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Cervical Cancer Screening: New Approaches Levi S. Downs, Jr.

Brotzman, Spitzer. Colposcopy, 2 nd Ed., 2008 ASCCP Modern Colposcopy, 2 nd Ed.

1 Cervical Cancer Screening: New Approaches Levi S. Downs, Jr., MD Disclosures & images During the previous 12 months, I have been a consultant for and received honoraria from Merck. Images are attributed where appropriate Numerous images are utilized from : ABS: Apgar, Brotzman, Spitzer. Colposcopy, 2 nd Ed., 2008 ASCCP Modern Colposcopy, 2 nd Ed., 2004 Unlabeled images are from the University of Michigan All ASCCP Guidelines are from: Wright TC, Massad S, Dunton CJ, et al. J Lower Genital Tract Disease, 2007; 11: and 2007; 11:

2 Objectives Early detection or prevention of cervical cancer Prevent mismanagement of screening Discuss current cervical screening guidelines: ACS/ASCCP/ASCP Consensus American Cancer Society, American Society for Colposcopy and Cervical Pathology, American Society for Clinical Pathology. Obstet Gynecol 2012; 120: ACOG ACOG Practice Bulletin #131, November 2012 U.S. Preventive Services Task Force Ann Int Med 2012; 156: Discuss ASCCP 2006 screening guidelines Revisions due March 2013 Outline The original Pap test Better understanding of etiology and natural history Evolution of cervical cancer screening The newest guidelines for screening 2

3 Median Age of Events Associated with Cervical Infection by HR HPV Menarche 1st intercourse High-risk HPV Infection ASC-US or LSIL and HPV positive Pap normal, HPV (-), Type specific antibody (+) CIN 3/ Carcinoma in situ, HPV (+) Microinvasive cancer, HPV (+) Invasive HPV(+) Evolution of the Pap Test Publications 1917 A rhythmical heat period in guinea pigs 1928 New cancer diagnosis 1933 The sexual cycle in the human female as revealed by vaginal smears 1941 Publication of The diagnostic value of vaginal smears in carcinoma of the uterus 1949 Widespread introduction of the Pap test begins Image from US Postal Service 3

4 Cervical Cytology Normal LSIL HSIL (CIN2) ASCUS HSIL (CIS) Invasive SCC The Good News About Pap Tests: Cervical Cancer Mortality, year mortality, per 100,000 Caucasian females American Cancer Society Statistical Report 4

5 Why does screening fail? Annual contribution to squamous cervical cancer screening failure in USA % # Never screened 50% 6280 >5 yrs since screened 10% 1260 False Negative Pap 30% 3770 Errors in follow up 10% 1260 Total 100% 12,560 Sawaya Obstet Gynecol 1999 Have causes of screening failures changed since 1999? Retrospective Study of Cervical Cancers Diagnosed at Kaiser Northern California Pap results 3-36 months prior to diagnosis, N=833 Failure to screen No Pap % No visit: 19% 1-2 visits 18% >3 visits 63% Failure in detection: 1 st Pap WNL % Failure to follow-up: 1 st Pap abnormal % Leyden MA, Manos M, Kinney W et al JNCI 2005;97:

6 System Failures Leading to Cervical Cancer Diagnosis Patient does not get appropriate therapy Health care providers do not screen women at visits Patient gets cervical cancer Colposcopy for abnormal screen not done Women do not come in for screening Courtesy of Connie Trimble, MD, Johns Hopkins University School of Medicine, Baltimore, MD Who are the rarely and never screened? Proportion of Women Receiving Cervical Cancer Screening, National Health Interview Survey, United States, 2000 Group %P Pap testt past 3 years All women 82% Insured Yes No Country of birth US born Foreign born in U.S. <10 yrs 85% 62% 83% 61% Swan et al, Cancer. 2003;97:

Prevalence of pap tests during last 3 years

Meta-analyses: Biopsy proven CIN 2,3 Sens.

