Transcript Update on Cervical Cancer Screening

Update on Cervical Cancer
Screening
Barbara S. Apgar, MD, MS
Professor of Family Medicine
University of Michigan Health System
Ann Arbor, Michigan
Disclosures
1. Apgar B, Brotzman G, Spitzer M. Integrated Text and Atlas of
Colposcopy. Elsevier Publishers, 2004, 2008.
2. Brotzman G, Spitzer M, Apgar B. Colposcopic Image Library on CD.
SABK, Inc. 2004.
3. ASCCP Board of Directors. 2007-current.
Images
Apgar B, Brotzman G, Spitzer M. Integrated Text and Atlas of Colposcopy.
Elsevier Publishers, 2004, 2008.
The good news
is that another cervical cancer
guideline conference
is NOT planned until 2017.
The bad news is there are women
who are not being screened for
cervical cancer
1/10 women aged 21-65 have not been
screened in the past 5 years
1/ 4 have no health insurance or PCP
Benard VB et al. MMWR Nov 5, 2014;63:1-6
Natural
history
of
HPV
infections
Natural hx of HPV infections
• Most are transient and do not increase a
woman’s risk for cervical cancer.
• If oncogenic HPV is persistent, the risk of cervical
cancer is increased substantially.
– Longer persistence = greater the risk.
• The early natural history of HPV infections
does not predict the outcomes.
Women >age 30
Women < age 30
Behavior of HPV 16
during 30 months of
follow-up (800
infections)
Rodriquez AC et al. J Natl Cancer Inst 2008;100:513-517
Progression to Cervical Cancer
Apgar, Brotzman, Spitzer
oncogenic HPV, persistent for 10 years
Natural History of CIN3
McCredie MRE et al. Lancet Oncol 2008;9:425-434
• NZ women who were not treated for CIN 3
• Primary outcome = cumulative incidence of
invasive cervical or vaginal cancer.
• 1063 (86%)/1229 from 1955-1976) were
managed by:
– Punch or wedge biopsy, conization
McCredie MRE et al. Lancet Oncol 2008;9:425-431
Key Points on Cervical Carcinogenesis
Infection of the metaplastic epithelium
of the cervical transformation zone with
1 or more oncogenic HPV types starts
the process.
Time from HPV infection to CIN 3 is shorter than
the decades-long time from first development of
a CIN 3 lesion to cancer.
HPV infection
Apgar, Brotzman, Spitzer
HSIL (CIN 3)
Cancer
Cumulative relative contributions of 8 most common HPV types by
histologic category (38 countries) in women with Cancer.
de Sanjose S et al. Lancet Oncol 2010;11:1048-56.
FDA-approved HPV tests
• cobas 4800 HPV test. (approved 2011)-Roche
• PCR-based.
• 14 HR HPV types.
• Genotyping for HPV 16 and 18 integrated into the
assay.
• Concurrently detects remaining 12 HPV types as a
group (like hybrid capture- prior HPV test).
Importance of HPV types
CYTOPATHOLOGY GYNECOLOGIC REPORT UMHS Labs
Diagnosis:
Negative for intraepithelial lesion or malignancy.
Adequacy:
Satisfactory for evaluation. Transformation zone present.
Human Papillomavirus Genotype Results:
Type 16: Detected
Type 18: Not detected
Other High Risk Type: Not detected
SURGICAL PATHOLOGY REPORT
A. Cervix, 12, 3, 5, 7 o'clock, biopsies: HSIL (CIN 3).
B. Endocervix, curettage: HSIL (CIN 3)
Finding carcinogenic HPV types
does not
provide a diagnosis of CIN 3 or cancer
It identifies a group of women
in whom CIN 3+ is more likely
Women testing negative for HPV have
extremely low risk of developing cervical cancer
over 5 years
Cumulative Incidence of CIN 3+ After Single HPV+
Followed for 10 years Among Women > 30
HPV 16
HPV 18
HR-HPV other than 16/18
HPV neg
Khan MJ et al. JNCI 2005;97:1072-9.
Which one of the following tests provides
greater reassurance against CIN 3+ over an
extended time?
1. Pap test.
2. HPV test.
3. Both are equal.
4. Neither test able to
provide reassurance.
Apgar, Brotzman, Spitzer
“Reassurance” against cervical cancer is the
crucial factor for deciding screening intervals
Large studies needed to establish actual cancer
risks for each possible cytology and HPV result
(including negatives)
 If effective, each successive screen should
lower the subsequent risk.
Why?
Because women with disease have already been
identified and treated.
They do not contribute to the overall risk.
Katki HA et al. Gynecol Oncol 2011;12:663-72
Kaiser Permanente Northern California data
2003: shifted to co-testing
Annual Pap's continued to be available.
 2007: 95% of patients co-tested q 3 yrs.
Colposcopy after 2 HPV+/negative Paps
5 year risk of CIN 3+ following a negative co-test
was comparable to a 3-year risk following a
negative Pap.
CIN 3+ and Cancer risks 3 and 5 yrs. after
negative HPV and cytology
Huh WK et al. Interim Clin Guidance. OG 2015;125(2):330-7.
Cumulative Risk Of Invasive Cancer
Based on Initial Co-Test
Kaiser Study
N=331,818 women > 30
years in prospective cotesting study
