1. Sarah Feldman MD MPH Co-Director Ambulatory Gynecologic Oncology Brigham & Women’s Hospital Dana Farber Cancer Institute Lowell Cancer Center Associate Professor Harvard Medical School

2. I, Sarah Feldman. have been asked to disclose any significant relationships with commercial entities that are either providing financial support for this program or whose products or services are mentioned during my presentations. I have no relationships to disclose.

3. Requires a programmatic approach including:  primary vaccination  screening  active management of abnormalities to prevent progression

4.  There are still 12,360 women diagnosed in the US annually with cervical cancer, and 4,020 deaths  The 5 year survival of this preventable disease is 67.9%  We have to do better…

5. Evidence Based Logical, simple to understand and clearly written Clearly address areas of patient and provider confusion

6.  <21 No screening  21-29 Pap q 3 years  regardless of sexual activity(no HPV screening)  30- 65 Pap alone q 3 years or Cotesting/Pap with HPV q 5 years  if both results negative, and normal and negative screens  > age 65 Stop screening if adequate screening – Defined as 3 neg Paps within prior 10 years or 2 neg cotests within 10 years – Poorly screened women still need to be screened in this age group.  S/p hyst with cervix removed & normal screening history No screening Any abnormal findings require more aggressive evaluation and follow up as per the new management guidelines Excluded “high risk patients”

7.  ASCCP excluded  ACOG: annual screening for immunosuppressed, DES unclear  NCCN: HIV, solid organ transplant, or long term steroid use, DES  USPTF: excluded  AMA: not addressed  WHO: HIV, prior treatment for dysplasia  ACP: Excluded

9. Management of Abnormal Pap Smears (cytology) Management of Colposcopy Biopsies (histology) Follow up after treatment (excision, ablation)

10. 2013 Management Guidelines Very complicated and difficult to follow

11.  30 pages long  12 algorithms  7 for pap smear follow up  5 for colposcopy finding follow up  Unclear which are evidence based and which are only expert opinion

13.  Review data:  HIV positive  Immunosuppressed  Patients with abnormal or inadequate prior screening histories

14.  Onset of screening within 1 year of sexual activity or by age 21; pap q 6 months x2  If normal results-> annual cytology and pelvic exam, including vulva, anus, cervix and vagina  All women with abnormal test results need evaluation and more frequent follow up  Status of disease (poor CD4 counts or expected life expectancy less than 2 years) may alter recommendation New guidelines expected soon that may lengthen the interval for women with all normal results

15.  Definition of “immunocompromised” varies  May include various rheumatologic diseases, organ transplants or women on immunosuppressive medications  Increased rates of vulvar (greatest relative increase), vaginal and cervical cancer relative to immunocompetent women— need annual pelvic exam including the cervix, vagina, vulva and anal areas  Increased rates of LSIL abnormalities  Increased rates of cervical HSIL/cancer were generally modest D o thorough pelvic exam, and make sure immunosuppressed patients at a minimum adhere to standard screening schedules. Consider more frequent screening for severely immunosuppressed patients. Evaluate and treat all abnormal results

16. Are women with a prior abnormal or inadequate screening history “high risk” ?  Information mostly derived from Kaiser’s large dataset  Health system with excellent tracking, insurance, systems to bring patients back for appropriate testing and management  Data based on earlier screening practices with more frequent evaluation and more aggressive management  true rates of cancer or pre-cancer with the current guidelines cannot be assessed (since patients are not being detected and treated as often)  May not be generalizable to all settings

17. Kaiser data >30 year old women, tested positive for HPV Past positive HPV test OR abnormal Pap -significantly higher risk CIN2+ than newly acquired infection unknown prior screening history for ASCUS /HPV+ women with unknown screening history: -the 4 year cumulative risk of CIN2 was 23 % and of CIN3 was 13% -similar to women known to have had known prior abnormal results THUS KNOWLEDGE OF THE PAST SCREENING AND RESULT HISTORY MATTERS

18.  Kaiser women >25 years old Screening results antecedent to colposcopy affected 5 year risk of CIN2  No group had sufficiently low risk to return to “routine” screening  If prior Pap showed ASC-H or HSIL, there was no group that could be returned to even less frequent co-testing Pap cytology Colposcopy histology 5 year risk of CIN2+ ASCUS/LSI L CIN1 or less10 % ASC-HCIN1 or less16% HSILCIN1 or less24%