7 Prevalence of pap tests during last 3 years by education level in the U.S Health US 2007.CDC, National Center for Health Statistics. How good is the Pap Test? Meta-analyses: Biopsy proven CIN 2,3 Sens. Spec. Fahey 49% 62% Follen-Mitchell 67% 77% Nanda 51% 97% Nanda K et al. Ann Intern Med 2000;132:

8 Pap Test Evolution AHCPR report on Evaluation of Cervical Cytology Meta-analysis of existing literature Sensitivity Conventional pap 51% Liquid cytology 80% AHCPR, Evaluation of Cervical Cytology, 1999 Conventional vs. Liquid Cytology: Another Meta-analysis Arbyn et al, Obstet Gynecol 2008; 111:

9 What has been done to improve screening? Screening Interval 3 y 2 y 1 y Decrease in incidence 51% 57% 70% Decrease in mortality 57% 61% 72% Decrease in simple hyst 44% 50% 64% Decrease in rad hyst 43% 50% 67% Decrease in radiation 58% 65% 73% AHCPR Evaluation of Cervical Cytology, 1999 Pap Test Evolution Cost / life-year saved vs. no screening Screening Interval Liquid Conventional One year $17,600 $13,271 Two years $8,882 $6,368 Three years $5,918 $4,079 Comparison Mammogram cost / life-year saved is $50,000 AHCPR, Evaluation of Cervical Cytology,

10 Pap Test Evolution 1995 Automated re-screening system approved by FDA 1996 thin-layer cytology system approved by FDA 1997 Cell location system approved by FDA 1998 Computer assisted primary screening device approved by FDA 2001 The Bethesda System of nomenclature 2006 HPV Vaccine approved by FDA Finding lesions is not the objective of screening?! We can t tell which lesions will progress Emphasis should be placed on: Persistent HPV infections CIN 3 (no margin for error) Persistent CIN 2 and CIN 2,3 in non- adolescent women 10

especially in young women Precancerous changes (HSIL) result from

11 What is the rationale for combined screening with HPV test plus Pap? + Premise for clinical use of HPV Most HPV infections are transient especially in young women Precancerous changes (HSIL) result from persistent HPV infections Absence of HPV highly predictive of absence of CIN 11

12 Cumulative incidence of HPV infection from time of coitarche Moscicki AB et al. J Adol Health 2005;37:S1-S The Probability of Clearing an HPV Infection 0 1 to 6 6 to to 18 Months Since Positive Test Ho GYF et al, NEJM 1998; 328:

HPV Prevalence and Cervical Cancer - Incidence by Age 30 25 Hi risk HPV Cancer 20 15 10 5 30 25 15 10 5 0 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 0 Sellors et al. CMAJ. 2000;163:503.

13 HPV Prevalence and Cervical Cancer - Incidence by Age Hi risk HPV Cancer Sellors et al. CMAJ. 2000;163:503. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, Prevalence of HPV by Age Manchester, U.K. Percentage HPV (+) Age Group Peto et al Br. J. Cancer (2004:91:942-53) 13

14 Prevalence of HPV types in females, ages 14-59, United States, (NHANES) Prevalence % Age, yrs Low Risk High Risk Dunne E, et al., JAMA, 2007 Sensitivity and specificity to diagnose CIN3 Cytology threshold LSIL or ASC-US X2 HR-HPV testing by HC2 Sens Spec Refer NPV Pap 57.2% 89.9% 11.6% 98.4% HR-HPV 90.8% 72.6% 29.4% 99.6% Kulasingam et.al. JAMA 2002;288:

15 Combined HPV and Pap Testing The Portland Kaiser Study 20,810 women followed for up to 122 months Over 45 mo, incidence of CIN 3+ = 4.54% if HPV+ or Pap > ASC-US. If both neg, incidence = 0.16% Efficacy of Pap (> ASC), HR-HPV, and Pap +HPV to predict CIN3+ within 45 mo. Sensitivity PPV NPV Pap + HPV 86.4% Pap alone 49.2% HPV 75.4% Sherman et.al. JNCI 2003;95:46-52 HPV Testing Requirements Tests must be analytically and clinically validated Proven acceptable reproducibility, clinical sensitivity, specificity, PPV and NPV for cervical cancer and CIN2/3 Based on FDA approval and/or publication in peer-reviewed scientific literature Restrict testing to high risk HPV types 15

16 FDA approved screening and triage The first FDA approved test was: Hybrid Capture 2 (hc2), using a solution hybridization method. Two panels were approved, including a HR panel with 13 types. Low-risk 6, 11, 42, 43, 44 Because this is a cervical cancer triage test, HPV testing for ASC management and primary screening should be by high-risk panel only High-risk 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 FDA approved screening and triage The second FDA approved test was Cervista HPV HR, using an isothermal enzymatic DNA amplification process. The test detects 14 HR types. High-risk 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 16

