Transcript Powerpoint Cells Template

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56
Annual Ob-Gyn Update
New Cervical Cancer Screening
Recommendations
Methods, Intervals, Screening Risks
and Cancer Risks
Walter Kinney M.D.
Division of Gynecologic Oncology
The Permanente Medical Group
Clinical Professor of Ob/Gyn, U.C. Davis
Sacramento, California
30
30
25
25
20
20
15
15
10
10
5
5
0
0
Cancer incidence per 100,000
HPV Prevalence (%)
HPV Prevalence and Cervical
Cancer - Incidence by Age 1,2
15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54
Age (Years)
1. Sellors et al. CMAJ. 2000;163:503.
2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
HPV types
0.2
0.4
0.6
0.8
16
52
51
62
31
89
18
53
56
61
average
0.0
Proportion of persistent infections
1.0
New Infections Go Away Quickly!
0
ALTS
6
12
Time (months)
18
24
Plummer et al., JID, 2007
Time To LSIL/CIN 1 Regression
•187 KPNC members, age 13-22
•Median followup 61 months
•61% Spontaneous regression at 12 months
•91% Spontaneous regression at 36 months
Moscicki AB et al, Lancet 2004 Nov 6-12;364(9446):1642-4
Rate of and Risks for Regression of CIN2
in Adolescents and Young Women
•95 KPNC Members Age 13-24
•38% spontaneous clearance by year 1,
63% by year 2 and 68% by year 3
•15% progression to CIN3 by year 3; no
cancer
2008 interval analysis shown, full data in Moscicki AB
et al, Obstet Gynecol 2010 December; 116(6):1373-1380
Natural History of Cervical Cancer
Natural History
of Cervical Carcinogenesis
Timeline
CIN 1/2
HPV
Infection
0.5 – 10+
CIN 3
10+ Avg
HPV
0.67
Disappearance
Avg
Time in Years
Invasive
Cancer
Cervical Screening Guidelines Timeline: 2011-14
• Fall 2011
– USPSTF declined to recommend
HPV & Pap cotesting
• Spring 2012
– USPSTF, ACS, and ASCCP
recommend cotesting for
screening women age 30-65
• March 2013
– Management guidelines for every
abnormal cotest and biopsy
• April 2014
– FDA allows HPV testing without
Pap smears
Slide courtesy of Dr. Hormuzd Katki, NCI
Skeleton key: Screening literature
 Less screening = more cancer. The only questions are




How much more cancer?
What are the risks?
What are the costs?
What compromises would we prefer to make (and pay for)?
 There are no randomized controlled trials comparing cancer
prevention or risk outcomes or costs between three year
cotesting and 5 year cotesting, or annual versus 3 year
cytology. This leaves us with observational studies and
modeling. YOU CAN’T DO RCTs WITH CANCER ENDPOINTS.
 Currently available modeling of the consequences of
interval extension is not reassuring (personal opinion)
 Study design issues
 CIN3+ is not the same as cancer
 No screening is not a clinical option and hence not a valid
comparator
 Screening benefits and risks accrue over a lifetime
Cervical Cancer Screening Interval
and Risk of Invasive
Squamous-cell Cervical Cancer
1 Year
1.0
Odds
Ratios
2 Year
1.7
P=.013 vs 1
Odds
Ratios
Ever Abnl
Pap
1.0
Odds
Ratios
2 Neg Paps
1.0
2.1
P=.002 vs 1
2.2
P=..02 vs 1
3 Year
2.1
P=.007 vs 1
2.2
P=.005 vs 1
3.6
P=.004 vs 1
Miller MG et al, Obstet Gynecol 2003 Jan;101(1):29-37
Cervical Cancer Risk Within 3 Years Of
Negative Screening Cytology In
Longterm Members Of A Prepaid
Health Plan


