Objectives. I have no financial interests in any product I will discuss today. Cervical Cancer Screening Guidelines: Updates and Controversies

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Mitchell Gordon
5 years ago
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Cervical Cancer Screening Guidelines: Updates and Controversies I have no financial interests in any

Jody Steinauer, MD, MAS University of California, San Francisco Objectives Background To understand

manage HPV+ and cytology To know current CDC recommendations for HPV vaccination of women ~12,000

1 Cervical Cancer Screening Guidelines: Updates and Controversies I have no financial interests in any product I will discuss today. Jody Steinauer, MD, MAS University of California, San Francisco Objectives Background To understand the latest cervical cancer screening guidelines (updated in 2012) To review HPV co testing and how to manage HPV+ and cytology To know current CDC recommendations for HPV vaccination of women ~12,000 cervical cancer cases and 4,200 deaths per year in the US (ACS, 2010) Most successful cancer screening program in US 70% reduction in deaths over last 60 years *Obstet Gynecol 94:

2 Why does pap screening work? Sensitivity and specificity of pap/cytology not great BUT The organ is easily accessible for screening Natural history is favorable : precursor exists that is detectable and treatable; time course before cancer develops is long many opportunities to detect. Even if one test is false negative, get another chance. It is cost effective because many years of life are saved because cancer is actually prevented. Can we do better? Half occur in women who are not screened or inadequately screened. Tend to be poor, uninsured, with lack of access to care A more sensitive test (like many marketed directly to the public eg Thin Prep), will not fix this problem! In poor countries, cervical cancer remains a huge problem. SEER Cervical Cancer Rates: Can we do better? YES! False +: False positives cause anxiety and cost. Spacing the screening interval, starting screening later and HPV typing used correctly in conjunction with cytology, will reduce false + s and colposcopies Over treatment: Only 30% of untreated CIN3 becomes invasive cancer (over 30 yrs). Destroying all CIN3 =over treatment. Main harm is preterm delivery. Smart screening, biomarkers, risk based approaches and less aggressive (but still evidence based) treatment guidelines can help. 2

From virus to cancer Cytology Primer ASC US: atypical squamous cells of undetermined significance LSIL: low grade squamous intraepithelial lesion HSIL: high grade squamous intraepithelial lesion AGC:

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 a 6 month period; treatment

3 From virus to cancer Cytology Primer ASC US: atypical squamous cells of undetermined significance LSIL: low grade squamous intraepithelial lesion HSIL: high grade squamous intraepithelial lesion AGC: atypical glandular cells of undetermined significance (AGUS) Schiffman and Wright NEJM 2003;348(6): Histology Primer Cervical intraepithelial neoplasia (CIN) Graded based on proportion of 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 a 6 month period; treatment may be deferred in young women CIN 3: proximal cancer precursor US Guidelines: the Big 3 American College of Obstetricians and Gynecologists (ACOG) 2012: Screening for Cervical Cancer. Number 131, November American Cancer Society, American Society for Colposcopy and Cervical Pathology, American Society of Clinical Pathologists (ACS/ASCCP/ASCP) US Preventive Services Task Force (USPSTF) 2012 Cervical cancer screening. At htm Guidelines do not apply to immunocompromised women (HIV+), those with in utero DES exposure and those with prior CIN 2 or 3. 3

4 Evidence Review Evidence Based Practice Center: Evidence Report, May 2011 Liquid based and conventional cytology do not differ HPV testing finds more precancerous lesions but has unclear effects on cancer and on harms (e.g., additional colposcopies) HPV positivity incurs short term adverse psychological effects Women with negative HPV tests and normal cytology may be at particularly low risk Age to Begin Screening Age to Begin Screening ACOG (2012): same as ACS/ASCCP/ASCP ACS/ASCCP/ASCP (2012): begin at age 21 ( no screening under age 21) USPSTF (2012): begin at age 21 regardless of sexual history, D recommendation (don t screen under age 21) All agree: do not screen before age 21 years 4

Why is it ok to delay screening until age 21?

tends to be low grade and transient (90% regression at 3 yr).

typically cleared. Screening in adolescents therefore leads to treatment that is largely over treatment.

