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.