56 th Annual Ob-Gyn Update New Cervical Cancer Screening Recommendations Management of Abnormal Results 56 th Annual Ob-Gyn Update New Cervical Cancer Screening Recommendations Management of Abnormal Results Walter Kinney M.D. Division of Gynecologic Oncology The Permanente Medical Group Clinical Professor of Ob/Gyn, U.C. Davis Sacramento, California

Cervical Screening Guidelines Timeline: Fall 2011 –USPSTF declined to recommend HPV & Pap cotesting Spring 2012 –USPSTF, ACS, and ASCCP recommend cotesting for screening women age 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

ASCCP/KP 2012: Why bother? 1) 1)ASCCP just approved 5 year screening! The phrase “return to routine screening” in the 2007 Guidelines now means not annual but 5 years later! Who is at low enough risk to go to 5 years after an abnormal? 2) 2)Cotesting is now recommended, so the results that providers start with will be fundamentally different. Examples: HPV negative HSIL or ASC-H or LSIL 3) 3)Recommendations are too complicated! Nobody knows them, not even the “experts”

ASCCP 2012 Goals and Principles   Goals   Define management of abnormals that did not exist before cotesting   Define which combinations of test results after an abnormal permitted “safe” return to routine, i.e. 5 year screening   Reflect new data on management of specific results (ASC-US and LSIL < 25; ECC CIN1 for example)   Principles   Management by risk – similar risk means similar management   Immediate risk determines immediate management; risk over time determines followup interval

ASCCP 2012 Principles and Methods   Principles (continued)   High or low risk population doesn’t matter: Provide management consistent with what you are providing currently for results with like risks   Methods   Examination of cotest results and histology outcomes over time in 1.4 million cotested women followed up to 9 years   Risk similar to risks found after negative cytology at 3 years or negative cotesting at 5 years are considered acceptable   Outcome measures: Use what you have. Anything is better than nothing, which is what we have had up to this point. Cancer if you have it, CIN3+ if not, even CIN2+. Real EBM – use the best data that you have.

Castle PE et al, AJOG 2007

Pap Risks Over Time – Not Stratified by HPV Status Katki et al, JLGTD, 2013

High Grade Pap Risks by HPV Status Katki et al, JLGTD, 2013

Monograph contents 1. Using risk to develop guidelines 2. HPV & Equivocal Paps 3. HPV & Low-grade Paps 4. HPV & High-grade Paps 5. HPV & negative Paps 6. Risks for women under age Risks after non-precancer biopsies 8. Risks following treatment for precancer Katki et al, J Low Genit Tract Dis, 2013

ASCCP What We Learned   Risks are not evenly distributed. Thankfully they fall into a few bands that facilitate assigning management. Nothing is perfect – risks are not identical, and some judgment is unavoidable about what is a clinically meaningful difference.   Risk order is almost always similar between immediate and long term risks. Hence 5 year risk was the default comparator   Endpoints matter more than we wanted them to. Cancer is the only ideal endpoint for screening schemes. CIN3+ is right for comparing test characteristics but not ideal for screening plans   Cotesting is better – by a LOT – for followup. Totally different from screening and totally counter- intuitive. Neg cotest = longer interval.

ASCCP Example of Pap vs HPV vs Cotest Risks   In every clinical circumstance, negative cotesting provides greater reassurance and thus longer followup intervals than negative cytology alone or negative HPV testing alone. Examples:   After a minimal abnormality (Pap negative HPV positive x 2, ASC-US or LSIL) followed by a colposcopy with negative or CIN1 histology, women with a single negative cotest at 1 year had a 5 year risk of CIN2+ of 1.1%, versus 1.8% with 2 negative HPV tests or 4.0% with 2 negative Paps.   Women with ASC-H or HSIL followed by a negative or CIN1 colposcopy and a negative cotest had a 5 year risk of CIN2+ of 2.2% versus 4.4% after a negative HPV test and 7.0% after a negative Pap