5 Why is it ok to delay screening until age 21? Cervical cancer extremely rare in younger women HPV infection very common immediately after onset of intercourse and 90% is cleared by host within 2 yrs When dysplasia does occur in adolescents, it tends to be low grade and transient (90% regression at 3 yr). If persists, plenty of time to detect and treat because long progression time of pre invasive lesions to invasive cancer Excision of dysplasia associated with harm Bottom Line: HPV infection typically cleared. Screening in adolescents therefore leads to treatment that is largely over treatment. Harms>>>Benefits Potential adverse effects of LEEP Preterm delivery 70% Low birth weight 82% PPROM 169% Lancet : Potential adverse effects of cold knife cone Perinatal mortality 187% Severe preterm delivery 178% Extreme low birthweight 186% BMJ 2008 Sep 18;337 Caution: No randomized trials. Screening Interval Cervical Cytology Guidelines ACOG Practice Bulletin #109 (2009) Criteria Recommendation Women under 21 yrs old Avoid screening (regardless of age or other risk factors) years old Screen every 2 years 30 to 65 or 70 years old May screen every 3 years 65 or 70 years old and older May discontinue screening HIV positive Immunosuppressed Exposed in utero to DES Screen annually 5

6 Triple A Guideline: ACS, ASCCP, Am Society for Clinical Pathology CA CANCER J CLIN March 2012 Age Screening <21 No screening Cytology alone every 3 years Preferred: Cytology + HPV every 5 years* OR Acceptable: Cytology alone every 3 years* >65 No screening, following adequate neg prior screens After total hysterectomy No screening, if no history of CIN2+ in the past 20 years or cervical cancer ever *If cytology result is negative or ASCUS + HPV negative USPSTF Cervical Cytology Guidelines March 2012 Criteria Grade Recommendation Cytology only, 21 to 65 years old A Every 3 years Cytology + HPV co testing, years A Every 5 years old Women under 21 yrs old D Avoid screening Age >65 with adequate prior screening D Avoid screening and not high risk Total hysterectomy; benign disease D Avoid screening HPV testing, alone or in combination, < 30 years old D Avoid screening Screening frequency: ages ACOG (2012): same as ACS/ASCCP/ASCP ACS/ASCCP/ASCP (2012): cytology every 3 years USPSTF (2012): cytology every 3 years ( A ) All agree: no annual screening ACS/ASCCP/ASCP: Women of any age should not be screened annually by any screening method. Screening frequency: ages ACOG (2012): same as ACS/ASCCP/ASCP ACS/ASCCP/ASCP (2012): screen every 3 years with cytology alone or every 5 years with cytology plus HPV testing ( preferred strategy, but a weak recommendation) USPSTF (2012): screen every 3 years with cytology alone or every 5 years with cytology plus HPV testing (but only for women who want to lengthen the screening interval ) All agree: no HPV testing for primary screening USPSTF: D recommendation women under 30 6

7 Why the difference between <30 and >30 yo? HR HPV co testing becomes clinically useful after age 30 In <30yo: HPV often positive, often transiently. Therefore, HPV testing not clinically useful. > Age 30: HPV positivity more likely to represent persistent HPV which is a significant risk factor for dysplasia/cancer. Conversely, HPV negativity is a strong negative predictor. Summary of Important Guideline Changes 1 st time that all 3 organizations involved with cervical cancer prevention have endorsed equivalent guidelines Co testing is ready for prime time for women >30 But, co testing every 5 years (NOT every 3 years) Women 21 29: cytology every 3 years (NOT 1 or 2) 3 consecutive documented negatives no longer required Stop screening women under 21 years of age Stop screening women 65 and older if negative results and adequate prior screening Common Questions About Cytology Intervals Do virginal women need Pap smears? Are the intervals any different for women With multiple sexual partners? Using hormonal contraceptives, menopausal hormone therapy? Who only have female partners? Who are pregnant? ACOG: Speculum examinations for cervical cancer screening should begin at age 21 years, irrespective of sexual activity of the patient. ACOG Committee Opinion No. 534 August 2012 Modeling False Colposcopies CIN 2 3 Cancers Cancer deaths positives Cytology q3 years, ages Cytology q3 years until age 30 then cotesting q5 years Per 1000 women screened over a lifetime. NB: Women with normal cytology and persistent HPV+ were returned to routine screening if colposcopy was normal. Modeling studies support similar benefits of co testing every 5 years and cytology every 3 years, demonstrating small differences in expected cancer cases and cancer deaths. 7

