cervical cancer screening - the final word? · associated with annual paps. • relative risk of...

10/9/2015

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Cervical Cancer Screening - The Final

Word?Mark Spitzer, MD

Professor of Obstetrics and GynecologyHofstra North Shore-LIJ School of Medicine

Medical DirectorCenter for Colposcopy

Lake Success, NY

CONFLICT OF INTEREST DISCLOSURE STATEMENT

Merck: Speakers Bureau, Advisory Board

Qiagen: Speakers Bureau

SABK: Stock ownership

Elsevier: Book Editor

Hologic: Consultant

Biop Medical: Medical Advisory Board

Illumigyn: Scientific Advisory Board

Objectives

Review of the 2012 cervical cancer screening guidelines

Review advantages and problems with using HPV for primary screening

Does the Pap test still have value as a screening test? The benefits of co-testing.

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Audience Response

In women between 30-65 years, how do you screen for cervical cancer in your practice?A. Annual Paps (with or without HPV reflex)

B. HPV testing every 3 years

C. Co-testing with HPV and Pap every 3 years

D. Co-testing with HPV and Pap every 5 years

E. Some other way

Optimal Screening Strategy Should maximize benefits by identifying only true cervical

cancer precursors and minimize harms by avoiding detection of transient HPV infection.

Cytology works yet identifies many transient benign conditions.1, 2

HPV testing is more sensitive, less specific and is better at forecasting who will develop CIN3+ over the next 5-15 years.3-5

Evidence-based guidelines must balance the tradeoffs of benefits and harms of screening

HPV testing increases detection (improving benefits) but only makes sense if you increase the screening interval

1. Castle, et al. Obstet Gynecol 2010;116(1):76-84. 2.ALTS Group. Am J Obstet Gynecol2003;188(6):1383-92. 3. Sherman, et al. JNCI 2003;95(1):46-52. 4. Dillner, et al. BMJ2008;337:a1754. 5. Schiffman, et al. Cancer Epid, Biomarkers & Prev 2011;20(7):1398-409.

Population ACOG1 ACS/ASCCP/ASCP2 USPSTF3

Women under age 21

Women should not bescreened regardless of theage of sexual initiation orthe presence of other behavior-related risk factors.

Level A recommendation

Women aged younger than 21 years should not be screened regardless of the age of sexual initiation or other risk factors.

Recommends against screening for cervical cancer in women younger than age 21 years.

Grade D recommendation

Women ages 21–29

Women should be tested withcervical cytology alone, andscreening should be performed every 3 years.

No HPV screening before age 30 (can be used as a reflex test for ASC-US Paps)


For women 21-29 years, screening with cytology every 3 years is recommended.


Recommends screening with cytology every 3 years.


Grade A recommendation

Women ages 30–65

Co-testing with cytology and HPV testing every 5 years is preferred or screening with cytology alone every 3 years is acceptable. Annual screening should not beperformed.Level A recommendation

Women aged 30-65 should be screened with cytology and HPV testing (‘cotesting’) every 5 years (preferred) or cytology alone every 3 years (acceptable).

Recommends screening with cytology every 3 years or screening with a combination of cytology and HPV testing every 5 years. (no preference)

Grade A recommendation

Women >65 or following hysterectomy for benign disease (with removal of the cervix)

Discontinue screening in women with adequate negative prior screening and no HG disease in the last 20 years. Screening should not be resumed for any reason (even new partner)Level A recommendation

Discontinue screening in women with adequate negative prior screening and no HG disease in the last 20 years. Screening should not be resumed for any reason (even new partner)

Recommends against screening in women with adequate negative prior screening and no HG disease.

Grade D recommendation

2012 Cervical Cancer Screening Guidelines Summary

1. ACOG Committee on Practice Bulletins -- Gynecology. (2012) ACOG Practice Bulletin no. 131: Screening for Cervical Cancer. Obstet. Gynecol. 120. 2. Saslow, D. et al. (2012) Am. J. Clin. Pathol.137,516. 3. Moyer, V.A. (2012) Ann. Intern. Med. Epub available at: http://www.annals.org/content/early/2012/03/14/0003-4819-156-12-201206190-00424.full.

