A User-Friendly Guide To Cervical Cancer Prevention · PDF fileS e n s itivi ty 0 Â0 0 Â2 0 Â4 0 Â6 0 Â8 1 Â0 S P O CCS I 83 Â1 (73 Â3 ± 90...

Philip E. Castle, PhD, MPH

December 5, 2012

A User-Friendly Guide To

Cervical Cancer Prevention

My Disclosures & Potential Conflicts of Interest

• I have received commercial HPV tests for research at a

reduced or no cost from Roche, Qiagen, Norchip, and

MTM.

• I am a paid consultant for BD and GE Healthcare; I have

received a speaker’s honorarium from Roche.

• I am a paid consultant for Immunexpress on sepsis

diagnostics.

• I am compensated as a member of a Merck Data and

Safety Monitoring Board for HPV vaccines.

Today’s Talk

1. Global Perspective of Cervical Cancer

2. Natural History of HPV: Rational Basis for Cervical Cancer

Prevention

3. Targeting the Causal Factor: HPV Vaccines and Testing

4. New Screening Guidelines

5. Reaching the Hard-to-Reach

George Papanicolaou (1883-1962):

Inventor of the Pap Smear

TIME TRENDS

IN AGE-

STANDARDIZED

(WORLD)

CERVICAL

CANCER

INCIDENCE IN

FOUR NORDIC

COUNTRIES

http://globocan.iarc.fr/

Today’s Talk

1. Global Perspective of Cervical Cancer

2. Natural History of HPV: Rational Basis for Cervical Cancer

Prevention

3. Targeting the Causal Factor: HPV Vaccines and Testing

4. New Screening Guidelines

5. Reaching the Hard-to-Reach

Cervical Cancer Continuum: Old Model of

Cervical Carcinogenesis

Transient infection Persistent HPV

Normal

cervix

HPV-infected

cervix Precancer Cancer INVASION

PROGRESSION

REGRESSION?

INFECTION

CLEARANCE

Molecular Pathology Model of Cervical Cancer New Model of Cervical Carcinogenesis

Etiologic Contribution of HPV Genotypes

0

10

20

30

40

50

60

70

80

90

100

16 18 45 31 X 33 52 58 35 59 56

Fra

cti

on

of

Ca

nc

ers

HPV Genotype

de Sanjose et al., Lancet Oncol, 2010

Regional Variation of HPV Genotypes in CxCa

Eur

(2058)

N.A

(160)

L.A.

(3404)

Africa

(544)

Asia

(2641)

Oceania

(170)

Natural History Profile of Prevalent HPV

Schiffman et al., Lancet, 2007

%C

leara

nce (

100

%-%

Pers

iste

nce)

Today’s Talk

1. Global Perspective of Cervical Cancer

2. Natural History of HPV: Rational Basis for Cervical Cancer

Prevention

3. Targeting the Causal Factor: HPV Vaccines and Testing

4. New Screening Guidelines

5. Reaching the Hard-to-Reach

Impact of Age on Vaccine Efficacy

Kjaer, Cancer Prev Res, 2009

Herrero et al., Cancer Discov, 2012

HPV-16/18 Clearance by Trial Arm

Hildesheim et al., JAMA, 2007

0%

10%

20%

30%

40%

50%

60%

70%

6-Month 12-Month 6-Month 12-Month 6-Month 12-Month 6-Month 12-Month

HPV16 HPV18 HPV16&18 HPV16&18 (all

doses)

Baseline HPV16/18 Status

%C

leara

nce

Vaccine

Placebo (Hep A)

Sensitivity: CIN2+

Combined

Seattle

Canada

HART

Jena

Tuebingen

Hannover

French Private

French Public

0% 10% 30% 50% 70% 90% 100%

Cytology Positivity

CIN 2+

Cuzick et al., IJC, 2006

Mayrand et al., NEJM, 2007

Combined

HART

Jena

Tuebingen

Hannover

Canada

Seattle

French Private

French Public

0% 10% 30% 50% 70% 90% 100%

HPV Positivity

CIN 2+

HPV Testing Cytology/Pap

CIN2+ CIN2+

Cuzick et al., IJC, 2006

Mayrand et al., NEJM, 2007

Castle et al., LO, 2011

Ferreccio et al., IJC, 2012

Combined

Seattle

Canada

HART

Jena

Tuebingen

Hannover

French Private

French Public

0% 10% 30%

Cytology Positivity

No CIN

0% 10% 30%

HPV Positivity

No CIN

%Cytology and HPV Positive: No CIN Cuzick et al., IJC, 2006

Mayrand et al., NEJM, 2007

Castle et al., LO, 2011

Ferreccio et al., IJC, 2012

Cu

mu

lati

ve in

cid

en

ce

of

CIN

3+

(per

10,0

00)

Time since initial testing (mos.) Dillner et al., BMJ, 2008

CIN3+ Risk Following a Negative Screening

Test

Today’s Talk

1. Global Perspective of Cervical Cancer

2. Natural History of HPV: Rational Basis for Cervical Cancer

Prevention

3. Targeting the Causal Factor: HPV Vaccines and Testing

4. New Screening Guidelines

5. Reaching the Hard-to-Reach

Benefits vs. Harms

Benefits Harms

Actual

Cervical cancer prevention

Anxiety associated with a positive screening test

Potential stigmatization

from the diagnosis of a sexually transmitted infection

Discomfort from additional

diagnostic and treatment procedures

Bleeding from treatment

Increased risk of pregnancy

complications such as preterm delivery due to treatment.