“Lesser abnormalities”: HPV+/ASCUS or LSIL or Pap- HPV x2 “Greater abnormalities”: HSIL or ASC-H or AGC <CIN2: normal, metaplasia, CIN1 1 negative cotest over 1 year – retest in 3 years 2 negative cotests over 2 years – retest in 5 years 2 negative cotests over 2 years – retest in 3 years Untreated CIN2 or CIN2/3 2 negative Paps and colposcopies over 1 year (ASCCP 2006) AND one negative cotest in another 1 year – retest in 3 years Treated CIN2, CIN2/3, CIN3, AIS 2 negative cotests over 2 years – retest in 3 years Summary of Followup Recommendations 25+

ASCCP 2012 What we got wrong and how 2012 recs for “routine screening” after ASC- US(-) 2012 recs for “routine screening” after ASC- US(-) based on 5 year risk of CIN3+ with HPV(-) alone vs HPV(-)/any positive Pap (0.16% vs 0.17%)based on 5 year risk of CIN3+ with HPV(-) alone vs HPV(-)/any positive Pap (0.16% vs 0.17%) Risk similar enough to justify routine rescreening intervalRisk similar enough to justify routine rescreening interval Population (300,000 women, 80 cancers) not large enough to evaluate risk for ASC-US(-) separately or for cancer endpointPopulation (300,000 women, 80 cancers) not large enough to evaluate risk for ASC-US(-) separately or for cancer endpoint Expanded data set of 1.4 million women allowed for comparing ASC-US(-) risk to benchmarksExpanded data set of 1.4 million women allowed for comparing ASC-US(-) risk to benchmarks 3 year return with Pap(-) alone 3 year return with Pap(-) alone 5 year return with HPV(-)/Pap(-) 5 year return with HPV(-)/Pap(-) 2011 study, 900,000+ women risk of CIN3+ at 5 years HPV(-) vs HPV(-) vs Pap(-) screening results. Because the risk of CIN3+ or cancer was minimally different between HPV(-) and HPV(-)Pap(-); an HPV(- )ASCUS was treated similarly to the above, with routine return screening recs Expanded data set of over 1.4 million women risk of CIN3+ with ASC-US HPV negative approximates that of the risk after 5 years of negative cytology alone (0.43% vs 0.26%) Katki, HA et al; 2011

ASCCP 2012 Fix for ASC-US (-) with more data 1.4 million women and 388 cancers instead of 300,000 women and 80 cancers permits examination of ASC-US (-) risks specifically including cancer risk1.4 million women and 388 cancers instead of 300,000 women and 80 cancers permits examination of ASC-US (-) risks specifically including cancer risk Risk at 5 years of CIN3+ with an ASC-US(-) is similar to that of a negative Pap alone at 3 years (0.43% vs 0.26%); cancer risk at 5 years was also similar to that of a negative Pap at 3 yearsRisk at 5 years of CIN3+ with an ASC-US(-) is similar to that of a negative Pap alone at 3 years (0.43% vs 0.26%); cancer risk at 5 years was also similar to that of a negative Pap at 3 years But risk of cancer at 5 years was 5 times greater with ASC-US(-) than with Pap(-)HPV(-) (0.050% vs 0.011%)But risk of cancer at 5 years was 5 times greater with ASC-US(-) than with Pap(-)HPV(-) (0.050% vs 0.011%) With recommendations of rescreen with Pap(-) alone at 3 years the updated 2013 recommendations are for rescreening ASC-US(-) at 3 year intervalsWith recommendations of rescreen with Pap(-) alone at 3 years the updated 2013 recommendations are for rescreening ASC-US(-) at 3 year intervals Massad LS et al

ASCCP 2012 What was totally made up Any recommendation for return to 5 year screening for any abnormality greater than “lesser abnormalities” (ASC-US, LSIL, Pap negative HPV positive times 2), followed by any biopsy <CIN2Any recommendation for return to 5 year screening for any abnormality greater than “lesser abnormalities” (ASC-US, LSIL, Pap negative HPV positive times 2), followed by any biopsy <CIN2 No path to 5 year rescreening with low enough risk could be discerned from the available data for any abnormality > ASC-US, LSIL or Pap negative HPV positive OR any biopsy >CIN1No path to 5 year rescreening with low enough risk could be discerned from the available data for any abnormality > ASC-US, LSIL or Pap negative HPV positive OR any biopsy >CIN1 Everything else is “expert opinion”Everything else is “expert opinion”

