“Risk”: How does it define
cervical cancer screening ?
Alan G. Waxman, MD, MPH
Dept. of Obstetrics and Gynecology
University of New Mexico
The University of New Mexico
Disclosures
• I have no commercial interests to disclose.
• Photos:
• George Papanicolaou – NIH
• Monkeys and Apes are mine
Educational Objectives
• Review screening intervals historically and basis for current
recommendations.
• List three different risk levels used in setting the threshold for
colposcopy.
• Discuss the inconsistencies in our understanding of “acceptable risk”
in cervical cancer screening.
Finding Balance in Cervical Screening
agw
• We use imperfect tests for screening and
diagnosis.
• False positive results lead to unnecessary
colposcopy and treatment with possible
adverse consequences.
• False negative tests can result in cancers
developing in the interval between
screening.
• How much risk are we willing to accept and
how do we define risk?
The public health perspective of risk focuses on benefits and
risks for the overall population.
•How many precancers and
cancers will develop in a
population despite screening at
a given interval?
•Can we as a society accept
these numbers?
•How many unnecessary
colposcopies and treatments are
we willing to accept to prevent
one cancer?
agw
The individual woman and her provider want a simpler
estimation of risk.
•What are my chances of getting
cancer before my next screening?
•What are my chances of getting a
treatment I didn’t need?
agw
How often should women get a Pap Test?
• 1928: Papanicolaou -cervical cytology
• 1943: Papanicolaou and Traut publish
monograph
• 1957: ACS – “Uterine Cancer Year”
promotes annual Pap
• 1960: Birth Control Pill
Papanicolaou
• Between the 1980 and 2012, U.S.
guidelines changed 7 times.
Current U.S. Guidelines:
ACS/ ASCCP/ ASCP, ACOG, USPSTF
• Start screening at age 21 with cytology every 3 years.
• From age 30 – 65, co-testing every 5 years is
recommended. If HPV not available, continue with
cytology alone every 3 years.
• Primary HPV screening after age 25 using FDA approved
test is also acceptable.
Saslow et al J Low Genit Tract Dis. 2012; 16(3)
Does a negative cytology every 3 years or a negative
HPV test every 5 years offer a risk that’s “acceptable”?
Joint European Cohort Study compared HPV testing with conventional
Pap in 6 countries
N=24,295
Rate of CIN 3+ after baseline negative test
3 yrs
4 yrs
5yrs
6yrs
Pap –
0.51%
0.69%
0.83% 0.97%
HPV0.12%
0.19%
0.25% 0.27%
Dillner, J. et al. BMJ 2008;337:a1754
Does a negative cytology every 3 years or a negative
HPV test every 5 years offer a risk that’s “acceptable”?
•1.4 million women followed with cotesting since 2007 Kaiser
Permanente Northern California (KPNC)
•Pap negative at baseline
• 5 year Risk of CIN 3+
0.26%
•Pap and HPV both negative at baseline
• 5 year Risk of CIN 3+
0.08%
Katki et al J Lower Genital Tract Dis 2013;17(5):S28-35
So a woman with a negative
cotest screened every 5 years
can be reassured that her risk of
getting CIN 3 or worse before
her next screening is only 8 out
of 10,000.
That seems like a reasonable risk
to take.
AGW
Recently a “Minority Viewpoint” suggested that the
risk of cancer with cotesting every 5 years is too high.
• Changing cotesting interval from q 3 years to q 5 years
• 2.71 additional cancers / 1,000 women (1 in 369)
• 0.61 additional deaths / 1,000 women (1 in 1,639)
• Assuming 72 million women aged 30 – 64 in U.S.
• 195,000 additional cancers over lifetime
• 44,000 additional deaths over lifetime
Kinney et.al. Obstet Gynecol. 2015 (2);311-315
Calculating number of deaths
on a population level puts
“risk” in a different
perspective!
agw
With the strategy of “equal
management for equal risk” it’s
important to know what the risk is
for different screening results.
AGW
For example, if a woman has
LSIL on her Pap, what’s the
chance she will have CIN 3 or
cancer in the near future?
AGW
In the ALTS trial, the 2 year cumulative risk of CIN 3+ for a cytology
result of LSIL was 10 %
HSIL
LSIL
HPV+/ASC-US
10%
ASC-US
Castle. Am J Obstet Gynecol. 2007 October; 197(4): 356
By convention, we set that level of risk as the threshold for
colposcopy.
HSIL
LSIL
ASC-US
HPV+/ASC-US
Colposcopy
10%
Observe
Castle. Am J Obstet Gynecol. 2007 October; 197(4): 356
Did we choose the threshold for colposcopy because 10% represented
a high enough risk? Or because LSIL seemed a risky enough Pap?
HSIL
LSIL
ASC-US
HPV+/ASC-US
Colposcopy
10%
Observe
Castle. Am J Obstet Gynecol. 2007 October; 197(4): 356
In the KPNC study, the 5 year cumulative risk of CIN 3+ for a cytology
result of LSIL was only 5.2 %. Our patients’ understanding of “What is
my risk?” becomes blurred.
HSIL
LSIL
ASC-US
HPV+/ASC-US
Colposcopy
5.2%
Observe
Castle. Am J Obstet Gynecol. 2007 October; 197(4): 356
Our patient with LSIL might
well be confused. Is her risk
10% in 2 years (Undoubtedly
higher over 5 years)
Or is it 5.2% over 5 years?
agw
Some have criticized the ASCCP
Guidelines as being based on data
that is specific to a population that
may not be typical of the U.S. as a
whole. The population make up of
N. California Kaiser subscribers is
different from the state-wide
registry of New Mexico, yet the
determination of risk is quite similar
as is the rank order of diagnoses.
5 year cumulative risk of CIN 3+ in
two different U.S. populations
NM HPV
Pap
Cytology
registry
HSIL
53.1
LSIL
6.5
ASC-US
3.4
ASC-US / HPV+ 7.7
ASC-US / HPV- 0.7
Cytol negative 0.5
KPNC
50.4
5.4
3.4
7.1
0.5
0.3
Gage J. Obstet Gynecol. 2016;128 :1248-57
What level of risk is
acceptable?
• Can we set the colposcopy threshold based
on a numeric level of risk or should we base
it on a consensus agreement that LSIL
cytology is too “risky” to watch?
• Is .08% risk of CIN 3+ at a 5 year screening
interval a safe threshold on which to base
our screening interval?
• Should we abandon CIN 3+ as an untenable
surrogate endpoint for our studies and
require instead the considerable rarer
endpoint of cancer?
agw
These are questions without
easy answers that challenge us
as we develop guidelines and
counsel our patients.
Thank you.
agw