPV testing:

1) Primary screening

2) Triange of abn PAP

3) Test of cure

SCREENING

How good are PAPs ?

(Pooled European and Canadian studies)

Sensitivity 53%

Specificity 96%How good is HPV testing ?

Sensitivity almost 100%

Specificity very lowLogic for primary HPV screen

HPV is common (80%)Only 10 to 20% persistOnly some of the persistent HPV lead to High-Gr SilPeak at 20 sharp decline by 30Only persistent HPV is a problem but current tests

only show presence

HPV TESTING - Problems

TRIANGE OF ABN PAP

ASCUS 43% HPV PositiveLSil 76% HPV PositiveTherefore only worthwhile in ASCUSLow-Gr Sil needs ColposcopyIn ASCUS HC2 identifies 37% more CIN2 than repeat

cytology

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

TEST OF CURE

6 months post treatment HPV test showed 99% sensitivity

Cytology + HPV 100%Good test of cureLonger follow up needed

LIQUID BASED CYTOLOGY

No convincing evidence of better detection of High-Gr SilTwo advantages:

1) Reflex HPV test if ASCUS found

2) Better in automated screeningWhat will it’s place be in future?

Take home message

• Vaccinate all women 10 to 50

• Vaccinate boys on request

• Continue screening after vaccination