17 FDA approved screening and triage The FDA approved type-specific p testing in 2009: Cervista HPV 16/18 Pitfalls of HPV DNA Testing Positive HPV at any point in time may be from infection destined to resolve HC2 reports positive at threshold of 1 pg/ml (5000 viral copies) Report of equivocal or indeterminate if the levels approach threshold No clear next step most labs recommend repeat After cytology ~4-5% of specimens have insufficient i liquid id for HPV testingti HC2 and Cervista have differing thresholds. The clinician should be aware of the potential impact upon clinical management. 17

18 Validation of Co-Testing and Screening Intervals Negative HPV identifies a very low risk group, whether cytology is negative or not Kaiser Study N= women age > 30 in prospective co-testing study Katki HA, et al. Lancet Oncol 2011; 12: 663 HPV testing finds more women at high 5-year risk of cancer or pre-cancer Test 5-year Excess HPV Pap 5-year Excess Result Risk Risk Test Test Risk Risk HPV+ 7.6% 7.4% HPV+ Pap+ 12% 6% HPV- 0.2% RR 38 HPV+ Pap- 6% RR 2 Pap+ 4.7% 4.3% HPV- Pap+ 0.9% 0.7% Pap- 04% 0.4% RR 11.7 HPV- Pap- 02% 0.2% RR 4.5 Katki HA, et al. Lancet Oncol 2011; 12:

19 Proportion of Co-Test Results in 331,061 Kaiser Patients over 30 24% 2.4% 3.7% 1.4% 92.5% Discordant Katki HA, et al. Lancet Oncol 2012; 12: 663 Kaiser Northern California % Pap-/HPV 813,000 co-tests % Pap-/HPV- 89.3% 86.8% 8% 91.4% 90.4% 93.5% 92.3% 94.1% 93.3% 94.3% 93.6% 92.5% Total = 90.9% Castle PE, et al. Five-year experience of human papillomavirus DNA and Papanicolaou test co-testing. Obstet Gynecol 2009;113:

20 Percent of women Pap Normal / HPV positive Kaiser/Northern California N = 813,000 co-tests 6.76% % Pap-/HPV+ 5.01% 3.81% 3.08% 2.89% 2.72% 2.56% 2.94% 3.02% 2.87% 2.59% Total = 3.90% Castle PE, et al. Obstet Gynecol 2009 What About HPV (+) and Cytology (-)? Rates of HPV persistence - 6mos: Clavel - France: 40% Cuzick - England: 55% mo: 35% 20

21 HPV (+) and Cytology (-) Risk for CIN 2+ at 6 mos: Clavell - France: 4.2% Cuzick - England: 2.8% Wright South Africa: 7.8% Clavel C et al. Br J Cancer 2001;84: Cuzick J et al. BMJ 2003;362: Wright TC et al. JAMA 2000;283:81-6 Proportion of Co-Test Results in 331,061 Kaiser Patients over 30 24% 2.4% 3.7% 1.4% 92.5% Baseline Pap % Neg 96.2 Katki HA, et al. Lancet Oncol 2012; 12: 663 ASC-US 2.6 LSIL 0.76 AGUS/NOS 0.23 ASC-H/HSIL/SCC

22 Risk of Future CIN 3: Baseline HPV & Pap Test Concordance Summary of Portland Data Lorincz et al. Arch Pathol Lab Med 2003; 127: Baseline Status N Woman yrs followup CIN 3 N Rate/100 Woman Years RR (95% CI) Pap - HPV + Pap - HPV ( ) Association of Initial Pap Abnormalities with Histology Kaiser study N= women age > 30 in prospective co-testing study ASC-H/HSIL/SCC LSIL AGUS/NOS HPV+/Pap- HPV+/ASC-US Katki HA, et al. Lancet Oncol 2011; 12: Years since enrolment 22

23 Rate of cervical cancer following negative HPV test or normal Pap For all women with normal Pap test: 7.5 cervical cancers per 100,000 women / year For all women HPV-negative: 3.8 cervical cancers per 100,000 women / year For all women HPV-negative who also had a normal Pap test: 3.2 cervical cancers per 100,000 women / year Katki HA, et al. Lancet Oncol 2011; 12: 663 Cumulative Risk Of Invasive Disease Based on Initial Co-Test Kaiser Study N=331,818 women age > 30 in prospective cotesting study Katki HA, et al. Lancet Oncol 2011; 12:

24 Updated Consensus Guidelines: When to begin screening Women younger than 21 Years: 1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: and AJCP 2012; 137: Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: ACOG Practice Bulletin #131, November NCCN Cervical Cancer Screening Guideline v Rationale for Beginning Screening at Age 21 Cervical Cancer Incidence by Age Group USCS*, Age Rate per 100, All ages 9.4 *United States Cancer Statistics includes data from CDC s National Program of Cancer Registries and NCI s Surveillance, Epidemiology and End Results Program. Saraiya M et al. Obstet Gynecol 2007;109:

25 Updated Consensus Guidelines: When to cease screening Women older than 65 Years: Screening should not be resumed for any reason, even if a woman reports having a new sexual partner. Do not screen 1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: and AJCP 2012; 137: Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: ACOG Practice Bulletin #131, November NCCN Cervical Cancer Screening Guideline v Cessation of Screening Adequate negative prior screening is defined as: 3 consecutive negative cytology results 2 consecutive negative co-tests done within the 10 years before stopping screening with the most recent test within 5 years. 25

26 Updated Consensus Guidelines: Women with prior hysterectomy Evidence of adequate negative prior screening is not required (all but USPST). Screening should not be resumed for any reason, including if a woman reports having a new sexual partner. 1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: and AJCP 2012; 137: Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: ACOG Practice Bulletin #131, November NCCN Cervical Cancer Screening Guideline v Rationale for Stopping after Hyst Vaginal cancer rate 7/million/year 663 vag cuff Paps needed to find one VAIN 2066 women followed after hyst for average 89 months: 3% had VAIN, 0 had cancer Risk of Pap abnormality after hyst = 1%. Comparable to risk of breast cancer in men for which screening not recommended Pearce KF et al. NEJM 1996;335: Piscitelli JT et al. AmJOG 1995;173:

27 Updated Consensus Guidelines: Women with prior HPV Vaccination Recommended screening practices should not change on the basis of HPV vaccination Not addressed 1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: and AJCP 2012; 137: Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: ACOG Practice Bulletin #131, November NCCN Cervical Cancer Screening Guideline v Updated Consensus Guidelines: Screening Frequency Both liquid-based and conventional smears are acceptable. Co-testing should NOT be performed for women under age 30. Recommendations NOT intended for women with HIV, immunocompromise, or in utero DES exposure 1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: and AJCP 2012; 137: Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: ACOG Practice Bulletin #131, November NCCN Cervical Cancer Screening Guideline v

Updated Consensus Guidelines: Screening Frequency Co-testing ti preferred and cytology acceptable by all but USPSTF Recommendations NOT intended for women with HIV, immunocompromise, or in utero DES

28 Updated Consensus Guidelines: Screening Frequency Co-testing ti preferred and cytology acceptable by all but USPSTF Recommendations NOT intended for women with HIV, immunocompromise, or in utero DES exposure 1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: and AJCP 2012; 137: Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: ACOG Practice Bulletin #131, November NCCN Cervical Cancer Screening Guideline v ASCCP Guideline for Co-test Follow-up Wright TC, et al. J Lower Genital Tract Disease, 2007; 11: and

29 Updated ASCCP Guideline for Co-test Follow-up Updates Saslow. CA Cancer J Clin 2012; 62: 147 Routine Co-test in 5 years Wright TC, et al. J Lower Genital Tract Disease, 2007; 11: and What is the recommended strategy to incorporate HPV-type Specific Testing? There is no role for testing for low risk HPV types Testing for HPV 16/18 was approved in March 2009 by the FDA Individuals with HPV 16 or 18 are at much higher risk of developing HSIL or cancer 29

30 Percent of Squamous and AdenoCa of Cervix Due to HPV 16 or HPV 16 or 18 86% % All other types % 20 14% 10 0 Squamous cell carcinoma Adenocarcinoma Munoz N et al. Int J Cancer 2004;111: [Evidence Level B] Castellsague X et al. J Natl Cancer Inst 2006;98: [Evidence Level B] 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:

Changes of HPV Type Prevalence by Lesion

31 Changes of HPV Type Prevalence by Lesion Severity HPV Types in CIN 2, CIN 3 and Cervical Cancer Iceland, and Sigurdsson K et al. Int J Cancer 2007; What is the recommended strategy to incorporate HPV-type Specific Testing? 31

screening is the identification and treatment of true cervical cancer precursors Persistent hi-risk HPV, CIN2