53 cancers occurring at intervals of 1-3 years
following 3 consecutive negative Pap smears
collected over 1983-1995 in KPNC
Absolute risk of invasive cancer at different
intervals following last negative Pap
 One year (0-18 months)
 Two years (19-30 months)
 Three years (31-42 months)
1.43/100,000
4.24/100,000
4.73/100,000
Sawaya, GF. et al, Acta Cytol 2005 Jul-Aug; 49(4):391-7
Reported relative risks of cancer
between 1 and 3 year cytology
AUTHOR
q Year
q 2 Years
q 3 years
Rate q year:
Rate q 3 year
Eddy DM, 1980
85.0%
82.0%
78.0%
1:1.5
IARC (Day NE et al),
1986
93.3%
92.5%
91.4%
1:1.3
Eddy DM, 1987
96.3%
94.0%
91.8%
1:2.2
AHCPR, 1999
96.4%
89.9%
83.2%
1:4.7
Hutchinson ML, 2000
95.2%
88.3%
82.0%
1:3.8
Table courtesy of Dr. Jerry Pretorius,
Gynecologic Oncology, SCPMG
Risk of Cancer in KPNC Increases ~2x
5 Year versus 3 Year Cotesting
Information Available At Guidelines Meeting

Lancet Oncol, 2011 (80 cancers)
• 3 years after a negative cotest the risk of cancer is
.008% (.002-.035)
• 5 years after a negative cotest the risk of cancer is
.016% (.003-.072)
Cytology at 3 years vs
Cotesting at 3 and 5 years
intervals
Method
Colpos
Cancers
Deaths
Q3 Year
Cytol
Q5 Year
Cotest
Q3 Year
Cotest
758
8.50
1.55
626
7.07
1.29
825
4.73
0.74
Per thousand women, over a lifetime of screening,
starting at age 21; cytology only until age 30 in the
cotesting arms
Kulasingam et al (Duke): Decision Analysis for the USPSTF
funded by CDC and AHRQ; from Table 30a, page 49
Recent Changes In National
Screening
Recommendations
-
American Cancer Society and
ACOG
- Annual cytology or 3 year cotesting
changed to 3 year cytology or 5 year
cotesting
- Cotesting preferred
-
US Preventive Services Task Force
- 3 year cytology changed to 3 year
cytology or 5 year cotesting
Goals
ACOG: (Paraphrased) CIN3+ risk 3 years after a negative cytology =
CIN3+ risk 5-6 years after a negative cotest, therefore 5 years is the
correct interval for cotesting. Practice Bulletin #131 Obstet Gynecol
2012;120:1222-37
If you want to provide 3 year cytology level cancer
protection, then by all means, 5 year cotesting is
better in every way (though CIN3+ is not the
endpoint relevant to patients) BUT
Provide the level of cancer protection associated with q3
year cytology?
VERSUS
Provide the level of cancer protection associated with
annual cytology?
KPNC Cancer Risks for >1 million women cotested
Gage et al, JNCI, 2014
KPNC CIN3+ Risks for >1 million women cotested
17
Gage et al, JNCI, 2014
Lifetime Risk: Available Only From Modeling
Per 1,000
Colpo
CIN2,3
Cancer
Death Ca
Cotest q5
575
84
7.44
1.35
Cotest q3
825
93
4.73
0.74
9
2.71
0.61
Difference 250
•
If we move from q3 year cotesting to q5 year
cotesting
•
•
•
An additional 7.44-4.73/1000 women, = 1 additional
female member in 369 who screens as recommended will
get cervical cancer during her lifetime
An additional 1.35-0.74/1000 women = 1 additional female
member in 1,639 who screens as recommended will die of
cervical cancer
The harm of screening q3 is that one woman in 4 would
have one extra colpo in her lifetime (if risk was evenly
distributed), and an additional 1 woman in 111 would be
treated for CIN2+
Kulasingam et al, JLGTD, 2013
Consequences for Kaiser Northern California
Female Members If We Were To Move From
3 Year to 5 Year Cotesting
•
If we estimate that our 1,008,855 women who have
screened once or more in the 42 months prior to
12/31/12 will be “lifetime screening participants”,
then if we convert from 3 to 5 year cotesting
• 2,734 additional women will be diagnosed with cervical
cancer in their lifetime (7,506 instead of 4,772)
• 615 additional women will die of cervical cancer (1,362
instead of 747)
• One woman in 4 will be saved a colposcopy
• One woman in 111 will be saved treatment for CIN2+
Kulasingam et al, JLGTD, 2013
Opinion: Cervical Cancer Screening
Abstract
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 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 will result in an
additional 1 woman in 369 who is compliant with screening
receiving a cervical cancer diagnosis during her lifetime and and
additional 1 in 1639 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,
Manuscript in Press: Kinney, Wright, Dinkelspiel, Cox, DeFrancesco, Huh
Opinion: Cervical Cancer Screening
Harms of Cotesting at 3 Year Instead of 5 Year Intervals
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 CIN2+. 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?
Manuscript in Press: Kinney, Wright, Dinkelspiel, Cox, DeFrancesco, Huh
Does LEEP cause prematurity?
 Large number of studies with conclusions
roughly evenly divided between “Yes” and
“No”
 4 Metanalyses with differing conclusions
 Current consensus
 How the control groups are chosen defines the
results
 Women with CIN are at higher risk of
prematurity whether or not they have
undergone treatment
 More tissue removed = more risk
 A single LEEP with a 20x10 or 20x7mm loop is
not discernably associated with prematurity
Beware of Observational Data!
Confounding is real!
Does LEEP cause prematurity?
Three most important papers
 Castanon et al, BMJ 2012;345:e5174