Quiz 1.What is the clinical management for a.Pap negative HPV positive b.ASC-US HPV negative? c.LSIL HPV negative? d.ASC-H HPV negative? e.HSIL HPV negative? f.AGC-NOS HPV negative? g.AGC-NEO HPV negative? 2.What does it take to get back to 3 year screening after a <=CIN1 colpo and a.Pap negative HPV positive x 2 b.ASC-US HPV positive? c.LSIL HPV positive? d.ASC-H HPV negative? e.HSIL HPV negative? f.AGC-NOS HPV negative? g.AGC-NEO HPV negative?

ASCCP Algorithms Mobile App The ASCCP App is a historic step forward for teaching and communicating guidelines The ASCCP App is a historic step forward for teaching and communicating guidelines Can the App improve Can the App improve Understanding of the evidence underlying a guideline?Understanding of the evidence underlying a guideline? Acceptance of guidelines?Acceptance of guidelines? Could presenting the logic of “Equal Management of Equal Risks” help? Could presenting the logic of “Equal Management of Equal Risks” help? 5-yr CIN3+ risk: 0.08% 0.26% 2.6% 5.2% 25% HPV-/NILM NILM ASC-US LSIL AGC/ASC-H/HSIL Management: 5-year 3-year 1-year Colposcopy Colposcopy Risk for this result: 6.8%

A “Risk Bar” for the App “Equal Management of Equal Risks” logic must be obviously and immediately apparent “Equal Management of Equal Risks” logic must be obviously and immediately apparent The risk calculation underlying the recommendation is displayed on the continuum The risk calculation underlying the recommendation is displayed on the continuum “Why is the recommendation for HPV-negative/ASC- US a 3-year return?” “Why is the recommendation for HPV-negative/ASC- US a 3-year return?” “Oh, the data say it’s just like a negative Pap. I get it.”“Oh, the data say it’s just like a negative Pap. I get it.” 5-year CIN3+ risk: 0.08% 0.26% 2.6% 5.2% 25% Management-defining Result: HPV-/Pap-Pap- ASC-US LSIL AGC/ASC-H/HSIL Management: 5-year return 3-year return 1-year return Colposcopy Colposcopy Risk for this result: 0.43%

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

Primary Screening with HPV Only FDA Approved April 2014  April 2014: US FDA approved a single HPV assay (Roche) for primary screening among women age 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 followed by cotesting at 3 year intervals 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)

Why Is It time For Screening Cytology To Go Away? HPV Plus Cytology “Cotesting” HPV First, p16/Ki67 Second Cytology Manual Both Automated Cytology Equivocal Result Dichotomous Cytology Irreproducible Reproducible Sensitivity = Less Specific More Specific More Colpo Less Colpo

ASCCP vs KPNC and Conduct of Colposcopy   The recommendations are a LOT closer than we were in Where there are differences we are (with rare exceptions) slightly more aggressive and those differences result from one of 3 issues   We concur with the literature that “colposcopic impression” is completely irreproducible and of no clinical value. If we take someone to colposcopy we want to know what the histologic answer is – every patient, every time.   We have had access to more of our data for longer and in greater granularity   The committee writing this document felt that a different balance of risk of cancer versus risk of overscreening was more advantageous to the women members of KPNC

Interobserver Agreement in the Evaluation of Digitized Cervical Images Conclusions  “The agreement among the whole group of evaluators was poor.”  “Colposcopic diagnosis using static images is poorly reproducible and might reflect similar problems in clinical practice.” Jeronimo J et al for the NIH-ASCCP Research Group, Obstet Gynecol 2007;110:833

