Download Increased cervical cancer risk associated with screening at longer

Current Commentary
Increased Cervical Cancer Risk Associated
With Screening at Longer Intervals
Walter Kinney, MD, Thomas C. Wright, MD, Helen E. Dinkelspiel,
J. Thomas Cox, MD, and Warner Huh, MD
The 2012 national recommendations for cervical cancer
screening will produce a lower level of cervical cancer
protection than previously afforded by annual cytology
or 3-year cotesting. After a single negative cotest result,
the risk of cervical cancer is twice as large at 5 years as it
is at 3 years. Modeling published since the 2012 guidelines were drafted indicates that extending the cotesting
screening interval from 3 to 5 years at ages 30–64 years
will result in an additional 1 woman in 369 compliant
with screening receiving a cervical cancer diagnosis during her lifetime, and an additional 1 in 1,639 dying of
cervical cancer. The authors believe that a significant
number of patients and providers would not choose to
accept these additional risks if they understood them,
despite the recognition of potential harms associated
with more intensive screening.
(Obstet Gynecol 2015;125:311–5)
DOI: 10.1097/AOG.0000000000000632
See related editorial on page 308.
From the Department of Women’s Health, the Permanente Medical Group,
Sacramento, California; the Department of Pathology (emeritus) and the Division of Gynecologic Oncology, Columbia University College of Physicians and
Surgeons, New York, New York; the University of Connecticut, Farmington,
Connecticut; the University of California (retired), Santa Barbara, California;
and the University of Alabama, Birmingham, Birmingham, Alabama.
Corresponding author: Helen E. Dinkelspiel, MD, Columbia University College
of Physicians and Surgeons, Division of Gynecologic Oncology, 161 Fort
Washington Avenue, HIP 8-838, New York, NY 10032; e-mail: hed2117@
cumc.columbia.edu.
Financial Disclosure
Dr. Wright has worked on studies of HPV diagnostics for Roche, BD, Cepheid
and Gen-Probe. Dr. Cox has served on the Scientific Advisory Boards of Hologic,
Trovagene, and Zilico, the Data Steering Committee for Roche, the HPV Vaccines
Data and Safety Monitoring Board for Merck, and on the Speakers Bureaus for
Roche and Hologic. Dr. Huh serves on the Scientific Advisory Board for Merck.
The other authors did not report any potential conflicts of interest.
© 2015 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/15
VOL. 125, NO. 2, FEBRUARY 2015
MD,
Mark DeFrancesco,
MD,
I
n 2012, the American Cancer Society (ACS), the
American Society of Colposcopy and Cervical Pathology, and the American Society of Clinical Pathology,
cosponsored a conference to develop cervical cancer
screening guidelines that were subsequently adopted by
the American College of Obstetricians and Gynecologists
(the College).1 The purpose of this article is to provide
what is acknowledged to be a minority viewpoint: it is
the authors’ opinion that there needs to be additional
discussion concerning the level of cervical cancer protection we want to provide to our patients and the level
of protection that women would prefer.
Our understanding of screening interventions is
changing as our understanding of the balance between
risks and harms evolves. This is particularly problematic
in the area of screening for cervical cancer prevention,
where the time course of the disease prevents randomized prospective trials with cancer endpoints and mortality is sufficiently rare in screened women that most of
the differences in benefit between different screening
schemes have to do with quality of life (avoidance of the
morbidity of cancer treatment compared with the
morbidity associated with screening). Test sensitivity
and specificity for dysplasia endpoints are therefore less
important than the human cost and benefit associated
with applying those tests to populations.
For a number of decades, cervical cancer screening
guidelines developed by both the ACS and the College
made certain that any recommended screening strategy
would offer women at least the same level of protection
as annual cytology. When the previous screening
guidelines were developed in 2002, the available data
indicated that liquid-based cytology done at 2-year
intervals provided an equivalent level of protection as
annual cytology, and therefore both screening approaches were considered acceptable. Moreover, modeling studies indicated that cotesting with both cytology
and human papillomavirus (HPV) testing at 3-year
intervals provided as much protection as annual
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311
cytology, a prediction that has been borne out over
a decade of experience at Kaiser Permanente Northern
California.2 Therefore, the 2002 recommendations also
considered cotesting at 3-year intervals an acceptable
screening approach for women aged 30 years or older.
Since the 1960s, annual cytologic screening had been
recommended in the United States, and the incidence
of cervical cancer has dropped dramatically.