 18,441 singleton first births in women who had abnormal screening
tests and colposcopy with histology (before or after delivery)
 Women with abnormal screening tests have elevated risk of
prematurity before colpo
 “After adjusting for confounding, the increased risk of preterm
delivery after treatment for CIN ceases to exist.”
Conner et al Obstet Gynecol 2014;123:752-61
 Metaanalysis of 19 studies with different control groups
 History of LEEP had a relative risks of 1.61 (95% CI 1.35-1.92) for
delivery prior to 37 weeks, corresponding to absolute risks of 8.8%
versus 5.1%;
 When women who had undergone LEEP were compared to women with
a history of cervical dysplasia but no excisional procedure, the relative
risk of prematurity fell to 1.08 (0.88-1.33).
 Arbyn et al, BMJ 2008:337:a1284
 Metanalysis, 20 studies, no increase in perinatal mortality with
large loop excision of the transformation zone
Primary Screening with HPV Only
FDA Approved April 2014

April 2014: US FDA approved a single HPV assay for primary screening
among women age 25-65 following 3 year 47,000 woman registration trial
“Athena”

“Candidate Algorithm” Primary HPV with immediate colpo for 16/18
positive and cytology triage of other HPV starting at age 25

Compared in the FDA registration trial to
 Cytology at 3 year intervals: “More sensitive and at least equally
specific”
 Cytology at 3 year intervals 25-29 followed by cotesting at 3 year
intervals 30-64. One year followup of Pap negative HPV positive, and
not 16/18 triage. “More sensitive than cotesting”

Large number of CIN3 in 25-29, more than half of which were Pap negative

Significant loss to followup for Pap negative HPV positive women in the
cotesting arm
ACS/ASCCP/ASCP (Saslow et al. J Low Genit Tract 2012)
ACOG (Practice Bulletin # 131, Obstet Gynec, 2012)
Cumulative
Risk of
Cancer
3-year HPV-negative vs.
3-year Pap-negative:
0.020 vs. 0.011, p<.0001
Gage JC, Schiffman M, Katki HA, Castle PE et al. JNCI, 2014
Cumulative
Risk of
Cancer
3-year HPV-negative vs.
3-year Pap-negative:
0.020 vs. 0.011, p<.0001
3-year HPV-negative vs.
5-year cotest-negative:
0.011 vs. 0.014, p=.21
Gage JC, Schiffman M, Katki HA, Castle PE et al. JNCI, 2014
Cumulative
Risk of
Cancer
Comparisons of HPVnegative and cotestnegative risks at the
same time point are
very close.
p=.11
p=.03
Gage JC, Schiffman M, Katki HA, Castle PE et al. JNCI, 2014
Enrollment screening results among women
age 30-64 who had cancer detected within 5
years from KPNC cohort of 1,036,360 women
Enrollment screening
result
TOTAL
HPVnegative
HPVpositive
#
%
407
100.0
50
12.3
4
1.0
LSIL+
22
5.4
Pap-negative
79
19.4
ASC-US
33
8.1
219
53.8
Pap-negative
ASC-US
LSIL+
Slide courtesy of Dr. Mark Schiffman, NCI
p16: A marker of transforming HPV infections
o Adjudicated pathology
Bergeron 2010 AJCP
o LAST guidelines: Adjudication of
CIN2
Darragh 2012 JLGTD
o p16/Ki-67 dual stain
o Triage of ASC-US/LSIL
Schmidt 2011 Cancer
Petry 2011 Gyn Onc
Wentzensen 2012 Clin Cancer Res
Comparison with baseline p16 data from
Italian screening trial (NTCC)
Kaiser Permanente Northern California
No colposcopy
No CIN
CIN1
CIN2
CIN3+
Total
Total
728
397
437
53
81
1696
%
DS+
32%
44%
55%
85%
90%
45.1%
NTCC (Italy)