19.  Kaiser >30 year old women  5 year risks of recurrence after treatment varied by antecedent screening result and path  No subgroup of women achieved risk sufficiently low to return to the new routine screening  Recommendation is co-test at 12,24,36 months then “routine” Pap –CytologyColpo biopsy- histology 5 year risk of recurrence post rx ASCUS/HPV+ or LSIL CIN 2 5% ASCUS –H or worseCIN3/ACIS16%

20. -after any abnormal cytology ? -after any abnormal histology? -after treatment for histologic abnormality? Recommendations for surveillance post abnormality -based on weakest data, may be misleading

21. Cost effectiveness study Surveillance strategies after treatment for HSIL Hypothetical Women >30 yo British Columbia Cohort Study Results: Paps at 6 and 12 months followed by annual conventional cytology surveillance reduced cervical cancers and cancer death compared with triennial cytology HPV cotesting increased cost but did not improve outcome Adding colposcopy at 6 months for high risk women, increased life expectancy

22. Makes key points with respect to how data is interpreted and understood with respect to guideline development.  Cost and benefits need to be considered and may vary with different life situations/populations.  Q 3 year Pap or q 5 year cotesting are known to increase cancer rates relative to annual cytology.  Adverse effects of treatment (LOOP) may have been overstated.  Annual cytology remains the gold standard for cancer prevention

23.  Studied cost-effectiveness of current screening practice v. guideline screening  Used data from New Mexico HPV Pap registry  Assumed pap q 3 years 21-65 OR pap q 3 years 21-30 and Cotesting q 5 years  Assumed 100% compliance with colposcopy for abnormals and 100% compliance with excisional procedures as per guideline  Found that the most cost-effective option was pap q 3 years with evaluation of all abnormals and excisional treatment of all precancers as per guideline  Over and under screening/management were both less cost-effective  Did not stratify by risk group or prior treatment

24. Date of download: 10/15/2015 From: Inefficiencies and High-Value Improvements in U.S. Cervical Cancer Screening Practice: A Cost- Effectiveness AnalysisImproving U.S. Cervical Cancer Screening Practice Ann Intern Med. Published online September 29, 2015. doi:10.7326/M15-0420 Copyright © American College of Physicians. All rights reserved.American College of Physicians

25.  Screen q 3 years or cotest q 5 after 30 if all normal results  Evaluate all abnormal results  Treat all HSIL, AIS or persistent LSIL (in some cases)  Ensure 100% compliance with screening, evaluation and management Treat all patients with a history of abnormal results or an inadequate screening history as “high risk” and increase surveillance of this group

26.  HPV 16/18 account for 77% cervical cancers and 54% high grade lesions in US  As successive cohorts are vaccinated, fewer women may get these infections  Primary screening with HPV and triage to cytology might be the logical next step

27. Canadian Cervical Cancer Screening Trial Women ages 30-69 Compared conventional Pap and HC2 Mayrand, M-H. N Engl J Med 2007 Human Papillomavirus DNA versus Papanicolou Screening Tests for Cervical Cancer

28.  Combined results of 4 studies (Sweden, the Netherlands, England and Italy).  Primary HPV 60-70% greater protection against invasive cervical cancer than primary cytology after first 2.5 years.  Negative HPV at 5 years had better negative predictive value (NPV) than normal cytology at 3 years.  However, studies involved many different treatment and management algorithms reporting markedly different costs for screening, depending on strategies used.

29. Methods:  Cobas HPV test  Cytology and HPV co-collected  Options compared included:  Reflex HPV  Hybrid (cytology under 30 and cotesting above 30)  Primary HPV with 16/18 triage or cytology triage (if HPV12+) Results:  Primary HPV detects more CIN2+ but at cost of more colposcopies Limitations of the study : Only 3 years of follow up data Patients managed by specific study algorithms which may not be available in all clinic settings.

30.  12,000 women are still getting cervical cancer in the US—could we initiate primary HPV screening on unscreened women?  Young women who have been vaccinated have a lower risk of getting HR HPV, so fewer women will test positive and need evaluation. HRHPV screening may increase detection of AIS in this age group.

32. Primary HPV Screening 16/18CytologyVIAColpoSee & Treat Options for triage for HPV+ Different situations determine which is best Need ongoing studies to guide management

33. Ultimately a combination of vaccine in younger women and screening for carcinogenic HPV in older women may revolutionize cervical cancer prevention See Schiffman, M, Castle, PE. The Promise of Cervical Cancer Prevention. NEJM 353:20, 2101-2104, 2005