We are concerned that the 2012 ACS and College
recommendations will produce a lower level of cancer
protection than that previously provided by annual
cytology. The new recommendations are based on
consensus that the best balance between the benefits
and harms of screening is achieved by cytology at
3-year intervals. The benefits are measured in terms of
cervical intraepithelial neoplasia (CIN) grade 3 immediately detected and the reduction in CIN 3 and
cancer (CIN 3+) in the interval before the next screening test, and the harms are measured by the number of
colposcopies. Once it was decided that cytology at
3-year intervals provides an acceptable level of cervical cancer protection, this level of protection became
the benchmark for other screening recommendations.
Because modeling suggests that cotesting at 5-year
intervals will provide cancer protection at least as
good as cytology at 3-year intervals with fewer colposcopies, this option became “preferred.”
The authors see no reason that the transition to the
molecular age of screening should be associated with
a decrement in cancer protection. It is our opinion that
the decision to consider the level of cancer protection
provided by cytology at 3-year intervals as acceptable
should be reconsidered, and that we should return to
using the level of cancer protection provided by annual
cytology as the benchmark. Failing that, if we are going
to recommend a screening approach that will result in
more cervical cancer cases in screened women than
previously, the justification for that recommendation
needs to be better defined and communicated to both
patients and providers. Otherwise, we cannot expect
compliance with the extended screening intervals that
have been recommended. What follows is not an
argument for any specific screening scheme, and it is
not a request to return to annual cytology. Although
the level of cancer protection offered by annual
cytology is an important benchmark, annual cytology
is a profoundly inefficient system that requires recognizing and following a large number of lesions that will
resolve on their own and that, as a consequence, have
little to do with cancer prevention. Instead, this
commentary is a plea for a more informed and
complete discussion of what level of cancer risk (not
CIN 3+ risk) is preferred by women and their health
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Kinney et al
care providers, as well as the assertion that a greater
measure of patient and provider autonomy should be
permitted by payers while that discussion takes place.
The first opinion that we want to offer is that rates
of cancer, and not CIN 3+, are the most relevant endpoints to patients. As it was during the 2012 guidelinedevelopment process, CIN 3+ has been substituted for
cancer when statistical power is inadequate using cancer alone, but with the greater experience now available, the discussion should be about cancer risk, which
is the paramount concern of patients and providers.
The second point that we want to emphasize is
how changing the screening benchmark from annual
cytology to cytology at 3-year intervals will affect our
patients. The short-term risk of cancer associated with
cytology at 1- compared with 3-year intervals always
has been measurably different. There is no report that
the authors are aware of that suggests that cancer risks
do not increase when the interval for cytology is
extended from annually to every 3 years. Historically
the only disagreement has been about the magnitude
of the increased risk. Relative risks of cancer associated with cytology done every 3 years compared with
annually range between 1.3 and 4.7,3–6 and this
increase in risk is not mitigated by limiting 3-year
intervals to women with previous negative screening
results,7 nor by requiring three negative cytology results before extending intervals.8 Before the development of the 2012 guidelines, Katki et al quantified the
cancer risk at different time periods after a single negative cytology result in 80 women diagnosed with
cervical cancer in the relatively low-risk Kaiser Permanente Northern California population. They found
that the risk of cervical cancer after a single negative
cytology result doubled between 1 and 3 years,
although the 95% confidence intervals (CI) widely
overlapped.9 They now have extended this analysis
to 500 previously screened women in Kaiser Permanente Northern California who subsequently developed cancer, 405 of whom did so within 5 years of
cotesting; the doubling of risk between 1- and 3-year
intervals after a negative cytology result is still present,
but the 95% CIs no longer overlap. The absolute risk
of cancer in women age 30–64 after a negative cytology result are 0.009% (0.008–0.012%) at 12 months
and 0.020% (0.017–0.024%) at 36 months.10 A similar
effect is observed with extending the cotesting interval
from 3 to 5 years. The absolute risks of cancer double
from 0.007% (0.006–0.010%) at 3 years after a single
negative cotest result to 0.014% (0.011–0.017%) at 5
years.10 Cancer risk at 3 years after a negative HPV
test result alone was very similar but not identical to
cancer risk at 3 years after a negative cotest result.10
Cervical Cancer Risk With Screening-Interval Extension
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The third point that is important to understanding
cervical cancer risk with different screening schemes is
the appropriate timeframe. The differences in risk after
a single test will no doubt seem small to many readers,
but the consequences of cervical cancer screening are
not those of a single year or a single test—in the United
States they accrue over the many tests in the course of
a woman’s life. For this reason, modeling is essential to
grasp the magnitude of the risks and benefits associated with different screening choices over a woman’s
lifetime, which the assessment of risk or benefit per test
or per annum does not accurately convey. Kulasingam
et al11 have published the modeling that they conducted at the behest of the U.S. Preventive Services
Task Force to inform the guideline process. The consequences of different screening modalities and intervals predicted by this model are essential to grasp the
magnitude of changes in cancer risk and in numbers of
procedures because they are reported as events per
1,000 women over a lifetime of screening. This perspective allows what we perceive to be a more realistic