32 What is the recommended strategy to incorporate HPV-type Specific Testing? Updates Saslow. CA Cancer J Clin 2012; 62: 147 Co-test 5 years Colposcopy Fundamental Principles The goal of cervical cancer screening is the identification and treatment of true cervical cancer precursors Persistent hi-risk HPV, CIN2 and CIN3 are accepted as cervical cancer precursors Transient HPV infection, LSIL, and CIN1 are not considered cervical cancer precursors 32

33 Conclusion The biggest gain in reducing cervical cancer incidence and mortality would be achieved by increasing screening rates among women who have not been screened or who have not been screened regularly... ACS, 2002 Recommendation Caveats Clinicians, patients, payers, IRBs, and the courts should never view recommendations as dictates. Strong recommendations based on high-quality evidence will not apply to all patients. Users of guidelines may reasonably conclude that following guidelines will be a mistake for some patients. However, screening in excess of guidelines has been shown to cause potential harm to patients and to increase cost without sound justification 33

34 What might a future screening strategy include? New Biomarkers may enhance our ability to detect cancer precursors, e.g. DNA methylation of cell adhesion molecule 1, or expression of p16 ink4a When the HPV vaccine is fully deployed, the alteration of disease prevalence will greatly decrease the PPV of Pap testing. It is likely that primary screening will be based on HPV testing 2008 ASCCP Biannual Meeting Questions? 34

35 Citation Summary ABS: Apgar, Brotzman, Spitzer. Colposcopy, 2 nd Ed., 2008 ACOG Practice Bulletin #131: Screening for Cervical Cancer, November 2012 ACS/ASCCP/ASCP Consensus Conference of American Cancer Society, American Society for Colposcopy and Cervical Pathology, American Society for Clinical Pathology. Obstetrics & Gynecology 2012: 120: ASCCP Modern Colposcopy, 2 nd Ed., 2004 ASCCP Copyright 2004, 2009 American Society for Colposcopy and Cervical Pathology. All rights reserved. Arbyn et al. Obstet Gynecol 2008; 111: Castellsague X et al. J Natl Cancer Inst 2006; 98: [Evidence Level B] Castle PE, et al. Five-year experience of human papillomavirus DNA and Papanicolaou test co-testing. Obstet Gynecol 2009; 113: Clavel C et al. Br J Cancer 2001; 84: Connie Trimble, MD, Johns Hopkins University School of Medicine, Baltimore, MD Cuzick J et al. BMJ 2003; 362: Dunne E, et al. JAMA 2007, 297(8): doi: /jama Ho GYF et al. NEJM 1998; 328: Citation Summary (continued) Katki HA, et al. Lancet Oncol 2012; 12:663 Khan MJ et al. JNCI 2005; 97: Kulasingam et al. JAMA 2002; 288: Leyden MA, Manos M, Kinney W, et al. JNCI 2005; 97:67583 Moscicki AB et al. J Adol Health 2005; 37:S1-S9 Moyer VA, et al. USPSTF, Ann Int Med 2012; 156: Munoz N et al. Int J Cancer 2004; 111: [Evidence Level B] NCCN Cervical Cancer Screening Guideline v , Nanda K et al. Ann Intern Med 2000; 132:810-9 National Center for Health Statistics, Health, US, 2007, Centers for Disease Control and Prevention, /d /h /h df Pearce KF et al. NEJM 1996; 335: Peto et al. Br. J. Cancer (2004:91:942-53) Piscitelli JT et al. AmJOG 1995; 173:

36 Citation Summary (continued) Saraiya M et al. Obstet Gynecol 2007; 109: Saslow et al. ACS/ASCCP/ASCP Cancer J Clin 2012; 62: and AJCP 2012; 137: Sellors et al. CMAG. 2000; Sherman et al. JNCI 2003; 95:46-52 Sigurdsson K et al. Int J Cancer 2007; Swan et al, Cancer. 2003: Wright TC, et al. JAMA 2000; 283:81-6 Wright TC, Massad S, Dunton CJ, et al. Journal of Lower Genital Tract Disease 2007, 11:201-22; 11:

ASCCP 2013 Guidelines for Managing Abnormal Cervical Cancer Screening Tests

ASCCP 2013 Guidelines for Managing Abnormal Cervical Cancer Screening Tests www.treatmentok.com Barbara S. Apgar, MD, MS Professor of Family Medicine University of Michigan Ann Arbor, Michigan Disclosures