I II IV III

METHOD OF DIAGNOSING WOMEN WITH CIN 2 OR WORSE (SPOCCS II) Colpo biopsy 208/364 (57.1%) Colpo biopsy + 2 o’clock 256/364 (70.3%) Colpo biopsy + 2, 4 o’clock 297/364 (81.6%) Colpo biopsy + 2, 4, 8 o’clock 329/364 (90.4%) Colpo biopsy + 2, 4, 8, 10 o’clock 344/364 (94.5%) Colpo biopsy + 2, 4, 8, 10 + ECC 364/364 (100%) 57.1% vs. 70.3% vs. 81.6% vs. 90.9% vs. 94.5% vs. 100%, Chi- Square = 326, df=5, P<.001 Pretorius et al, Int J Ca, 2007

The accuracy of colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials Stoler MH et al, Int J Cancer, 2010 NegCIN1CIN2 CIN3/AI S Neg CIN CIN Total Colpo Directed Biopsy LEEP Histology CIN2+ called CIN1 or Neg 128/226 (57%) CIN3/AIS called CIN1 or Neg 71/145 (49%)

You can’t only do the full biopsy complement on women with the worst Paps: PROPORTION OF CIN 2 OR WORSE AS A FUNCTION OF CERVICAL CYTOLOGY Pretorius RG. et al. J Reprod Med 2002;47:290-6 CYTOLOGY CYTOLOGY CIN 2 OR WORSE CIN 2 OR WORSE ASC-US/HPV POS 44/159 (27.7%) 44/159 (27.7%) ASC-H OR LSIL 72/159 (45.3%) 72/159 (45.3%) HSIL, CANCER, AGUS, ENDO OUT OF PHASE 43/159 (27.0%) 43/159 (27.0%)

You can’t only do the full biopsy complement on women with a bad looking cervix COLPOSCOPIC IMPRESSION OF WOMEN WITH ECTOCERVICAL CIN 2 OR WORSE SCPMG-FONTANA, 4/96 – 11/99 Pretorius RG et. al. J Reprod Med 2001;46:724-8 NORMAL NORMAL HPV OR CIN 1 HPV OR CIN 1 CIN 2 OR CIN 2 OR WORSE WORSE 146/642 (22.7%) 359/642 (55.9%) 137/642 (21.3%)

Pretorius RG et al, JLGTD, 2011

Changes for 2012 Changes for 2012   Age 21-24: No colposcopy for ASC-US and LSIL KPNC publication drives the national recommendations No colpo for ASC HPV positive means ASC-US triage not needed for ages Goal: reduce screening now in a population that does not benefit; eventually start screening at 25 No colposcopy for LSIL HPV negative at any age KPNC publication drives national recommendations Goal: save colposcopy for women more likely to benefit No colposcopy for a single Pap negative HPV positive even if previous abnormal KPSC unpublished data Clinical history can’t identify women at risk unless their previous abnormality was not evaluated Goal: abandon an unsuccessful triage strategy; save colposcopy for women more likely to benefit

Changes for 2012 Changes for 2012   No more annual returns for ASC-US HPV negative KPNC data drives the national recommendations (again)KPNC data drives the national recommendations (again) Note that risk does not permit a 5 year return!Note that risk does not permit a 5 year return! For access this is HUGEFor access this is HUGE 300,000 ASC-US = 12,000. 2/3 HPV negative means that there are 8,000 followup appointments in a year that we are no longer going to do, plus all of the followup that those tests would generate 300,000 ASC-US = 12,000. 2/3 HPV negative means that there are 8,000 followup appointments in a year that we are no longer going to do, plus all of the followup that those tests would generate We redid the cancer risks ourselves to make 100% sure that this was OKWe redid the cancer risks ourselves to make 100% sure that this was OK ECC CIN1 no longer mandates excision Dr. Littell drives the national recommendations (again)Dr. Littell drives the national recommendations (again)