Surrogate Early detection of

CIN3 Number of colposcopic referrals

Inc

reas

ing

Ris

k o

f P

reca

nce

r (C

IN3)†

100%

~0%

2%

10%

40%

Cyto-

ASC-US

HPV-/ASC-US

HPV-/Cyto- All ♀

CIN3 Biopsy

CIN2 Biopsy#

HSIL & HPV+ &

H-G Colpo

HPV+*

HPV-*

HPV+/ASC-US LSIL

HSIL

HPV+/Cyto-

<CIN2 Biopsy

Post-

Colpo

HPV+/Cyto-*

Cytology HPV Testing Colposcopy Biopsy

Screening

Harmonizing Management According To Risk

Castle et al., JLGTD, 2008

Screening

Lower risk =

interval

Increased

Surveillance

Colposcopy

Treatment

Current ACS Cervical Cancer Screening

Guidelines (2012)

Age (Years)

<21

21-29

30-64

65 and Older

Recommended Screening

No Screening!!!!

Cytology (3 Year)

HPV and Cytology Cotesting (5 Year) (Preferred)

Cytology (3 Year) Acceptable)

No Screening with a 10-Year Negative Screening

History

Saslow et al. , CA Cancer J Clin, 2012

Castle and Carreon, JLGTD, 2010

Cervical Cancer Incidence by Age (USA)

Cytology Screening Interval: Cancer Risk vs.

Colposcopy

Saslow et al. , CA Cancer J Clin, 2012

Real

World

Perform

ance

Cum

ula

tive I

ncid

ence o

f C

IN3+

Years Since Enrollment

HPV & Pap

Individually

HPV & Pap

Combined

Katki et al., Lancet Oncol, 2011

3-yr risk for Pap- = 0.17%

5-yr risk for HPV- = 0.17%

5-yr risk for HPV-/Pap- = 0.16%

Algorithm for Cotesting in Women 30-64 Y.O.

Guideline Failures

Yabroff et al., AIM, 2009

0 50 100

Composite Measure (all 4 vignettes)

66-year old, non-resectable lung cancerwith 3 normal Pap tests

35-year old, hysterectomy for benigncause with 3 normal Pap tests

18-year old, sexually experienced 3 yearsbefore first visit

18-year old, non-sexually experienced,first visit

Obstetrics & Gynecology Internal Medicine Family Practice/General Practice

Percentage With Guideline-

Consistent Recommendations

When Would Next HPV Test?

35 years, Pap Normal and HPV Negative?

Saraiya et al., Arch Intern Med, 2009

10%

20%

30%

40%

0%

50%

60%

Today’s Talk

1. Global Perspective of Cervical Cancer

2. Natural History of HPV: Rational Basis for Cervical Cancer

Prevention

3. Targeting the Causal Factor: HPV Vaccines and Testing

4. New Screening Guidelines

5. Reaching the Hard-to-Reach

Cervical Cancer Mortality Map for The U.S.

Freeman HP, Wingrove BK. Excess Cervical Cancer Mortality: A Marker for Low

Access to Health Care in Poor Communities. Rockville, MD: National Cancer Institute,

Center to Reduce Cancer Health Disparities, May 2005. NIH Pub. No. 05–5282.

Chapter 3, Maryland Comprehensive Cancer Control Plan

Cervical Cancer in Maryland

US Incidence:

~8 per 100,000

Sensitivity

0·0 0·2 0·4 0·6 0·8 1·0

SPOCCS I 83·1 (73·3 – 90·5) SPOCCS II 87·5 (83·7 – 90·6) SPOCCS III-(1) 86·4 (65·1 – 97·1) SPOCCS III-(2) 60·0 (26·2 – 87·8) SPOCCS III-(3) 88·2 (63·6 – 98·5)

Sensitivity % (95% CI)

Pooled Sensitivity = 86·2% (82·9 to 89·1)

Chi-square = 5·37; df = 4 (p = 0·25) Inconsistency (I-square) = 25·5 %

Specificity

0·0 0·2 0·4 0·6 0·8 1·0

SPOCCS I 85·9 (84·2 – 87·5) SPOCCS II 77·1 (76·2 – 78·0) SPOCCS III-(1) 84·3 (81·7 – 86·7) SPOCCS III-(2) 87·5 (85·1 – 89·6) SPOCCS III-(3) 93·1 (91·2 – 94·7)

Specificity % (95% CI)

Pooled Specificity = 80·7% (75·6 to 85·8)

Chi-square = 242·53; df = 4 (p < 0·0001) Inconsistency (I-square) = 98·4 %

86.2% 80.7%

SENSITIVITY (CIN3) SPECIFICITY (<CIN3)

Self Collection and HPV Testing in China

Zhao … Castle, JNCI, 2012

0

10

20

30

40

50

60

70

80

90

Self-Collection & HPV Testing Clinic-Based Pap Testing

Nu

mb

er

of

Wo

me

n A

ge

d 2

6-6

5

Not Completed

Completed

Screening in the Mississippi Delta

Castle et al., Prev Med, 2011

Final Comments

• HPV is the necessary but infrequent cause of cervical

cancer.

• HPV vaccines and tests can be highly effective if used in

an age-appropriate manner. HPV vaccines will prevent

cancer and clinically important disease from occurring in

the future. Screening prevents cancer now.

• Current screening guidelines are based on two basic

principles:

Benefits to the few at-risk women must outweigh the

harms to the generally healthy population.

Equal Risk = Equal Care

Final Comments

• It is impractical and very costly, and potentially very

harmful, to screen women excessively in an attempt to

prevent ALL cervical cancer.

• The greatest gains in cancer prevention will achieved by

reaching those not currently getting services.