Eradicating Mortality from Cervical Cancer

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1 Eradicating Mortality from Cervical Cancer Michelle Berlin, MD, MPH Vice Chair, Obstetrics & Gynecology Associate Director, Center for Women s Health June 2, 2009

2 Overview Prevention Human Papilloma Virus (HPV) Vaccine Early Detection & Treatment Pap Screening Evaluation of Pre-Cancer

3 Cervical Cancer 500,000 new cases worldwide each year Leading cause of cancer-related death in women in underdeveloped countries United States ~11,070 new cases & 3,870 deaths (est. 2008) Oregon: 90 new cases (est. 2008) % association with HPV HPV 16 associated with >60%

4 Natural History of Cervical Cancer HPV Infection Low-Grade Cervical Dysplasia High-Grade Cervical Dysplasia Invasive Cancer Source: PATH, 2001

5 History 1943 Papanicolau & Traut, USA, report exfoliative cytology as research tool c Pap smears become used in clinical medicine

6 Prevention Current best strategy: Human Papilloma Virus (HPV) Vaccine

7 Human Papilloma Virus (HPV) HPV Capsid, Dr Xiaojiang Chen, University of Colorado Health Sciences Center

8 Human Papilloma Virus (HPV) Approximately 20 million Americans and 630 million persons worldwide are infected with HPV Most common STI in the US with 6.2 million individuals acquiring a new infection each year CDC estimates that 80% of women will acquire an HPV infection by age 50

HPV Vaccine: The New Frontier June 8, 2006: FDA approved first HPV vaccine for clinical use Quadrivalent vaccine consisting of recombinant viral-like

9 HPV Vaccine: The New Frontier June 8, 2006: FDA approved first HPV vaccine for clinical use Quadrivalent vaccine consisting of recombinant viral-like particles (VLPs) of HPV 6, 11, 16, 18. Administered IM as 3 injections: 0, 2 and 6 months Bivalent vaccine for HPV 16 and 18 likely to be approved in the near future

10 HPV Subtypes High risk due to strong association with cervical cancer 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 In US, HPV16 associated with 59% of cervical cancer cases, HPV18 with 18%, HPV 45 with 7% Low risk subtypes (6, 11) associated with low grade dysplasia, genital warts

proteins made indicating virion assembly at this

replication continues rapidly 6 Week Early gene

11 Episomal vs. Integration Episomal HPV 16 Releasing infectious particles into the cervical and vaginal secretions Integrated HPV 16 8 week L1 L2 capsid proteins made indicating virion assembly at this level of cellular differentiation Viral DNA replication continues rapidly 6 Week Early gene expression E6/E7 4 Week Early gene expression E4/E5 HPV Basal Stem Cell HPV Infection CIN 2/3

12 Lifetime Risk Reduction for Cervical Cancer after Vaccination

13 Vaccine Indications a vaccine indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18: Cervical cancer, genital warts, cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia grade 2 and grade 3, vulvar intraepithelial neoplasia grade 2 and grade 3, vaginal intraepithelial neoplasia grade 2 and grade 3, cervical intraepithelial neoplasia grade 1

14 ACIP Recommendations Routine vaccination of year old females Vaccination can begin as early as 9 years of age Also routine vaccination of year old females Females who are sexually active should still be vaccinated CDC Advisory Committee on Immunization Practices: m

15 Vaccine Contraindications Hypersensitivity to the active substances of the vaccine Not recommended for use in pregnant patients, Pregnancy Category B Package insert available on FDA website:

16 Vaccine Issues Long term efficacy of vaccine Current data suggest average of up to 8.5 years Current vaccine: Gardisil (Merck) Price quoted as $120 per dose ($360 for course) Most large primary insurers now provide coverage Second vaccine Cervarix (GSK) likely to be approved soon

17 Remaining Issues Vaccination for males? Vaccination of women beyond age 26? If not exposed to HPV? Yes If already sexually active? Likely not to be as effective

18 HPV Vaccine: Key Points to Remember Will prevent infection from occurring for many For those who receive vaccine before exposure to HPV, can prevent pre-cancer and cancer NOT a cure for HPV infection or abnormal cervical findings NOT a replacement for other preventative strategies such as cervical screening Regular Pap smears still needed by women who receive HPV vaccine

19 Screening and Early Detection Screening and Early Detection Pap smear Add HPV test? (Current debate)

20 Pap Smears 50 million/ year 3.5 million (7%) abnormal

21 Screening Guidelines When to Start? When to Stop? Screening after hysterectomy Screening Interval

22 When to Start Old Recommendations: age 18 or with sexual activity American Cancer Society recommendations: 3 years after onset of vaginal intercourse no later than 21 years of age US Preventive Services Task Force: same (no supporting data) 2 1 Saslow D et al. CA Cancer J Clin 2002;52(6): USPSTF. Am Fam Physician 2003;67:

23 When to Stop No definitive data American Cancer Society: age 70 with intact cervix and 3 or more normal Paps in prior 10 years USPSTF: age 65 if adequately screened and not at high risk If older women have not been screened, or if past screening info not available, then need 3 normal Pap results before can stop screening