8 Co testing caveats HPV has decreased specificity so if we co screen more often than q5 years, patients will incur greater harm without benefit Before doing co test, ensure patient is willing to be screened every 5 years HPV based strategies also lead to more positives Some women will need prolonged surveillance Some women who would otherwise be able to stop at age 65 will require continued screening beyond age 65 What to do with HPV+, cytology negative? Cotesting: what to do with HPV positive/pap normal women? About 8 11% of women ages in the US will have a positive HPV test (HC2) and a normal Pap test (Ann Int Med April, 2008) At Kaiser Northern CA, about 3 7% of women ages have a positive HPV test (HC2) and a normal Pap test (Obstet Gynecol March 2009) HPV positive/pap normal women Recommendations by ASCCP and ACOG: Repeat co test at 12 months. If negative q 5yr screening If still HPV+ or if >= LSIL AS CUS colposcopy ASCCP Guidelines; ObstetGynecol, Apr 2013 Alternate recommendation by ASCCP: Perform HPV genotype specific typing for 16 or 16/18. if positive, perform colposcopy. If negative, repeat co test at 12 months. Age to End Screening ACOG (2012): same as ACS/ASCCP/ASCP ACS/ASCCP/ASCP (2012): end at age 65 in those with adequate negative prior screening (see next slide) Once ended, do not resume screening in women who have new partners. USPSTF (2012): end at age 65 in those with adequate negative prior screening 8

9 What is adequate prior screening? 3 consecutive negative cytology results or 2 consecutive negative co tests within the 10 years before ceasing screening, with the most recent test occurring within the past 5 years Ending screening: regardless of age ACOG, ACS and USPSTF: all agree that screening following total hysterectomy with removal of the cervix for benign disease is not indicated. USPSTF: D recommendation ACOG (2003): If hysterectomy for CIN 2 or 3, may stop screening after 3 normal tests. ACOG (2012): Continued routine screening (cytology ever 3 years) recommended for 20 years. ACOG: bimanual pelvic examinations No evidence supports the routine internal examination of the healthy, asymptomatic patient before age 21 years but Annual pelvic examination of patients 21 years of age or older is recommended by the College. Recommendation based on expert opinion No evidence supports or refutes the annual pelvic examination or speculum and bimanual examination for the asymptomatic, low risk patient. ACOG Committee Opinion No. 534 August 2012 The Prostate, Lung, Colorectal and Ovarian Cancer Screening Randomized Controlled Trial Randomized trial of women aged Annual screening with CA 125 for 6 years and transvaginal U/S for 4 years (n=39 105) versus usual care (n=39 111) 10 US screening centers Followed a median of 12 years Bimanual examination originally part of the screening procedures but was discontinued JAMA. 2011;305(22):

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial Routine exams The decision to perform an internal pelvic examination, breast examination, or both should

10 The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial Routine exams The decision to perform an internal pelvic examination, breast examination, or both should be made by the physician and the patient after shared communication and decision making. Concerns, such as individual risk factors, patient expectations, or medical legal concerns may influence the decision to perform an internal pelvic examination or clinical breast examination. More cancers found but no effect on mortality. JAMA. 2011;305(22): ACOG Committee Opinion No. 534 August 2012 After removal of the uterus and ovaries in asymptomatic, low risk* women The decision to receive an internal examination can be left to the patient Annual examination of the external genitalia should continue. *no history of vulvar intraepithelial neoplasia, cervical intraepithelial neoplasia grade 2+, immunocompromise and in utero DES exposure What s Better: Pap or LBC? Siebers, 2009 N=89,784, cluster RCT No difference in detection rate (sensitivity) or PPV, fewer unsatisfactory tests with LBC Conclusion: no difference 2nd RCT, different design, similar findings Evidence based practice center & 2 reviews conclude: no difference in relative or absolute sensitivity or specificity ACOG Committee Opinion No. 534 August

11 HPV Vaccination CDC: HPV vaccine advised for females ages Summary No cytology screening prior to age 21 Annual cytology not recommended for most women Annual screening is recommended for high risk women: immunocompromised (HIV+), in utero DES exposure and prior CIN grade 2 or 3 Annual screening recommended for at least 20 years in those with prior CIN grade 2 or 3 (ACOG, ASC) Co testing (HPV plus cytology) every 5 years may be equivalent to cytology every 3 years for women aged years Summary Women aged who are resistant to screening every 5 years are poor candidates for co testing (HPV plus cytology) Screening with (conventional) cytology alone (without HPV testing) every 3 years is still a great option (and perhaps the least complicated) Questions 11

I have no financial interests in any product I will discuss today.

I have no financial interests in any product I will discuss today. Cervical Cancer Prevention: 2012 and Beyond George F. Sawaya, MD Professor Department of Obstetrics, Gynecology and Reproductive Sciences Department of Epidemiology and Biostatistics University of California,