Katki HA, et al. Lancet Oncol
2011; 12: 663
Important points on 2011 Kaiser data
Although women Pap and HPV + had the
highest risk, those with negative Pap but HPV+
accrued substantial risk for CIN 3+ over 5 years.
A single negative HPV is sufficient to reassure
low risk of cancer and CIN 3+ over 5 years.
HPV testing predicted future disease much
better than Pap.
Meijer CLM et al. Gynecol Oncol 2011:12:
Katki HA, et al. Lancet Oncol 2011;12:663-72
Reassurance against future risk of CIN 3 and cancer
of a negative screening result
3 screening strategies.
Primary Pap testing every 3 years
Primary HPV testing every 3 years.
Primary cotesting every 5 years.
1,011,092 women (30-64 years) in Kaiser
Gage JC et al. JNCI 2014;106(8);dju153
Important points on 2014 Kaiser data
3 year risks following an HPV-negative test were
LOWER than:
3 year risk following a Pap-negative test.
5 year risk following an HPV and Pap-negative cotest.
A negative Pap provides less reassurance against
CIN 3+ than a negative HPV test or negative
cotest.
Gage JC et al. JNCI 2014;106(8);dju153
Which one of the following tests provides
greater reassurance against CIN 3+ over
extended time?
1. Pap test.
2. HPV test. ****
3. Both are equal.
4. Neither test able to
provide reassurance.
Apgar, Brotzman, Spitzer
Which test provides greater reassurance
against CIN 3+ or cancer?
HPV testing improves detection of CIN 3
at baseline resulting in fewer cancers.
Castle et al. Obstet Gynecol 2011;117:650-6. Ronco G et al.
Lancet Oncol 2010;11:249-57. Katki HA et al. Lancet Oncol
2011;12: 66 3. Ronco G et al. Lancet 2014;383:524-32.
Gage JC et al. JNCI 2014;106(8);dju153
2012 Cervical cancer screening guidelines
Age 30-65. Testing with cytology alone every 3 years or co-testing with
cytology and testing for high-risk HPV types every 5 years.
Co-testing “preferred” and cytology “acceptable” by all but USPSTF
Recommendations NOT intended for women with HIV, immunocompromise,
or in utero DES exposure
1.
2.
3.
4.
Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: 147-72
and AJCP 2012; 137: 516 – 542.
Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: 880-91
ACOG Practice Bulletin #131, November 2012
NCCN Cervical Cancer Screening Guideline v. 2-2012. www.NCCN.org
2012 Consensus Guidelines:
Screening Frequency
Age 21-29. Testing with cytology (Pap) alone every 3 years.
Co-testing should NOT be performed for women < age 30.
 Reflex HPV testing for ASCUS only.
1.
2.
3.
4.
Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62:
147-72 and AJCP 2012; 137: 516 – 542.
Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: 880-91
ACOG Practice Bulletin #131, November 2012
NCCN Cervical Cancer Screening Guideline v. 2-2012.
www.NCCN.org
Co-testing women < 30 years
 50 % of clinicians and clinics do co-testing in
women < 30 years (not guideline adherent).
 Despite significant rate of transient HPV infections
in this age group.
Bottom line: HPV testing increases cost, anxiety and
does not add clinical value in women < age 30 years
JUST SAY NO!
Solomon D et al. CA Cancer J Clin 2007;105. Kitchener HC et al.
Int J Gynecol CA 2008;18. Berkowitz et al. Obstet Gynecol 2010;116.
So where are we on decisions about
cervical screening since 2012?
What is the level of protection provided by
cotesting every 5 years or Paps every 3 years?
It has been assumed that any screening strategy
would offer at least the same level of protection as
annual screening.
Balance of benefits and harms
“Best” balance in the 2012 screening guidelines?
Harms (numbers of colposcopies)
and
Benefits (immediate detection of CIN 3 and reduction
of CIN 3+ in the interval before the next screening)
Paps every 3 years beginning at age 21 =
acceptable level of protection (USPSTF).
Cotesting every 5 years provides protection
with decreased colposcopies that is “at least as
good” as Paps every 3 years.
Moyer VA. USPSTF Rec Statement. Ann Intern Med 2012;156:880-91.
What are the “Harms”?
Colposcopy referral.
Treatment of cervical lesions destined to
resolve without intervention.
Burdening women with surveillance of unclear
efficacy or endpoint.
39% of women in surveillance had significant
psychological distress.
Sharp L et al. JLGTD 2014;18(2):142-50
Sawaya, Kuppermann. Obstet Gynecol 2015:125:1-3
Moyer VA. USPSTF Rec Statement. Ann Intern Med 2012;156:880-91.
How many colposcopies are a “harm”?
USPSTF: 3 year vs. 5 year cotesting intervals
Every cancer prevented by 3 year instead of 5 year
intervals, would require additional colposcopies
for 92/1000 women and treatment of 3/1000
additional women for CIN 2,3