No colposcopy
No CIN
CIN1
CIN2
CIN3+
Total
Total
629
241
175
50
42
1137
% p16
pos
36%
39%
53%
86%
91%
43.4%
Very similar referral rate and positivity in
disease categories
Carozzi Lancet Oncology 2008 and KPNC, Manuscript in Review
Triage of HPV-positive/NILM women
with
p16/Ki-67 dual stain
Test
Endpoint
CIN2+
p16(n=41)
ki67,
Intial Cyt
NILM
CIN3+
(n=875) (n=16)
Sensitivity
70.7%
(54.3-83.4)
81.3%
(53.7-95.0)
Specificity
69.9%
(66.673.0)
68.9%
(65.772.0)
PPV
NPV
10.4%
(7.2-14.7)
98.0%
(96.498.9)
4.6%
(2.6-8.0)
99.5%
Referr
al
32.0%
(98.499.9)
Wensentzen, Manuscript In Review
Triage of ASC-US and LSIL with
p16/Ki-67 dual stain (initial
cytology)
Populati
Endpoint
on
ASC-US
(n=298)
LSIL
(n=335)
CIN2+
(n=36)
Sensitivity
83.3%
(66.5-93.0)
CIN3+
(n=17)
82.4%
(55.8-95.3)
CIN2+
(n=38)
89.5%
(74.3-96.6)
CIN3+
(n=20)
90.0%
(66.9-98.2)
Specificity
PPV
NPV
55.3%
(49.161.4)
52.7%
(46.758.6)
44.1%
(38.450.0)
42.2%
(36.747.9)
20.4%
(14.428.0)
96.0%
(91.298.4)
9.5%
(5.5-15.8)
17.0%
(12.223.1)
9.0%
(5.6-14.1)
98.0%
(93.999.5)
97.0%
(92.199.0)
98.5%
(94.299.7)
Wensentzen, Manuscript In Review
Referr
al
49.3%
59.7%
Clinical performance of p16/Ki-67 in the
ATP cohort by study arm
Havrix
Endpoint
DS+
Sensitivity
Specificity
PPV
cNPV
CIN2+
22.9%
78.9%
82.3%
24.5%
1.8%
CIN3+
22.9%
84.6%
78.7%
9.1%
0.5%
Comparison
DS+
Sensitivity
Specificity
PPV
cNPV
CIN2+
11.8%
76.2%
91.5%
27.7%
1.1%
CIN3+
11.8%
83.3%
89.9%
16.4%
0.4%
Cervarix
Unpublished, NCI HPV Vaccine trial
Evaluation of p16/Ki-67 cytology in a
colposcopy referral population


