Pap Tests, HPV Screening, and the HPV Vaccine

Transcription

1 Pap Tests, HPV Screening, and the HPV Vaccine George F. Sawaya, MD Associate Professor Department of Obstetrics, Gynecology and Reproductive Sciences Department of Epidemiology and Biostatistics University of California, San Francisco Director, Cervical Dysplasia Clinic, San Francisco General Hospital Member, US Preventive Services Task Force I have no financial interests in any product I will discuss today. Focus United States guidelines American Cancer Society (ACS) 2002 Saslow D, Runowicz CD, Solomon D, et al. American Cancer Society Guideline for the Early Detection of Cervical Neoplasia and Cancer. CA Cancer J Clin. 2002;52: American College of Obstetricians and Gynecologists (ACOG) 2003 ACOG practice bulletin. Cervical cytology screening. Number 45, August Int J Gynaecol Obstet. Nov 2003;83(2): US Preventive Services Task Force (USPSTF) 2002 U.S. Preventive Services Task Force. Cervical cancer screening at ASCCP Guidelines 2007 (HPV triage) 1

2 Main Questions Addressed At which age should screening begin? At which age should screening end? How often should women be screened? What techniques should be used? Focus on guidelines, rationale and evidence Cytology Primer ASC-US: atypical squamous cells of undetermined significance LSIL: low-grade intraepithelial lesion HSIL: high-grade intraepithelial lesion AGC: atypical glandular cells of undetermined significance (AGUS) Histology Primer Cervical intraepithelial neoplasia (CIN) Graded based on proportion if epithelium involved CIN 1: indicates active HPV infection; treatment discouraged since spontaneous resolution is high CIN 2: most are treated, but about 40% resolve over 6 month period; treatment may be deferred in young women CIN 3: the most proximal cancer precursor 2

3 Age to begin screening: Guidelines American Cancer Society (2002): Cervical cancer screening should begin approximately 3 years after the onset of vaginal intercourse and no later than age 21 American College of Obstetricians and Gynecologists (2003): same as above US Preventive Services Task Force (2002): begin screening within 3 years of onset of sexual activity or age 21 (whichever comes first) Age to Begin Screening: Rationale Most dysplastic lesions low-grade and transient Long progression time of preinvasive lesions to invasive cancer Potential adverse effects of treatment (e.g., LEEP) on pregnancy Lancet :

4 Potential adverse effects of LEEP Preterm delivery 70% increase Low birth weight 82% increase Preterm premature 169% increase ROM No randomized trials. Lancet : Age to Begin Screening: Rationale ACS: Screening before the 3-year period may result in an over diagnosis of cervical lesions that will regress spontaneously leading to inappropriate interventions that may do more harm than good. Age to End Screening: Guidelines ACS: Women who are age 70 and older who have had 3 or more documented, consecutive, normal tests, with no abnormal tests within the 10 years prior may elect to cease screening ACOG: no upper age to end screening. USPSTF: Women who are age 65 and older who have had 3 or more documented, consecutive, normal tests, may cease screening ACOG, ACS and USPSTF: screening following total hysterectomy with removal of the cervix for benign disease is not indicated. If hysterectomy for CIN 2 or 3, may stop screening after 3 normal tests (ACOG). 4

5 Age to End Screening: Rationale Small benefits in well-screened women Risks incurred due to false-positive testing Choice of cytology screening method, liquid-based cytology versus conventional cytology: Guidelines ACS: Screening should be performed annually with conventional cervical cytology smears OR every 2 years using liquid-based cytology ACOG: does not distinguish between LBC and conventional cytology. Both deemed acceptable. USPSTF: Overall, the quality of this literature is poor for the purposes of making decisions about choice of screening systems in US populations. Choice of cytology screening method, liquid-based cytology versus conventional cytology: Rationale and Evidence Lack of randomized studies cited. Davey et al Lancet 2006; 367:

6 Randomized trial: Switzerland Design: randomized trial, Switzerland, n=1,999 Final status: colposcopy in all ASCUS+ Results: No difference in any cytologic outcome No differences in CIN 2+ found (but low power) More satisfactory but limited by (SBLB) tests in LBC group (5.5% versus 2.5%) More wholly unsatisfactory tests in LBC group (1.4% versus 0%) Obwegeser et al Acta Cyto : Randomized trial: Italy Design: randomized trial, conventional cytology vs. LBC, 9 centers in Italy, n = 45,174 Final status: colposcopy in all ASCUS+ (NB: 2 centers did repeat cytology for LSIL with conventional cytology; less CIN found in the conventional group) Ronco et al BMJ May Randomized trial: Italy Results: Conventional cytology (ASCUS+) 855/22,466 (3.8%) Liquid-based cytology (ASCUS+) 1434/22,708 (6.3%) With LBC, more: ASCUS/AGC (3.6 versus 2.3%) LSIL (2.3 versus 1.3%) HSIL+ (0.4 versus 0.3%) With LBC, less: Unsatisfactory tests (1.2 versus 1.8%) Ronco et al BMJ May

7 Did more abnormal cytology mean more CIN2+ found? Randomized trial: Italy Conventional LBC CIN 1 CIN 2 CIN 3+ CIN 2+ Colposcopies With LBC, more colposcopies done and more CIN 1 found, but no difference in CIN 2+ or CIN 3+ detected. CIN 2+: 1.17 ( ) CIN 3+: 0.84 ( ) Ronco et al BMJ May ACS: Screening should be performed annually with conventional cervical cytology smears OR every 2 years using liquid-based cytology A longer interval for LBP i.e., every 2 to 3 years, compensates for the decrease in specificity. screening with LBP [annually] will likely lead to increases in the detection of ASC-US and low-grade abnormalities with subsequent increases in referral to colposcopy unnecessarily, risking the potential for overtreatment and increased health care costs. Screening Frequency: Guidelines ACS: At or after age 30, women who have had 3 consecutive, technically satisfactory normal results may be screened every 2 to 3 years ACOG: same as above* USPSTF: every 1 to 3 years Exceptions: women who are immunocompromised, HIV infected, have a history of in utero diethylstilbestrol exposure and/or have a history of CIN 2 or 3 *Exceptions: women who are immunocompromised (due to organ transplantation, chemotherapy, chronic corticosteroid treatment), HIV infected and/or have a history of in utero diethylstilbestrol exposure 7

8 Screening Frequency: Rationale After several normal tests, small likelihood of missed disease New preinvasive lesions have a long time to invasion Screening for uncommon diseases is associated with many false-positive tests if tests used are not very specific Annual screening: Harms False-positive testing and needless interventions 43% of women who had an abnormal Pap describe it as very scary or the scariest time of my life Sirovich et al Am J Med 2005 Feb;118(2) HPV DNA testing with cytology as a primary screen (age 30 and over): US Policy ACS: For women aged 30 and over, as an alternative to cervical cytology testing alone, screening may be performed every 3 years using conventional or liquidbased cytology combined with a test for DNA from high-risk HPV types. Frequency of testing should not be more often than every 3 years ACOG: same as above USPSTF: insufficient to recommend for or against poor evidence to determine the benefits and potential harms of HPV screening as an adjunct or alternative to regular Pap smear screening. Trials are underway... 8

9 HR HPV DNA testing (Hybrid Capture 2 ) Tests for one or more of 13 high-risk (oncogenic) HPV types The low-risk probe has no clinical utility Adding HR HPV DNA (HC2) testing to cytology: what to do with HC2 positive/pap normal women? Repeat HPV DNA testing and cervical cytology at 12 months. If test results of either are abnormal, do colposcopy If both are normal, routine screening at 3 years Wright et al AJOG 2007 October HPV DNA testing as a triage test for ASCUS cytology 9

