Erica Nelson, M.D. Dept. of Obstetrics & Gynecology SIU School of Medicine Springfield, IL

Disclosure No disclosures Some slides were prepared by ASCCP through its “Educate the Educators” program –Funded by Merck, Digene, & Roche –ASCCP controlled content: no industry input

Objective Participants should be able to screen women for cervical cancer, applying the epidemiology and natural history of human papillomavirus infections and of consequent preinvasive and invasive cervical cancers that underlie new ACOG guidelines

What is the objective of screening? To reduce morbidity/mortality from cervical cancer Not to find CIN or abnormal Paps Not to find HPV infection

15-19 yrs0.3 per 100, yrs2.6 per 100, yrs 7.8 per 100, yrs 11.4 per 100, yrs 14.4 per 100,000 *SEER A ll Races

What were the old standards? American Cancer Society, 1987, When to start? 18yo or at sexual debut 21yo or 3y after sex How often?AnnuallyAnnually till 30 (Q2y if LBP) Q3y after 3neg unless DES/HIV+ Q3y if Pap/HPV test When to stop? ???Age 70 if 3 prior consecutive/sat/ documented neg Paps within 10 years After hyst for benign dis

How well did the old standards work? Cervical cancer was once the leading cancer killer of U.S. women

Residual risk >1,000,000 abnormal Paps annually >400,000 CIN2,3 annually  Many are cervical cancers that screening/Rx will prevent  Cervical cancer risk in unscreened women remains high >50% of cervical cancers in un/underscreened women About 12% of cancers follow mismanaged abnormals  Only about 30% of cancers are screen failures Spence et al. Prev Med 2007;45:93-106

So if screening works, why change? (I) Better understanding of HPV natural history Most women contract HPV within 2y of first sex Most contract high risk types, esp. HPV 16 Most women clear HPV within 2 years of infection Only persistent HRHPV infections cause cancer Diagnosing a transient viral infection may lead to treatment that has no impact on cancer risk Even if a lesion is found Even if CIN1 or (sometimes) CIN2 is present

So why change (II)? Better understanding of CIN natural history, esp. clearance rates >75% of CIN1 regress without treatment Only 10% develop CIN3 within 2y (no cancers) Most are rapid-onset CIN are HPV infections with little neoplastic potential >65% of adolescents clear CIN2 within 3y >50% of adults clear CIN2 without treatment

What is the natural history of LSIL/CIN1 in adolescents? Moscicki AB et al. Lancet 2004;364:

What is the natural history of CIN2 in adolescents? 23 adolescents followed median of 18m 65% of CIN2 regressed 17% had persistent CIN2 13% progressed to CIN3 None had cancer  Avoid loss to follow-up AND overtreatment Moore et al. AJOG 2007;197:141.e1.e6

So why change (III)? New 2006 ASCCP management guidelines: For adolescents with ASC/LSIL/CIN1, follow Paps annually For adolescents with CIN2, CIN2,3 and satisfactory colpo, follow Pap/colpo q6m: no Rx Observe young women with HSIL/CIN2,3 desiring pregnancy without treatment

So why change (IV)? Better grasp of the futility of early screening “Cervical cancer screening has little or no impact on rates of invasive cervical cancer up to age 30.” OR for future cervical cancer, screened vs not For women 20-21: 1.5 For women 20-24: 1.1 But a significant reduction after age 30  Many European health programs delay screening till years of age Sasieni et al BMJ 2009;339:328

So why change (IV)? So if young women Have lots of HPV including HRHPV Have lots of abnormal cytology and CIN1-2 Clear most HPV, ASC, LSIL, and CIN1-2 Won’t be treated unless we find CIN3 And don’t benefit from screening because they only die from rapid-onset cancers Paps miss  Maybe we shouldn’t be looking!