Every cancer DEATH prevented would require 409
additional colposcopies/1000 women and
treatment of 14/1000 additional women for CIN
2,3
Moyer VA. USPSTF Rec Statement. Ann Intern Med 2012;156
Sawaya GK, Kupermann M. Obstet Gynecol 2015:125:1-3
Even after knowing the “harms” of more
intensive screening…..
Significant numbers of patients and providers
would not accept the additional lifetime cervical
cancer risk conferred by:
Cotesting every 5 years (0.74%).
Cotesting every 3 years (0.47%).
Some have argued that annual screening should
be the benchmark for screening guidelines.
Annual cytology (0.25%).
Sawaya GK, Kupermann M. Obstet Gynecol 2015:125:1-3.
Kinney W et al. Obstet Gynecol 2015:125:311-315.
What if the benchmark is annual screening
not cytology every 3 years?
Return to annual screening will result in following
a large number of lesions that:
1. will resolve on their own
2. have little to do with cancer prevention
Kinney W et al. Obstet Gynecol 2015:125:311-15.
Sawaya GK, Kupermann M. Obstet Gynecol 2015:125:1-3.
Low vs. high grade cervical lesions
Apgar, Brotzman, Spitzer
Changing cotesting from 3 to 5 years
Publications all agree that going from a 3 to 5
year interval moves screening farther away from
protection afforded by annual screening.
Results in an additional 1/369 women being
diagnosed with cancer.
Results in an additional 1/1639 dying of cancer.
2015 considerations
Recognize that risks associated with annual and 3/5 year
intervals are not identical.
Permit a range of acceptable screening options.
Option of better cancer protection should be an
acceptable choice for patients who want it.
Give patients the best available estimates of cancer risk.
Avoid 3 and 5 year intervals unless you have a recall system.
Those involved in guideline construction should be FREE
of commercial and intellectual conflicts of interest. ***
Kinney W et al. Obstet Gynecol 2015:125:311-315.
Sawaya GK, Kupermann M. Obstet Gynecol 2015:125:1-3.
Risk of cervical cancer will decrease over time
HPV vaccination
HPV vaccination.
Decreased
prevalence
of HPV
16 and
Decreased
prevalence
of HPV
16 and
18. 18
Multiple rounds of cotesting.
Multiple rounds of cotesting
May provide the desired effect of cancer
protection using 5 year or even longer
intervals in the future.
What do screened women 36-62 yrs. prefer ? (n-581)
55% knew that screening guidelines had changed.
74% believed women should have yearly Pap tests.
Knowledge of change in guidelines did not equate to
increased willingness to follow them.
68% were willing to extend screening to every 3 years if
recommended by health provider.
Only 25% were willing to extend to every 5 years after a
negative cotest.
Silver MI et al. Obstet Gynecol 2015;125(2):317-329
What do women age 36-62 years prefer ?
Women with lower incomes more likely to
accept longer screening intervals.
More barriers to scheduling time off
work and transportation.
Silver MI et al. Obstet Gynecol 2015;125(2):317-329
Concerns of patients
5 5 year cervical cancer screening intervals are a
stretch for most women.
There is continued reluctance among
adult women to accept
HPV-based screening algorithms
What concerns do physicians have?
Losing the well-women annual clinical
encounters as a result of less frequent
screening.
Common barrier to use of cotesting and extended
screening intervals.
However………
70% of women would continue well-woman
visits even if Pap testing was not done.
Perkins RB et al. Am J Prev Med 2013;45:175-81.
ACOG. Comm Gyn Prac 2012;120:421-424.
So what’s new on the horizon?
Cytology every 3 years
starting age 21
Cotesting every 5 years
starting at age 30
Now consider primary
HPV screening starting
at age 25
FDA approved HPV testing
Roche cobas® 4800 HPV test
 FDA approved as HPV test (pool + genotyping) 2012
 FDA approved as primary screening test 4-24-2014*
* It does not change current medical practice guidelines
for cervical cancer screening. These guidelines are
developed, reviewed and modified by groups other than
the FDA.
FDA News Release 4/24/14
Primary screening with HPV testing
 Screening may begin at age 25.
Despite 2012 recommendations discouraging HPV
testing in women < age 30.
High prevalence of HPV and transient infections.
Athena trial (GSK sponsored).
21% had + HPV tests and were referred to colposcopy
or placed in surveillance.
Comparison: 7% to colpo if Pap alone.
Huh WK et al. Interim Clin Guidance. OG 2015;125(2):330-7.
Moyer VA. USPSTF Rec Statement. Ann Intern Med 2012;156:880-91.
Wright TC et al. Athena HPV study. Am J Obstet Gynecol 2012;206:46e1-11.
Advantages of HPV-based Primary Screening