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Population ACOG

Women ages 21–29




Women ages 30–65

Co-testing with cytology and HPV testing every 5 years is preferredScreening with cytology alone every 3 years is acceptable. Annual screening should not be performed.Level A recommendation


ACOG Committee on Practice Bulletins -- Gynecology. (2012) ACOG Practice Bulletin no. 131: Screening for Cervical Cancer. Obstet. Gynecol. 120.

Balancing Benefits and Harms in Young Women 21-29 years

Screening more often or with a better test (HPV) decreases the cancer risk slightly but the increases harm significantly (increased detection of transient lesions requiring more procedures and possible unnecessary treatments) (measured by increase in colposcopies)

Compared to screening q3 years: Screening annually –2x the colposcopies1, 2

Screening every 2 years –40% increase in colposcopies1-4

Screening every 5 years – fewest colposcopies, highest risk of cancer1, 2

The cancer risk went up >3x when the interval since the last negative Pap was more than 3 years but was unaffected by the number of negative Paps prior to that5

4. Sasieni P, et al Br J Cancer 2003;89(1):88-935. Miller, et al. Obstet Gynecol 2003;101(1):29-37.

1.Kulasingam, et al. AHRQ 2011.2. Stout NK, et al. Archives Int Med 2008;168(17):1881-93.Sasieni, et al. Br J Cancer 1996;73(8):1001-5.

Population ACOG

Women ages 21–29


No cotesting before age 30


Women ages 30–65

Co-testing with cytology and HPV testing every 5 years is preferredScreening with cytology alone every 3 years is acceptable. Annual screening should not be performed.Level A recommendation


ACOG Committee on Practice Bulletins -- Gynecology. (2012) ACOG Practice Bulletin no. 131: Screening for Cervical Cancer. Obstet. Gynecol. 120.

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Cu

mu

lati

ve in

cid

ence

of

CIN

3+(p

er 1

0,00

0)

Time since initial testing (mos.)

Dillner et al., BMJ, 2008

Why co-testing at 5 year intervals? CIN3+ Risk Following a Negative Test

7 European follow-up Studies 24,295 women

Why Not Just do Annual Paps?

Annual Paps are more likely to identify low-grade disease that is likely to regress spontaneously within a short time frame.

Even some CIN-2 will regress spontaneously.

With annual Pap tests, these lesions are likely to be discovered, setting the patient on the colposcopy treadmill and they may even be treated for lesions that would have regressed spontaneously had they not been discovered.

Cumulative risks of CIN2 or worse, CIN3 or worse and cancer among women aged 30-64 at Kaiser Permanente Northern California by enrollment Pap and HPV test result, 2003-2012 (adapted from Gage, JC et al. JNCI 2014)

Risk of CIN 2+ Following a Negative Screening Test at KPNC

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Audience Response

Have you incorporated HPV 16/18 testing as part of cervical cancer screening in your practice?A. Yes

B. No

Munoz N et al. Int J Cancer 2004;111:278-85. Castellsague X et al. J Natl Cancer Inst 2006;98:303-15.

Percent of Squamous and AdenoCa of Cervix Due to HPV 16 or 18

0

40

50

60

70

80

90

Squamous cell carcinoma Adenocarcinoma

70%

86%

100

10

20

3030%

14%

HPV 16 or 18

All other types

CIN 3+ Risk for HPV 16/18

Women who are Pap-/HPV+ (any type) have about a 4% risk of CIN-3+ at their initial visit. Does not meet the threshold for immediate colposcopy.

If HPV persists for 1 year, their risk goes up to about 10% and this meets the threshold for colposcopy.

In women who are HPV 16 positive at their initial visit have a 11.7% risk of CIN-3+ which meets the threshold for immediate colposcopy.

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Management of Women ≥ Age 30, who are Cytology Negative, but HPV Positive

Cytology Negativeand

HPV Negative

≥ASCor

HPV positive

Repeat Cotesting@ 1 year

Acceptable

Repeat cotesting@ 3 years

HPV DNA Typing

HPV 16 or 18 Positive

Colposcopy

Manage perASCCP Guideline

Acceptable

Repeat Cotesting@ 1 year

HPV 16 and 18 Negative

Manage perASCCP Guideline

© Copyright , 2013, American Society for Colposcopy and Cervical Pathology. All rights reserved.

