1. Cervical Cancer Screening Cristin Colford, MD April 27,2010

2. This is why I do this talk… Sent: Wednesday, July 02, 2008 11:24 PM To: Colford, Cristin Subject: Questions Hi Dr. Colford, There is another thing. I just learned from my Intern friends that I might have to do some Pap-smears? Well that was something I did once at Med school but never since then. I hope in that case I can always ask a female attending (i.e. you?) otherwise I would say the patient is better of with a gyn/obst consult. Thank you in advance, Dr. Intern…

3. Objectives Review guidelines for cervical cancer screening Review methods for cervical cancer screening Review how to follow up abnormal results Review our process in clinic

4. Cases 1)18 yo female. Never been sexually active. Comes in because her mom tells her she needs a pap 2)45 yo female. Here for annual exam and PAP. s/p TAH for fibroids 3)72 yo female. Here for annual exam and PAP. Has had yearly normal paps for at least 10 years

5. Cervical Cancer 2009 www.cancer.org 11,270 new cases of invasive cervical cancer 4,070 women will die from cervical cancer Death rate declined 74% from 1955 to 1992 Most common in Hispanic women More common in African-American than Caucasian women

6. Cervical Cancer Most cases in women younger than 50 Rare in women younger than 20 60-80% of women diagnosed with invasive cancer have not had a PAP in last 5 years

7. USPSTF Recommends screening for cervical cancer in women who are sexually active and have a cervix (A recommendation) – Good evidence from multiple observational studies that screening with cervical cytology (PAP) reduces incidence of and mortality from cervical cancer – Direct evidence for optimal starting and stopping age and interval is limited. – Indirect evidence: Most benefit can be obtained by beginning at age 21 or within 3 years of onset of sexual activity and screening at least every 3 years.

8. USPSTF Recommends against routinely screening women older than 65 if they have had adequate screening and are not at high risk for cervical cancer (D recommendation) – Declining rates of cervical cancer in women over 65 – Increased risk of harms (false positives and invasive procedures)

9. USPSTF Recommends against routine screening with PAP in women who have had hysterectomy for benign disease (D recommendation) – Yield of cytology is low in women who have had hysterectomy for benign disease – Poor evidence that screening to detect vaginal cancer improves outcomes.

10. Clinical issues to consider Goal is to sample the transition zone – Study in Netherlands followed up no transition zone---no higher rates of cervical cancer when followed out for 3 years Optimal age to begin is unknown – Based on HPV data, within 3 years of sexual onset – Little value in screening women who have never had sex, but high prevalence of sexual activity by ages 21 and concern that sexual history may not be accurate

11. Clinical considerations No direct evidence that annual screening achieves better outcomes than every 3 yr Majority of cervical cancer cases occur in women not screened in 5 years or in those who did not have appropriate follow up for abnormal pap Sensitivity for single pap is low (60%-80%), most US agencies recommend annual pap for 2-3 yrs before extending interval (ACOG, ACS)

12. Thin prep or not? – Everyone else is doing it, why shouldn’t we? – Pathologists are most comfortable with liquid – Not a huge cost difference to patient – Particularly helpful for ASCUS Reflex HPV Don’t need to bring back to repeat pap, can automatically check off reflex hpv as sample already obtained – Studies combining HPV and cytology not cost effective – BUT new study suggest that HPV instead of cytology promising for early detection and reduced high grade changes

13. RCT: Accuracy of liquid based compared to conventional paps Ronco et al. BMJ 5/2007 44, 000 women aged 25-60 randomly assigned to conventional pap vs liquid based with HPV testing. Outcome: Relative sensitivity for CIN 2 or higher with PAP result of ASCUS or higher considered positive Results: No significant difference in sensitivity for detecting CIN 2 or greater. – Liquid based detected more CIN 1 or more lesions, but not CIN 3 or more. – Reduction in unsatisfactory cytology with liquid based

14. Meta-analysis: Liquid compared to conventional cytology Arbyn et al. Obstet Gyn 2008 Meta-analysis of seven studies that compared liquid to conventional pap using gold standard of colposcopy concludes that liquid based compared to conventional cytology revealed no statistically significant difference in se or sp. Except lower sp in liquid based with ascus. HSIL – Liquid based se 57.1% Sp 97% – Conventional se 55.2%, sp 96.7% LGSIL – Liquid based se 79.1%, sp 78.8% – Conventional se 75.6%, sp 81.2% ASCUS – Liquid based se 90.4%, sp 64.6% – Conventional se 88.2%, sp 71.3%

15. RCT Conventional Vs Liquid Siebers, et al. JAMA 2009 Cluster RCT – Practices randomly assigned liquid or conventional – Study personnel blinded to type of cytology – 90,000 women – Ages 30-60 – Q5yrs – Netherlands No significant difference between liquid and conventional