So why change (V)? Better appreciation of cost effectiveness and marginal benefit of annual testing Q3y screening reduces cervical cancer mortality risk by 10-20% and increases life by 100 days compared to no screening Compared to q3y screening, annual screening improves life expectancy by <5% and by <3 days costs >$500,000/LY Prevents 1 cancer in every 33,333 women screened Eddy Ann Int Med 1990;113: Chan et al ObGyn 2003;102:765-73

So why change (VI)? Treatment saves lives but also costs lives  Women with LEEP more likely to have  Preterm birth (O.R. 1.7)  LBW (O.R. 1.8)  PPROM (O.R. 2.7)  Single studies show association with perinatal death, incompetent cervix  Risk rises with depth, # LEEPs  Similar findings after CKC or laser cone  Absolute risk increase is small Kyrgiou M et al. Lancet 2006;367: and Bruinsma et al BJOG 2007;114:70-80

Changes from 2002 guidelines Later start to screening 21yo--previously 3y after sex or 21yo Longer screening intervals Screen q2y ages 20-29—was annually “May” screen q3y (after 3 consecutive neg Paps and no CIN2,3/immunocompromise/DES Screen annually after CIN2,3/Ca for at least 20y Conventional and liquid-based Paps equivalent

When to start screening “Begin at age 21 years” Sexually active adolescents need care for contraception and STD screening/treatment These don’t require Pap testing No speculum needed in asymptomatic pt STD testing can be done using urine

Rationale for later screening start Cervical cancer rare in teens (<1:1,000,000) HPV—including HRHPV occurs in over 80% of sexually active adolescents HPV infections usually transient Europeans start at years of age Screen only every 3-5 years But they have central screening systems

Rationale for later screening start Overdiagnosis may lead to overtreatment Overtreatment may cause preterm delivery Upper age limit protects women/providers unwilling to discuss onset of sex. Screening virgins optional, based on “provider discretion and patient choice.” What is “sex” and who is a virgin?

Rationale for longer interval Sensitivity of single smear only 50-70% Risk of cancer within 3 years of 3 neg Paps only 1/100,000 Risk of progression to HSIL/cancer <3y after negative Pap not significantly higher than after 1y Longer screening intervals (e.g., 5y) inappropriate for mobile US population Smoking, sexual risks “should not be used” to justify more frequent screening. LBC may be more sensitive than conventional Pap

When to stop screening If life-threatening illness at any age At 70yo if Intact cervix 3 or more documented, satisfactory, negative cytology tests within 10y  Must screen women without documentation

When NOT to stop at 70yo History of Prior Cervical or endometrial cancer In utero DES exposure HIV infection or other immunocompromise Possibly if high risk HPV+ No comment on what to do if Hx CIN ASCCP recommends screening “at least 20y” after treatment for CIN

Rationale for stopping at 70yo Most cervical cancers in older women occur in underscreened populations (poor, minority) New high risk HPV infections and de novo CIN unlikely in older women When they occur, they are unlikely to progress to cancer before years (competing mortality risk)

Screening after hysterectomy “Screening... following total hysterectomy for benign gynecologic disease is not indicated.” Path should exclude cervical neoplasia Women with SC hyst continue screening Women with CIN2/3 continue until 3 negs and no abnormal smears within 10y Women with DES exposure or CaCx continue screening as long as healthy

Rationale for stopping after hyst Incidence of vaginal cancer 1-2/100,000/yr Less common than small bowel cancer Since a priori risk for VAIN is very low, most abnormals are falsely positive. Abnormal Pap will lead to painful colpo, more intensive Pap surveillance, treatments that risk bladder/rectal injury, more cost Other indications for gyn visits may remain

Reasons to ignore guidelines People only think in 1-year cycles BMD testing Colonoscopy We need to make sure nothing is missed Daily Pap testing? Screening colposcopy or LEEP? No cost is too high, either from altruism or defensive medicine Convince mothers with PTD after LEEP

Reasons to ignore guidelines Women get HPV after age 70 But the natural history of HPV doesn’t change It still requires decades to progress from infection to integration to mutation to invasion to death Recall the objective of screening: to prevent morbidity/mortality from cervical cancer Mortality over 25 years after age 70 is HIGH Treatment in the very elderly is very difficult

Reasons to ignore guidelines My patients are high risk All women are high risk. Sensitivity of screening is adequate even for women with risk factors, given slow progression of precursors. (But follow guidelines for managing abnormal results!) Women want to know if they have HPV They have it. Diagnosing an incurable STD results in stigmatization without changing cancer risk or improving quality of life. Annual visits are important for other reasons This is too complicated...

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... Clinicians, hospitals, health plans, and public health officials should seek to identify and screen these women.” ACS, 20002