24 Pap Tests After Hysterectomy USPSTF (2003): If cervix removed as part of hysterectomy, no further Pap testing needed UNLESS: hysterectomy was performed for cervical cancer or cervical dysplasia (dysplasia = pre-cancer) American Cancer Society: same If CIN 2 or 3 (high grade dysplasia) reason for hysterectomy may stop after 3 normal Paps obtained at 6 month intervals If hysterectomy performed for Carcinoma-in-Situ, screen indefinitely

25 Frequency of Routine Cytologic Screening After a woman has had three or more consecutive annual Pap tests with normal findings, the Pap test may be performed less frequently in low risk women Issue: who is low risk? Estimates from models indicate that screening every 3 yrs would achieve 91-96% of the benefit of annual screening

26 How to obtain Pap screening? Oregon Breast and Cervical Cancer Program Primarily for women over 40 years of age Designed for screening and diagnosis; treatment handled differently Current legislation may expand access

27 How to obtain Pap screening? 211.org Good resource in Portland metro area Growing throughout the state Linked with Oregon SafeNet Other Resources

28 Guidelines for Abnormal Pap Smears

29 American Society for Colposcopy and Cervical Pathology (ASCCP) Established 1964 Convened several consensus conferences re: management of abnormal Pap smears Most recent: 2006

30 Reference Materials American Society for Colposcopy and Cervical Pathology (ASCCP) website Cytology: Algorithms Wright et al. AJOG 2007;197(4); Histology: Algorithms Wright et al. AJOG 2007:197(4):

31 ASCCP Guidelines (2006) Changes from prior guidelines Consistency of follow-up Adolescents: intervene for high grade dysplasia (HSIL) only Pregnant women: can defer colposcopy until after pregnancy

32 ASCCP Guidelines (2006) Clinical Caveat Important to consider patient s ability & likelihood to return for follow-up care If unlikely to follow-up, consider evaluation sooner. Examples: Pregnant women without insurance 6 weeks after delivery Patient unable to return for two visits for evaluation of high grade dysplasia (HSIL)

33 ASCCP Guidelines (2006) Why intervene in adolescents for HSIL (not LSIL)? Most likely to clear HPV infection, so intervention may not be needed for LSIL Consequences of Loop Endocervical Excision Procedure (LEEP) and Cone Biopsy

34 Risks of LEEP and Cone Biopsy Suh-Burgmann (2000) Risk of cervical stenosis after LEEP: % Risk of cervical stenosis after cone biopsy: 6-40% Martin-Hirsch (2004) Cone Biopsy vs. LEEP: no clear evidence Suh-Burgmann, E et al. Obstet Gynecol. 2000; 96: Martin-Hirsch, PL et al. Cochrane Library 2006.

35 Management of Cytologic Abnormalities (Everything you want to know about what to do when the Pap comes back ASCUS, LGSIL, HGSIL or AGUS or don t want to know) Wright TC, Massad S, Dunton CJ et al consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Ob Gyn 2007; 197 (4):

36 ASC-US Atypical Squamous Cells - Uncertain Significance 5-10% harbor serious disease One third of HSIL identified from ASC-US

37 ASC-US

38 Adolescents: ASC-US or LSIL

39 ASC - H Colposcopy If no identified abnormality- repeat Pap at 6 & 12 mos or HPV testing at 12 mos.

40 ASC-H

41 LSIL

42 Pregnant Women: LSIL

43 HSIL Rare % of all Paps 70-75% have biopsy confirmed CIN 2,3 1-2% have invasive cervical cancer

44 HSIL

45 Adolescents: HSIL

46 AGC- Atypical Glandular Cells Rare - 0.5% all Paps = 1/200 Risk of neoplasia significantly greater than ASC or LSIL 9-54% have CIN by biopsy 0-8% have AIS 1-9% have invasive carcinoma Premenopausal women - higher risk of CIN 2,3, AIS Postmenopausal women - higher risk of endometrial hyperplasia and cancer

47 AGC: Initial Workup

48 HPV Testing as Adjunct to Cytology (Women aged >30)

49 Management of Histologic Abnormalities (Or..what to do after you ve got the pathology results back from biopsies at colposcopy) Wright TC, Massad S, Dunton CJ et al consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ Am J Ob Gyn 2007:197(4):

50 Management CIN 1 preceded by ASC or LSIL

51 Management CIN 1 preceded by HSIL or AGC-NOS

52 Adolescents: Management CIN 1

53 Management CIN 2, 3

54 Adolescents: Management CIN 2, 3

55 Management AIS Diagnosed from Diagnostic Excisional Procedure

56 Summary Prevention Human Papilloma Virus (HPV) Vaccine Early Detection & Treatment Pap Screening When? Whom? Access to Services Evaluation of Pre-Cancer

Cervical Cancer Screening Guidelines Update

Frontier AIDS Education and Training Center Cervical Cancer Screening Guidelines Update Hillary Liss, MD Harborview Medical Center, Madison and Adult Medicine Clinics Frontier AETC, Medical Program Director