Cotesting 25-65: Rationale 1.There is invasive cervical cancer in women age Risk for women age in the SEER registry is 5.1/100,000/year, similar to the overall risk in KPNC of 5/100,000/year. 2.Detection of CIN3 and AIS are the goals of screening. CIN3 incidence is BIG in the late 20s 3.To make any progress against adenocarcinoma and adenosquamous carcinoma, HPV testing will have to be included in screening. 4.Simplification of Guidelines aids compliance 5.All of the current management recommendations for abnormals are and 25+, not and Screening is going to stop under 25 7.ASC-US triage “store and sort” will no longer be necessary 8.Cotesting permits enhanced cytology QC 9.Cytology negative HPV positive rates in women in KPNC are 6.1%, versus 10.1% for women Cotesting will not lead to overuse of LEEP if CIN2 and CIN2/3 are not lumped together with CIN3 as “histologic HSIL”

KP Regional Lab 2012 CIN3 By Age AGEPATIENTSCIN III% CIN III , % , % , % , % Kinney et al, IPV Abstract, 2014

ATHENA CIN3+ % of all CIN3+ diagnosed Wright, AJOG, 2011 % of all CIN3+ Pap Neg HPV Pos Huh, Abstract, IPV, 2011

Cotesting 25-65: Rationale 1.There is invasive cervical cancer in women age Risk for women age in the SEER registry is 5.1/100,000/year, similar to the overall risk in KPNC of 5/100,000/year. 2.Detection of CIN3 and AIS are the goals of screening. CIN3 incidence is BIG in the late 20s 3.To make any progress against adenocarcinoma and adenosquamous carcinoma, HPV testing will have to be included in screening. 4.Simplification of Guidelines aids compliance 5.All of the current management recommendations for abnormals are and 25+, not and Screening is going to stop under 25 7.ASC-US triage “store and sort” will no longer be necessary 8.Cotesting permits enhanced cytology QC 9.Cytology negative HPV positive rates in women in KPNC are 6.1%, versus 10.1% for women Cotesting will not lead to overuse of LEEP if CIN2 and CIN2/3 are not lumped together with CIN3 as “histologic HSIL”

Cotest Result SquamousNonsquamous Total Number of Women Cotest (72%) 96 (71%) Pap + HPV- Pap + HPV- 9 2 (3%) 2 (3%) Pap- HPV+ Pap- HPV (44%) 28 (44%) Pap+ HPV+ Pap+ HPV (25%) 16 (25%) Cotest (28%) 40 (29%) Total Cancer Antecedents: 136 Women Cotested 6 to 42 Months Prior to Diagnosis Dinkelspiel et al, WAGO Abstract, 2011

AIS Antecedents: 172 Women Cotested 6 to 42 Months Prior to Diagnosis Dinkelspiel et al, SGO Abstract, 2012 Pap neg HPV pos is by far the most important screening diagnosis prior to AIS Screening Results First cotest Months Prior to AIS Cotests + Pap+ HPV-8 (4.7%) Pap- HPV+ 91 (52.9%) Pap+ HPV+53 (30.8%) Cotests -20 (11.6%) Total172

CIN 3/AIS by year in facilities served continuously by the Regional Lab CIN 3/AIS by year in facilities served continuously by the Regional Lab Continuous Facilities CIN3AIS KPNC Unpublished, 2013

Cotesting 25-65: Rationale 1.There is invasive cervical cancer in women age Risk for women age in the SEER registry is 5.1/100,000/year, similar to the overall risk in KPNC of 5/100,000/year. 2.Detection of CIN3 and AIS are the goals of screening. CIN3 incidence is BIG in the late 20s 3.To make any progress against adenocarcinoma and adenosquamous carcinoma, HPV testing will have to be included in screening. 4.Simplification of Guidelines aids compliance 5.All of the current management recommendations for abnormals are and 25+, not and Screening is going to stop under 25 7.ASC-US triage “store and sort” will no longer be necessary 8.Cotesting permits enhanced cytology QC 9.Cytology negative HPV positive rates in women in KPNC are 6.1%, versus 10.1% for women Cotesting will not lead to overuse of LEEP if CIN2 and CIN2/3 are not lumped together with CIN3 as “histologic HSIL”

Cancer Rate Trend Among Previously Screened Women - Effects of “screening with prejudice” and QC review of all Pap-HPV+ KPNC 2014, Unpublished Exclusions: Unscreened women and women screened in both Regional and Facility Labs