16. Siebers et al. Results

18. Siebers et al Results

20. How to do a pelvic exam http://content.nejm.org/cgi/video/356/26/e26/

21. What to do with an abnormal PAP? ASCUS LGSIL HGSIL

22. Atypical Squamous Cells of Undetermined Significance 2 million paps yearly Of patients with cytology finding of ASCUS – 80.5% had normal biopsy – 12.8% had Grade 1 CIN – 6.6% had Grade 2 CIN – 0.1% had Invasive Cancer

23. Options for Management of ASCUS Repeat cytology Immediate colposcopy Reflexive HPV DNA testing

24. Reflex HPV testing with ASCUS ASCUS-LSIL Triage Study (ATLS) – Determined that Reflex HPV compared to repeating PAP had equivalent sensitivity and slightly increased specificity. If high risk HPV detected, refer for colposcopy If no high risk HPV detected, return to routine screening interval Reduce number of women undergoing colposcopy by identifying high risk patients – Reduce costs, reduce patient anxiety

25. Cost Effectiveness of liquid based cytology with reflex HPV testing in women over 30 Bidus et.al, Obstet Gynecol. Triennial screening with liquid based cytology and reflex HPV for ASCUS ($95,300 per year of life saved) Triennial combined screening with HPV and cytology for women 30 and over ($228, 700 per year of life saved) Annual combined HPV and cytology ($2,215,100 per year of life saved)

26. ASCUS follow up

27. Refer for immediate colpo LGSIL HGSIL

28. Following up PAPs in clinic New system 3/01

29. Interns mapped the process and made suggestions. We made revisions… Kiran Venkatesh Amanda Allen Tara O’Brien Jacob Kurlander

33. Pap Normal Nurse letter to patient via pt correspondence If there is a finding of an infection ie bv, trich or candida, phone message sent to doctor for management advise ASCUS Nurse letter to pt, set up 6 month follow up, ASCUS tracking sheet* ASCU-H/AGS/LGSIL/HGSIL Nurse phone correspondence to doc Doc informs patient, replies to nurse* Nurse schedules GYN appt and tracks until appt kept in Gyn If doc does not follow up in timely fashion, period review by Colford Colford will inform patient to prevent delay in referral Letter to nonresponding doc Pap completed and logged into notebook by nurse Normal Nurse letter to patient via pt correspondence If there is a finding of an infection ie bv, trich or candida, phone message sent to doctor for management advice ASCUS Reflex HPV If negative, routine repeat If positive, go to colposocpy ASCU-H/AGS/LGSIL/HGSIL Nurse phone correspondence to doc (includes that protocol calls for referral to GYN) Doc informs patient, replies to nurse* Nurse schedules GYN appt and tracks until appt kept in Gyn If doc does not follow up in timely fashion, period review by Colford Colford will inform patient to prevent delay in referral Letter to nonresponding doc

34. Start our new process March 1 st. Theressa Brown will send letters to patients with normals. – She will contact you via Webcis if there is an infection to be addressed. Robin Woodford will address abnormals, – communicate via webcis – Please inform your patients. – She will help you refer to gyn follow to completion.

35. Trich on PAP What to do? Liquid based paps have low sensitivity (61%) but high specificity (99%). So if see Trich on pap, treat Metronidazole 2 grams po x 1 Or metronidazole 500 mg bid x 7 days

36. BV on pap Not reliable diagnostic method. Not associated with CIN Would need clinical symptoms to warrant treatment

37. Case 1 18 yo female. Never been sexually active. Comes in because her mom tells her she needs a pap -All recommendations say that she does not need a pap until sexually active or age 21 (? Do you need a pap if you are 30 and never have had intercourse?)

38. Case 2 1)45 yo female. Here for annual exam and PAP. s/p TAH for fibroids – If no history of CIN, no PAP

39. Case 3 1)72 yo female. Here for annual exam and PAP. Has had yearly normal paps for at least 10 years – USPSTF and ACS say that you can stop after a discussion between patient and provider. ACOG cites limited evidence for setting age limit

40. HPV testing instead of cytology Ronco et al, Lancet Oncology, Jan 2010 HPV based screening more effective than cytology for preventing invasive cervical cancer For women >35, HPV based testing increased detection of CIN2 and 3 in first round, decreased incidence in second round But in younger women, overdiagnosis of CIN-2 which regresses 3000 additional colposcopies in HPV compared to cytology group. – 332 additional per cancer prevented – Promising….perhaps instead of direct referral to colposcopy there could be some repeat testing interval to determine persistent HPV and then refer to colpo

43. Next step What is our cervical cancer screening rate? How to improve? – Visit planners….