What About HPV DNA Testing for Cervical Cancer Screening?

More sensitive and reproducible than the Pap test

More “upstream” in the carcinogenic process, thus enabling a longer safety margin for screening intervals

Assesses future risk (and not just the presence of current disease)

Can be automated, centralized, and be quality-checked for large specimen throughput

May be more cost-effective than cytology if deployed for high volume testing, such as in primary screening

A more logical choice for screening women vaccinated against HPV infection

Gage J et al, JNCI, 2014

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FDA Approves First Human Papillomavirus Test for Primary Cervical Cancer Screening

April 24, 2014

For women 25 and older

Roche Cobas HPV test detects 14 HR HPV types including a separate test for HPV 16 & 18.

ASCCP interim clinical guidance in Feb 2015

Primary Screening with HPV: ASCCP Clinical Guidance1

HPV screening can begin at age 25 (not before) Supporting evidence

In ATHENA2

30% of CIN 3+ cases were found in women age 25-29

37% of CIN 3+ cases were found in women age 30-39

Starting at age 25 (compared to age 30) increased colposcopies 2X but increased CIN 3+ detected by 54%

BUT it is unclear if identifying these CIN 3+ lesions would result in a meaningful reduction in cervical cancer

1. Huh WK, et al. Obstet Gynecol 2015;125(2):330-72. Wright TC, et al Gynecol Oncol 2015;136:189–197

Colposcopy

12 other hrHPV + Cytology

Routine Screening

Primary HPVScreening

Negative

Type 16/18 Positive

≥ASC-US

Follow up in 12 months

NILM

Primary HPV Screening Algorithm

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Cumulative risks of CIN3 or worse and cancer among women aged 30-64 at Kaiser Permanente Northern California by enrollment Pap and HPV test result, 2003-2012 (adapted from Gage, JC et al. JNCI 2014)

3-year cumulative incidence of CIN 3+ was lower in women following a negative HPV result (0.069%) than following a negative Pap test (0.19%) and lower than 5-year cotesting(0.11%)

Basis For HPV Primary Screening

• The widely accepted risk profile for cervical screening is the one associated with Annual Paps.

• Relative risk of cancer increases 1.3-4.7 fold with q3-year Paps• Limiting q3-year Pap to

women with a neg screening history or only after 3 negPaps does not help

• Annual Pap has the same risk as 3 years after a negative HPV test.

• However a negative co-test at 3 years is better.

So You Think You Have Clarity and Unanimity? A Minority Opinion1

1. Kinney W, Wright TC, Dinkelspeil HE, DeFrancesco M, Cox JT and Huh W. Obstet Gynecol 2015;125 (2):311-52. Gage, et al J Natl Cancer Inst. 2014 ;106(8):1-4

Limitations of HPV Primary Screening* Risk of false negative tests due to lack of

cellular control in some assays Even the assays with cellular controls do not

test for the presence of cervical cell

Missed opportunity to detect endometrial and ovarian cancer 28% of endometrial cancers and 10-30% of

ovarian cancers have malignant cells on Pap BUT there is no data that detection of these cells on cytology improves outcomes

*Issues raised by ACS/ASCCP 2012 guidelines

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How Did Primary HPV Screening do so Well Compared to Co-testing in Athena?

Wright TC, et al GynecolOncol 2015;136:189–197

• Cytology Strategy -Cytology with reflex HPV testing• Hybrid Strategy –Women 25-29 got cytology with HPV reflex testing only, Women >30 got co-testing. Positive HPV was repeated in 1 year (nogenotyping).• HPV primary –Screening with HPV testing and genotyping

Athena - Comparing Apples to Oranges

Wright TC, et al Gynecol Oncol 2015;136:189–197

Benefits of Cotesting versus HPV Primary Screening*

Category No. CIN3/AIS SCC AdenoCa All CAs

All Women

331,818 747 49 27 87

Pap (-) 319,177 354(47%)

15 (31%)

23 (85%)

43 (49%)

HPV (-) 315,061 123 (16%)

18 (37%)

6 (22%)

27 (31%)

Cotest (-) 309,969 96 (13%)

10 (20%)