High sensitivity for CIN2+, CIN3+
Referral to colposcopy could be reduced by
almost half
Wentzensen Clin Cancer Res 2012
Figure 1
HPV DNA Methylation
HPV31
P-value
Methylation
10-6
100%
10-5
80%
10-4
60%
10-3
40%
10-2
20%
10-1
100
URR
URR
URR
E6
E6
E7
E7
E1
E1
E1
E1
E2
E2
E2
E2
E2
E2
E2
E2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
0%
Methylation of HPV18, HPV31, and HPV45 genomes is associated
with cervical intraepithelial neoplasia grade 3.
Wentzensen et al, JNCI, 2012
Figure 2
HPV DNA Methylation
HPV18
P-value
Methylation
10-6
100%
10-5
80%
10-4
60%
10-3
40%
10-2
20%
10-1
100
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
URR
URR
URR
E6
E6
E7
E7
E7
E7
E7
E1
E1
E1
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
0%
Methylation of HPV18, HPV31, and HPV45 genomes is associated with
cervical intraepithelial neoplasia grade 3.
Wentzensen et al, JNCI, 2012
Figure 3
HPV DNA Methylation
HPV45
Methylation
P-value
-6
10
100%
10-5
80%
10-4
60%
10-3
40%
10-2
20%
10-1
100
URR
URR
URR
E1
E1
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
E2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
E6
E6
E6
E7
E7
E7
E7
0%
Methylation of HPV18, HPV31, and HPV45 genomes is associated with
cervical intraepithelial neoplasia grade 3.
Wentzensen et al, JNCI, 2012
Prevention of CIN2/3 By Age At Vaccination
100%
B
MS (5-Year Interval)
MS (10-Year Interval)
KPNC (CA) (5-Year Interval)
KPNC (CA) (10-Year Interval)
80%
70%
60%
50%
40%
30%
20%
10%
Age Group of HPV Vaccination
Castle, Gyn Onc, 2009
65-69
60-64
55-59
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
0%
10-14
Approximate % CIN2/3 Prevented
90%
Case-Control Study of Human
Papillomavirus and Oropharyngeal Cancer
100 cases and 200 controls
ISH on tissue blocks and PCR on fresh frozen
tissue and oral mucosal swabs
Results:



More than 25 vaginal or oral sex partners
yields a OR of >3
HPV 16 positivity = OR 14.6, seropositivity to
HPV 16 = OR 32
Attributable risk: 72% of tumor blocks and
64% of fresh tumor tissue specimens were
positive for HPV 16
D’Souza G et al, NEJM 2007; 356:1944
37,000 cases of oropharyngeal cancer and 8,000 deaths in 2012
in the US – Oral Cancer Foundation
Vaccine Conversations
 “But MY daughter doesn’t need to be vaccinated yet” Penis and
vagina intercourse is not required for transmission!

“I’ll just test women and find out who is HPV positive and vaccinate all of
the rest regardless of age.” HPV tests turn positive at 5,000 HPV
copies per ML. a negative HPV test doesn’t mean that you don’t
have HPV.
 “This is a cervical cancer vaccine. It is only needed by those
women who have promiscuous sex out of wedlock.” The lowest
credible estimate for HPV 16 exposure per partner is 20%. HPV 16
is a ubiquitous human mucosal carcinogen. Anal and penile and
oropharyngeal cancers are not limited to women.
 “Regular use of condoms prevents HPV transmission, so my
daughter/son won’t be needing the HPV vaccine.” NOT!!
The Next 24-36 Months
 “Interim Guidance” for primary HPV screening
will be published – small but measurable
decrement in sensitivity compared to cotesting;
Issues: intervals, age to start, triage of HPV pos
 P16/Ki 67 is validated as triage for HPV positive
women
 Can be used to reduce colposcopy rates by almost 50%
with minimal change in sensitivity
 This totally changes the balance of risk versus benefit of
screening on which 5 year recommendation was based
 Enables primary HPV screening without cytology triage
 Nonavalent vaccines will be FDA approved
 Discussion will start in earnest about stopping
screening under 25 – vaccinated women first
 Pushback against 5 year intervals
Summary
1. Neither cervical cytology nor HPV testing is foolproof
for identifying women at risk for cancer, but
2. HPV testing does a MUCH better job of identifying
women at risk for glandular cancers or AIS than
cytology
3. Better triage of HPV positive women is imminent and
will minimize unnecessary colposcopy, making current
anxiety about “harms” obsolete
Conclusions
1. The desired level of cancer protection should
influence individual screening practice
2. Evidence for benefits and harms is not sufficiently
robust to mandate a single choice as defining “quality
care”
3. Management by risk remains the guiding principle
4. Diagnostic tools on the horizon will dramatically
change screening practice and perception of harms of
screening (AGAIN! Sorry…)
5. If CIN2 and CIN2/3 are going to be treated in young
women, then abolition of screening under the age of
25 becomes (even) more important
6. HPV is a ubiquitous human mucosal carcinogen –
vaccination is for boys and girls, at ages 9-13.