Cotesting 25-65: Rationale 1.There is invasive cervical cancer in women age Risk for women age in the SEER registry is 5.1/100,000/year, similar to the overall risk in KPNC of 5/100,000/year. 2.Detection of CIN3 and AIS are the goals of screening. CIN3 incidence is BIG in the late 20s 3.To make any progress against adenocarcinoma and adenosquamous carcinoma, HPV testing will have to be included in screening. 4.Simplification of Guidelines aids compliance 5.All of the current management recommendations for abnormals are and 25+, not and Screening is going to stop under 25 7.ASC-US triage “store and sort” will no longer be necessary 8.Cotesting permits enhanced cytology QC 9.Cytology negative HPV positive rates in women in KPNC are 6.1%, versus 10.1% for women Cotesting will not lead to overuse of LEEP if CIN2 and CIN2/3 are not lumped together with CIN3 as “histologic HSIL”

Risk of Untreated CIN2 and CIN2/3 KPNC ,659 CIN2 and CIN2/3 age followed with cytology without excision for an average of 25(CIN2) to 30 (CIN2/3) months (minimum 18), with an average of Paps or biopsies during followup1,659 CIN2 and CIN2/3 age followed with cytology without excision for an average of 25(CIN2) to 30 (CIN2/3) months (minimum 18), with an average of Paps or biopsies during followup Risk of invasive cancer was – predictably - proportional to grade and age, but low in all groupsRisk of invasive cancer was – predictably - proportional to grade and age, but low in all groups year old21-24 year old CIN2: 0/559(0%; CI %) CIN2: 0/559(0%; CI %) CIN2/3: 0/170(0%; CI %) CIN2/3: 0/170(0%; CI %) year old25-29 year old CIN2: 1/667(0.15%; CI 0.006%-0.71%) CIN2: 1/667(0.15%; CI 0.006%-0.71%) CIN2/3: 1/263(0.38%; CI 0.016%-1.8%) CIN2/3: 1/263(0.38%; CI 0.016%-1.8%) Ladwig-Scott et al, WAGO Abstract, 2013

Rate of and Risks for Regression of CIN2 in Adolescents and Young Women 2008 interval analysis shown, full data in Moscicki AB et al, Obstet Gynecol 2010 December; 116(6): KPNC Members Age % spontaneous clearance by year 1, 63% by year 2 and 68% by year 3 15% progression to CIN3 by year 3; no cancer

The Lower Anogenital Squamous Terminology (LAST) Project   “Consensus” conference held in March of 2012   Recommended that histology be described as   LSIL = CIN1   HSIL = CIN2, CIN2/3 and CIN3   p16 is to be used to assign CIN2 to LSIL or HSIL. “This will result in increased specificity of diagnosing HSIL.”   NO data concerning risk for the new diagnoses was presented   Use of –SIL terminology alone was voted down.   Revised motion permits the use of -IN terminology in parentheses passed (barely) “during the transition”   In place of information concerning risk, patient management is to go forward under the new system based on “clinical judgment”, placing the risk of adverse outcomes squarely on the clinician. (Waxman et al Obstet Gynecol)   Diagnostic irreproducibility will no doubt be reduced.   Whom does this benefit? Waxman et al, Obstet Gynecol 2012;120:

Summary 1.Cancer incidence can be decreased and outcomes can be improved 2.Like heart disease, understanding the causes is not enough 3.It takes time and resources and will and focus and a system approach 4.For cervical cancer prevention in unvaccinated women the system includes a)Increasing screening rates with outreach and the call center and inreach and tracking rates by facility b)Inclusion of HPV testing in screening c)“Screening with prejudice” if you are doing cotesting – show the techs the HPV and Focal Point results d)Tracking of abnormals e)Improved colposcopy sensitivity – 4 quadrant biopsy plus ECC with 2mm punches f)Followup of women with abnormal cytology and histology based on data about risk over the term until the next screen g)Comprehensible simple dichotomous reproducible test results, not “could be might be maybe” and variants thereon h)Standards of screening and followup of abnormals that deliver cancer protection equivalent to annual cytology