and clinically relevant assessment of the potential magnitude over a woman’s lifetime of the effects of seemingly small changes in cancer risk. The model indicates
that, among women who are compliant with screening
recommendations, changing the cotesting interval
from 3 years to 5 years results in an additional 1 in
369 (2.71/1,000) being diagnosed with cancer and an
additional 1 in 1,639 (0.61/1,000) dying of cervical
cancer. If one considers that there are 72 million
women between the ages of 30 and 64 years in the
United States, a better sense of the magnitude of the
additional risks associated with extending the screening interval can be obtained.12 A population of this size
initiating cotesting at the age of 30 would experience
an additional 195,000 cases of preventable invasive
cervical cancer, and 44,000 preventable deaths would
occur during their lifetimes if we change cotesting
from a 3-year interval to a 5-year interval. Other modeling publications cited in the U.S. Preventive Services
Task Force evidence review come to similar conclusions in that they all agree that extending the cotesting
interval from 3 years to 5 years moves us measurably
further away from the level of cancer protection afforded by annual cytology.13,14 The purpose of presenting these estimates is not to assert precision: the
kinds of models used to study cervical screening cannot provide CIs. This shortcoming has not prevented
the U.S. Preventive Services Task Force from paying
for this model to be developed, nor ACS and College’s
using the results to decide which screening strategy is
“preferred.” The purpose of presenting these results is
to make the reader aware of our current best under-
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Kinney et al
standing of the magnitude of the additional risk that
has been chosen. Are the clinicians, and more importantly the patients, ready to accept this?
The fourth point that we want to make is that we
are not convinced that the number of colposcopies
associated with a given screening strategy provides an
ideal surrogate endpoint for measuring the “harms” of
screening. We completely agree with the need to balance benefits with harms when developing screening
guidelines and believe that the steps taken in this direction by the 2012 guidelines are commendable, although
formal cost-effectiveness analysis was not and is not
available. Obviously there is a price for every additional
increment in cancer protection, which includes additional visits, procedures that may be potentially injurious, and costs to the health care system. Although the
number of colposcopies is quantifiable and therefore
useful as an outcome for modeling studies, we do not
believe it is an accurate measure of the potential
“harms” of screening. How many women would prefer
treatment of or death from invasive cervical cancer to
avoid the minor discomfort and inconvenience of colposcopy? The modeling work done for the U.S. Preventive
Services Task Force estimates the effect of different
screening intervals on the number of both colposcopies
and treatments for CIN 2+. The model predicts that
5-year cotesting would require 575.46 colposcopies
per 1,000 women and 3-year cotesting would require
824.74, hence the additional colposcopies required for
3-year cotesting would number 249 (824.74-575.46).
That means that every cancer prevented by cotesting
at 3-year intervals as opposed to 5-year intervals would
require 92 additional colposcopies and treatment of 3.2
additional women for CIN 2+. Every cancer death prevented would require 409 additional colposcopies and
treatment of 14.3 additional women. Is it possible that
these are risks that some women would consider acceptable, or even desirable, in contrast to the risk of cancer
or death from cancer? Should there be greater public
awareness of these tradeoffs if informed choices about
screening are to be made?
While the harm of colposcopy per se is small,
a potential “harm” of screening that both clinicians
and patients are more likely to consider significant is
potential for injury to a child as a result of premature
delivery secondary to detection and treatment of
a CIN 2 lesion that most likely would have spontaneously regressed if it had not been detected. This brings
us to the fifth and last point that we would like to
make, which is that the risk of premature rupture of
membranes, preterm labor, and low birth weight associated with a single one-pass loop electrosurgical excision procedure (LEEP) may have been overstated.
Cervical Cancer Risk With Screening-Interval Extension
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313
This relationship is presumed to exist despite a number
of well-designed studies that have failed to show a clear
association.15–22 The conflicting results reported in the
literature may be explained as follows: First, the volume of tissue removed appears to be relevant to
risk,16,23–26 and practices have undoubtedly varied
over time and between locations in this regard. The
trend that we observe in clinical practice toward smaller excisions may serve to make risk less than historical
reports suggest. Secondly, the issue of potential bias in
the design of retrospective observational studies is
only recently starting to be addressed. The effect of
attempting to control for bias is illustrated in recent
publications. Data from 18,441 births from 12
National Health Service hospitals indicate that the
observed increase in risk of prematurity associated
with LEEP was a consequence of confounding and
was not caused by treatment. Women who delivered
and subsequently received excisional treatment after
delivery had a similar increase in risk of prematurity
as those treated with excision before delivery.15 Even if
one takes the reports asserting a causal association
between prior LEEP and adverse pregnancy outcome
at face value, the reported increases in absolute risk are
modest. In the National Health Service, the difference
in delivery before 37 weeks was 9.1% with previous
excisional treatment compared with 8.3% with colposcopic biopsy alone.15 A recent systematic review of
the literature and meta-analysis that included 19 studies with different control groups found that a history of
LEEP had a relative risk of 1.61 (95% CI 1.35–1.92)
for delivery before 37 weeks of gestation, corresponding to absolute risks of 8.8% compared with 5.1%.