High sensitivity for detection of HSIL lesions

High negative predictive value of test

High test reproducibility

Results in higher detection of CIN2+ in women aged
25-29 compared to the same strategy starting at age
30 (is this an advantage?)
Wright TC et al. Athena HPV study. Am J Obstet Gynecol 2012;206:46e1-11.
Disadvantages of HPV-based Primary Screening




Prevalence of HPV positivity (14 pooled genotypes) was
almost twice as high in women 25–29 years (21.1%; 95% CI:
20.1–22.1%) as in women 30–39 years (11.6%; 95% CI: 11.0–
12.2%).
Double number of colposcopies (21%)
Unproven long term proof of equivalence of outcome
and cost effectiveness compared to consensus
guidelines
Unknown optimum screening intervals and follow-up
protocols
HPV only testing >>>>>
More colposcopies if direct referral
(especially if starting at age 25)
More CIN 2,3 detected
(includes CIN 2 which may regress)
More treatments (including for CIN 2)
Gage JC et al. JNCI 2014;106(8);dju153
Primary HPV Screening Algorithm-2015
Routine Follow-up
3 year intervals
cobas HPV DNA Test
12 mo. Follow-up
31
33
35
39
45
51
52
56
Other HPV HR DNA Present
Cytology
59
58
16
66
18
68
C
Colposcopy
Start at age 25
Colposcopy
Huh WK, et al, Use of primary high-risk human papillomavirus testing for cervical cancer screening:
Interim clinical guidance, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2014.12.022
Cost Estimate by Screening Strategy


Simple cost estimate for screening from age 21 to 65 years of age
assuming all scheduled screens are completed
Colposcopic exams: linear extrapolation from ATHENA trial rates
assuming 50% drop every 3 years x 4 with 50% less frequency in
CSG group
Consensus Screening
Guideline
Primary HPV
Screening
11 x $68 = $748
2 x $68 = $136
HPV tests
8 x $131 = $1048
15 x $291 = $4365
Office visits
11 x $125 = $1375
17 x $125 = $2125
15.4% x $1200 = $185
31% x $1200 = $372
$3356
$6998
Cytology tests
Colposcopic Exams
Cost
Analysis by R K Reynolds, MD. Gynecol Oncol, Univ Michigan 2015
Primary HPV Screening: The Future?
What is needed for broad acceptance?
 When enough data are available to justify using
this test as a replacement for other screening
methodologies. e.g. outcome and cost
comparisons
 When enough data are available to validate this
method on more than one platform besides
Roche e.g. competition to reduce cost.
We are not there yet!
The
End…..
Thanks all !