10 The ASCUS/Low-grade Triage Study (ALTS): ASCUS 3,488 women with one ASCUS Pap Birmingham, Pittsburgh, Oklahoma City, Seattle Mean age 29 Randomized to 1) colposcopy immediately 2) repeat cytology: colposcopy only if HSIL+ 3) HR HPV DNA triage: colposcopy if HC 2 positive Followed every 6 months for 2 years Am J Obstet Gynecol 2003;188: ASC-US: Colposcopy Upsides Expeditious diagnosis Downsides 90% of women will not have CIN 2+ Uncomfortable Expensive Will find CIN 2 (and treat) that will resolve over time ASC-US: HPV DNA testing Upsides Colposcopy of only about half of women to find almost all CIN2+ Can do reflex testing on liquid-based cytology or co-collection (no need for everyone to return) Downsides Optimal management of HPV+ women with a normal colposcopy unclear (ALTS: 40% of women) Counseling and psychosocial aspects of HPV diagnosis important Will find CIN 2 that will resolve over time 10

11 ASC-US: Repeat cytology in 6 months Upsides ASC-US threshold seems to have high sensitivity and similar referral rate as HPV testing Waiting 6 months identifies fewer cases of CIN 2 that will resolve Avoids adverse psychosocial effects of HPV testing Downsides Everyone must return What about HPV triage for ASC-US in the Italian RCT? Ronco et al BMJ May Colposcopy for ASCUS + (a single test) Colposcopy for ASCUS with HPV+ and LSIL+ Conventional LBC But most clinicians do not do colpo for a single ASC-US test. ASCCP Guideline Highlights (2007) ASC-US: colposcopy, repeat cytology or HPV testing are all acceptable, but prefer HPV triage for if liquid-based cytology used or with co-collection ASC-H: colposcopy for all women LSIL: colposcopy for all women (except pregnant women or adolescents) AGC (atypical glandular cells): colposcopy with HC2 testing (see guideline for algorithm) Adolescents with ASC-US or LSIL (age 20 and younger): repeat cytology at 12 months (do not do HPV testing) Pregnant women with ASC-US or LSIL: may defer colposcopy to 6 weeks post-partum 11

12 HPV Vaccine Gardasil HPV 6/11/16/18 HPV 16 and 18 implicated in 70% of all cervical cancers HPV 6 and 11 implicated in warts Interim results of 2 large, phase-3 trials reported in May 2007 (NEJM) The FUTURE Trials FUTURE I: ages years; N=5,455 FUTURE II: ages years; N=12,167 Intention to treat population (ITT) Everyone Unrestricted susceptible population (US) Naïve at entry Disease associated with HPV vaccine types Per protocol susceptible population (PPS) Naïve throughout vaccination period Disease associated with any HPV type 12

13 Efficacy against disease associated with HPV 16 or 18: 44% 95% FUTURE II: CIN 2,3,AIS Intention to treat (ITT) Unrestricted susceptible (UnS) Efficacy against disease regardless of HPV type: 17% (1-31%) Not reported 98% Per protocol susceptible population (PPS) Not reported NEJM 2007;356; Table 3 Cumulative incidence of CIN 2,3,AIS associated with HPV 16 or 18 (FUTURE II) NEJM 2007;356; Figure 1 Cumulative incidence of CIN 2/3/AIS associated with any HPV type (FUTURE II) NEJM 2007;356; Figure 1 13

14 CDC- Advisory Committee on Immunization Practices (ACIP) Recommend vaccination of year old girls Recommend catch-up vaccination up to the age of 26 Vaccination can begin as young as age 9 years CDC- Advisory Committee on Immunization Practices (ACIP) Special circumstances: - can be given to women with equivocal or abnormal Pap tests - can be given to lactating women - can be given to immunocompromised women although response to vaccine and vaccine effectiveness may be less than in immunocompetent women - not recommended for use in pregnancy American Cancer Society Similar recommendations as ACIP except: In women ages 18-26, decision to vaccinate should be based on a discussion about sexual history. Cancer

15 What we do at San Francisco General Hospital Conventional cytology Repeat cytology for ASC-US Encourage delayed screening initiation; discourage all cytology in all pregnant women under age 20. Encourage lengthening of screening intervals to 2-3 years in women over age 30 with 3+ normal Pap tests Encourage screening discontinuation of low-risk women (over age 65 with h/o normal tests, those without a cervix) We do not hold birth control hostage for want of a Pap test. Questions 15