6 (22%)

18 (21%)

Katki, et al 2011 Lancet Oncology Longitudinal data from Kaiser of N California

27 additional CIN3/AIS 9 additional Cancers

Number of Cases Detected in Women with Negative Tests

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Quest Study: Retrospective Analysis of Their Screening Experience

Retrospective study of cervical cancer screening: Over 8.6 million women2

256,648 biopsies 526 cases of cervical cancer (more than double KPNC)

Women aged 30-65 were evaluated with both Pap + HPV testing. Histology results within 1 year of initial screen were paired to screening result and analyzed based on performance of: Pap Alone HPV Alone Pap+HPV cotesting

1. Blatt A, et al. Comparison of Cervical Cancer Screening Results Among 256,648 Women in Multiple Clinical Practices. Cancer Cytopathology2015 May;123(5):282-8. (Study included ThinPrep®,SurePath® and Hybrid Capture® 2 High-Risk HPV DNA test™)2. Quest Diagnostics press release April 14, 2015 http://ir.questdiagnostics.com/phoenix.zhtml?c=82068&p=irol-news&nyo=0 accessed June 2015

18.6%

12.2%

5.5%

0.0% 5.0% 10.0% 15.0% 20.0%

Scr

een

ing

Str

ateg

y

HPV Alone

Percentage of the 526 confirmed cases of cervical cancer missed by each screening test

Quest Study: Detection of Invasive Cervical Cancer by Screening Test1

1. Blatt et al. Comparison of Cervical Cancer Screening Results Among 256,648 Women in Multiple Clinical Practices. Cancer Cytopathology 2015 May;123(5):282-8.

Pap + HPV

Pap Alone

% Missed Cancer

Quest Study: Detection of CIN3+ by Screening Test1

6.0%

8.7%

1.2%

0.0% 2.0% 4.0% 6.0% 8.0% 10.0%

Sc

reen

ing

Str

ateg

y

HPV Alone

% Missed CIN3+

Pap + HPV

Pap Alone

1. Blatt et al. Comparison of Cervical Cancer Screening Results Among 256,648 Women in Multiple Clinical Practices. Cancer Cytopathology 2015 May;123(5):282-8.

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Cumulative risks of CIN2 or worse, CIN3 or worse and cancer among women aged 30-64 at Kaiser Permanente Northern California by enrollment Pap and HPV test result, 2003-2012 (adapted from Gage, JC et al. JNCI 2014)

Risk of CIN 2+ Following a Negative Screening Test at KPNC

5 Year Screening Intervals: The Harms For every 1,000 US women age 30-64, increasing

the cotesting interval from 3 to 5 years results in: 2.71 cases of cervical cancer (195,000 over their lifetime)

0.61 cervical cancer deaths (44,000 over their lifetime)

249 extra colposcopies

Changing cotesting from 5 to 3 years would “cost” 92 extra colpos and 3.2 extra LEEPs for every cancer case prevented and 409 extra colpos and 14.3 extra LEEPs for every preventable death.

WOULD YOU MAKE THAT TRADE?

Is a 5-year interval really safe without a computerized call-recall system?

Kinney W, Wright TC, Dinkelspeil HE, DeFrancesco M, Cox JT and Huh W. Obstet Gynecol 2015;125 (2):311-5

What Do Your Patients Think?

Survey of 551 women aged 32-62 in the HPV in Perimenopause study 55.6% were aware that guidelines had

changed, yet 74.1% still believed women should be screened annually.

If recommended by their doctor, 68.4% were willing to extend the screening interval to 3 years, but only 25.2% would extend to 5 years

60.7% had a strong preference for Pap testing and 41.4% had at least moderate concern for HPV primary screening

Silver MI, et al. Obstet Gynecol 2015;125 (2):317-29

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Summary Cytology, HPV testing and cotesting are all

acceptable screening options Annual cytology and q3 year HPV testing

have approx. equal sensitivity which is a little higher than q5 cotesting but q3 cotesting is the most sensitive. However the more frequently you test the

more minor grade lesions you are likely to find (harm) Which is the best screening strategy for your

patients?

The Jury is Still Out

cervical cancer screening - the final word? · associated with annual paps. • relative risk of...

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