However, when women who had undergone LEEP
were compared with women with a history of cervical
dysplasia but no excisional procedure, the relative risk
of prematurity was not significantly increased at 1.08
(0.88–1.33).27 Therefore, we believe that, after putting
the potential harms into perspective, some women
would want to accept the risks associated with a 3-year
cotesting interval in return for decreasing their risk of
developing cervical cancer.
Most opinions come with caveats and those expressed above are no exception. First, our ability to
quantify the cancer risk associated with different screening choices (let alone the risks of those choices) is
imperfect and will remain so. There are no randomized
controlled trials comparing cancer risk at different
screening intervals, nor will there ever be. In a disease
where the outcome of interest (invasive cancer) occurs
in the United States at an incidence of single digits per
100,000 per year, the necessary trial size would be
unmanageable. Additionally, the risks and benefits of
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Kinney et al
screening aggregate over a lifetime. The use of surrogate
endpoints is no help: the time course from CIN 3 to
cancer is measured in decades, and CIN 3 and cancer
rates change in opposite directions as more effective
screening modalities are introduced. The pooling of
cancer and CIN 3 as CIN 3+ is therefore statistically
convenient for evaluating test performance, because one
wishes to detect both, but potentially misleading as an
outcome measure for population screening. We are only
trying to prevent cancer, not CIN 3, and changes in
detection rates of the vastly more common CIN 3 can
conceal changes in the occurrence of invasive cancer.
Second, it is possible that multiple rounds of
cotesting at 5-year intervals will provide cancer protection of a magnitude similar to annual cytology,
although this is not predicted by any of the models.
There is also reason to believe that risk will fall over
time with increasing adoption of the HPV vaccines.
These effects may combine (multiple rounds of
cotesting and decreased prevalence of HPV 16 and
18) to provide the desired level of protection using
5-year or even longer intervals in the distant future.
For the reasons cited above, the authors recommend the following steps to encourage trust in and
compliance with future screening recommendations:
1. Reexamine the benchmark cancer risk on which
all of the recommendations are predicated, recognizing that the risks associated with annual
cytology and cytology at 3-year intervals are
not identical.
2. Permit a range of acceptable screening options,
because this would better reflect the imprecision
involved in estimating lifetime risks and harms
associated with reducing risk as well as the expected diversity of informed patient and provider
preferences regarding these competing risks.
3. Give patients and providers the best available estimates for lifetime cancer risk associated with different screening options as opposed to making
judgments for them about what level of increased
risk they should consider to be “inconsequential.”
4. Avoid the implementation of 3-year intervals for
cytology and 5-year screening intervals for cotesting in settings without a formal computerized call
and recall system, unless we are ready to countenance screening intervals significantly in excess of
the recommendations for patients whose memory
of the date of their last screen is imperfect.
5. Understand that current risk data will not be correct forever. Less intensive screening will be
required in the vaccinated population now and
the general population in the future to meet the
desired benchmark level of cancer prevention.
Cervical Cancer Risk With Screening-Interval Extension
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6. Develop and expand data sources that permit
examination of cancer risks over time rather than
surrogate endpoints.
In conclusion, we believe that the option of
screening with: 1) cotesting with cytology and a U.S.
Food and Drug Administration–approved HPV test at
3-year intervals or 2) U.S. Food and Drug Administration–approved primary HPV testing at 3-year intervals should be available to all patients and
providers who want to maintain a level of cervical
cancer protection similar to what was previously available with annual cytology. None of the data that have
emerged since the guidelines were published have
served to change our opinion that the option of better
protection should be an acceptable choice for those
who prefer it. Ideally the advent of molecular screening should be used to permit previous levels of cancer
protection with fewer visits and procedures rather
than heralding an increase in cancer risk.
11. Kulasingam SL, Havrilesky LJ, Ghebre R, Myers ER. Screening for cervical cancer: a modeling study for the US Preventive
Services Task Force. J Low Genit Tract Dis 2013;17:193–202.
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