56

th

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

HPV Prevalence and Cervical Cancer - Incidence by Age

1,2 30 25 20 15 10 5 0 30 25 20 15-19 20-24 25-29 30-34 35-39 Age (Years) 40-44 45-49 50-54 15 10 5 0 1. Sellors et al. CMAJ . 2000;163:503.

2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.

New Infections Go Away Quickly!

HPV types 16 52 51 62 31 89 18 53 56 61 average ALTS 0 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 0.67

Avg HPV Disappearance 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

Odds Ratios Odds Ratios Odds Ratios Ever Abnl Pap 2 Neg Paps 1 Year 1.0

1.0

1.0

2 Year 1.7

P=.013 vs 1

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) 1.43/100,000 Two years (19-30 months) 4.24/100,000



Three years (31-42 months) 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 Eddy DM, 1980 q Year 85.0% q 2 Years q 3 years 82.0% 78.0% Rate q year: Rate q 3 year 1:1.5

IARC (Day NE et al), 1986 Eddy DM, 1987 AHCPR, 1999 Hutchinson ML, 2000 93.3% 96.3% 96.4% 95.2% 92.5% 94.0% 89.9% 88.3% 91.4% 91.8% 83.2% 82.0% 1:1.3

1:2.2

1:4.7

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)

Method

Cytology at 3 years vs Cotesting at 3 and 5 years intervals

Cancers Deaths 758 8.50

1.55

Q3 Year Cytol Q5 Year Cotest Q3 Year Cotest 626 825 7.07

4.73

1.29

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 - No preference

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 Cotest q5 575 Cotest q3 825 Difference 250 CIN2,3 84 93 9 Cancer 7.44

4.73

2.71

Death Ca 1.35

0.74

0.61

• If we move from q3 year cotesting to q5 year cotesting • An additional 7.44-4.73/1000 women, = get cervical cancer during her lifetime 1 additional female member in 369 who screens as recommended will • • An additional 1.35-0.74/1000 women = cervical cancer 1 additional female member in 1,639 who screens as recommended will die of 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)   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%;  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.”

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 HPV negative and cotest negative risks at the same time point are very close.

p=.03

p=.11

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 HPV negative Pap-negative ASC-US HPV positive LSIL+ Pap-negative ASC-US LSIL+ 407 50 4 22 79 33 219 100.0

12.3

1.0

5.4

19.4

8.1

53.8

Slide courtesy of Dr. Mark Schiffman, NCI

p16: A marker of transforming HPV infections

o o Adjudicated pathology Bergeron 2010 AJCP LAST guidelines: Adjudication of CIN2 Darragh 2012 JLGTD o o p16/Ki-67 dual stain 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

Total % DS+ No colposcopy

728 32%

No CIN

397 44% NTCC (Italy)

Total % p16 pos No colposcopy No CIN

629 241 36% 39%

CIN1

437 55%

CIN1

175 53%

CIN2

53 85%

CIN2

50 86%

CIN3+ 81 90% Total

1696 45.1%

CIN3+ 42 91% Total

1137 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

p16 ki67, Intial Cyt

NILM

(n=875)

Endpoint Sensitivity Specificity

CIN2+ (n=41) CIN3+ (n=16) 70.7% (54.3-83.4) 81.3% (53.7-95.0) 69.9% (66.6 73.0) 68.9% (65.7 72.0)

PPV

10.4% (7.2-14.7) 4.6% (2.6-8.0)

NPV

98.0% (96.4 98.9)

99.5%

(98.4 99.9)

Referr al

32.0%

Wensentzen, Manuscript In Review

Triage of ASC-US and LSIL with p16/Ki-67 dual stain (initial cytology)

Populati on Endpoint Sensitivity Specificity PPV NPV Referr al ASC-US

(n=298)

LSIL

(n=335) CIN2+ (n=36) CIN3+ (n=17) CIN2+ (n=38) CIN3+ (n=20) 83.3% (66.5-93.0) 82.4% (55.8-95.3) 89.5% (74.3-96.6) 90.0% (66.9-98.2) 55.3% (49.1 61.4) 52.7% (46.7 58.6) 44.1% (38.4 50.0) 42.2% (36.7 47.9) 20.4% (14.4 28.0) 9.5% (5.5-15.8) 17.0% (12.2 23.1) 9.0% (5.6-14.1) 96.0% (91.2 98.4)

98.0%

(93.9 99.5) 97.0% (92.1 99.0)

98.5%

(94.2 99.7) 49.3% 59.7%

Wensentzen, Manuscript In Review

Clinical performance of p16/Ki-67 in the ATP cohort by study arm

Havrix

Endpoint

CIN2+ CIN3+

DS+

22.9% 22.9%

Sensitivity

78.9% 84.6%

Specificity

82.3% 78.7%

PPV

24.5% 9.1%

cNPV

1.8% 0.5% Cervarix

Comparison

CIN2+ CIN3+

DS+

11.8% 11.8%

Sensitivity

76.2% 83.3%

Specificity

91.5% 89.9%

PPV

27.7% 16.4%

cNPV

1.1% 0.4%

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 10 -6

P-value

10 -5 10 -4 10 -3 10 -2 10 -1 10 0

HPV DNA Methylation HPV31 Methylation

100% 80% 60% 40% 20% 0%

Methylation of HPV18, HPV31, and HPV45 genomes is associated with cervical intraepithelial neoplasia grade 3. Wentzensen et al, JNCI, 2012

Figure 2

P-value

10 -6 10 -5 10 -4 10 -3 10 -2 10 -1 10 0

HPV DNA Methylation HPV18 Methylation

100% 80% 60% 40% 20% 0%

Methylation of HPV18, HPV31, and HPV45 genomes is associated with cervical intraepithelial neoplasia grade 3. Wentzensen et al, JNCI, 2012

Figure 3

P-value

10 -6 10 -5 10 -4 10 -3 10 -2 10 -1 10 0

HPV DNA Methylation HPV45 Methylation

100% 80% 60% 40% 20% 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% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% B MS (5-Year Interval) MS (10-Year Interval) KPNC (CA) (5-Year Interval) KPNC (CA) (10-Year Interval)

Age Group of HPV Vaccination Castle, Gyn Onc, 2009

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” vagina intercourse is not required for transmission!

Penis and “I’ll just test women and find out who is HPV positive and vaccinate all of the rest regardless of age.” copies per ML. a negative HPV test doesn’t mean that you don’t have HPV.

HPV tests turn positive at 5,000 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

1.

2.

3.

Summary

Neither cervical cytology nor HPV testing is foolproof for identifying women at risk for cancer, but HPV testing does a MUCH better job of identifying women at risk for glandular cancers or AIS than cytology Better triage of HPV positive women is imminent and will minimize unnecessary colposcopy, making current anxiety about “harms” obsolete

1.

2.

3.

4.

5.

6.

Conclusions

The desired level of cancer protection should influence individual screening practice Evidence for benefits and harms is not sufficiently robust to mandate a single choice as defining “quality care” Management by risk remains the guiding principle Diagnostic tools on the horizon will dramatically change screening practice and perception of harms of screening (AGAIN! Sorry…) 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 HPV is a ubiquitous human mucosal carcinogen – vaccination is for boys and girls, at ages 9-13.