Cervical Cancer Screening - Improving PAP Rates. Objectives

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1 Cervical Cancer Screening - Improving PAP Rates Dineo Khabele, MD, FACOG, FACS Assistant Professor Division of Gynecologic Oncology Vanderbilt University Medical Center Objectives 1. Review the current guidelines for cervical cancer screening. 2. Review human papillomavirus (HPV) testing and vaccination. 3. Discuss disparities in cervical cancer screening and prevention. 1

2 Cervical Cancer 11, 070 new cases and 3,870 deaths from cervical cancer in the US in million women undergo Pap testing in the U.S./ year 3.5 million (7%) are diagnosed with a cytological abnormality requiring additional follow-up or evaluation Approximately 500, new cases in the world, mainly in developing countries 273,500 deaths worldwide Jemal, CA Cancer J Clin Wright, JAMA Cervical Cancer: Risk Factors Persistent high risk human papilloma virus (HPV) infection Three or more lifetime sexual partners First sexual intercourse before age of 18 Smoking Maternal DES (diethylstilbesterol) exposure during pregnancy A previous abnormal Pap smear Never having had a Pap or not having one in the previous 5-10 years 2

United States since 1950 1 Specificity 86-95% Sensitivity 50-80% 1 Herrero R.

3 Conventional Cervical Cytology (Papanicolaou Smear) Dr. George N. Papanicolaou Introduced in Responsible for a >80% reduction in the incidence of invasive cervical cancer & in mortality in the United States since Specificity 86-95% Sensitivity 50-80% 1 Herrero R. Monogr NCI 1996; 21:1-6 Cervical Cancer: Have we decreased the incidence in the U.S.? With the advent of the Pap smear, the incidence of cervical cancer has dramatically declined. However.the curve has been stable for the past decade in part because we are not reaching the unscreened population. 3

4 Disparities in cervical cancer mortalitiy. All White African American Asian American/ Pacific Islander American Indian/ Alaskan Native Hispanic/ Latino (TN = 7.2) Pap screening in African-American women is underutilized Current Pap test screening rates (~84%) fall short of the Healthy People 2010 objective:screening of 90% of age-appropriate women The rate of not having had a Pap test in the past 3 years remains unchanged at approximately 16% for African American women BRFSS,

CLINICAL MANAGEMENT GUIDELINES FOR OBSTETRICIAN GYNECOLOGISTS NUMBER 45, AUGUST 2003 (Replaces Committee Opinion Number 152, March 1995) Cervical Cytology Screening ACOG Screening Guidelines: When to

5 CLINICAL MANAGEMENT GUIDELINES FOR OBSTETRICIAN GYNECOLOGISTS NUMBER 45, AUGUST 2003 (Replaces Committee Opinion Number 152, March 1995) Cervical Cytology Screening ACOG Screening Guidelines: When to Start 3 yrs after onset of intercourse & no later than age 21 Earlier screening might over-diagnose lesions that would regress spontaneously, leading to over intervention Cancer rarely seen 19 Only 1.7% adolescents estimated to harbor HSIL 70-90% HPV regression rates within 3 years 1, % LSIL regression in yo (50-80% in adult women) 1 1 Moscicki AB. J Pediatr 1998; 132: Ho GY. NEJM 1998; 338:

6 ACOG Screening Guidelines: When to Stop Difficult to set an upper age limit for screening ACS Guideline Discontinue After Age 70 USPSTF Guideline Discontinue After Age 65 Cervical cancer in older women almost entirely among unscreened & underscreened Screening in women over 50 may be less efficient Continue routine screening if: Remains sexually active w/ multiple partners Has previous Hx of abnormal pap smears ACOG Screening Guidelines: After Hysterectomy Not indicated after total hysterectomy (includes removal of cervix) for benign gynecologic disease 1.1% vaginal paps after hysterectomy abnormal 1 Mean length of time after hysterectomy 19 years vaginal paps needed to detect one case of vaginal dysplasia 2 1 Pearce KF. NEJM 1996; 335: Piscitelli JT. Am J Ob Gyn 1995; 173:

7 ACOG Screening Guidelines: After Hysterectomy w/ CIN 2/3 prior to or at time of hysterectomy, y annually until 3 consecutive normal smears w/ history DES exposure or Cervical Cancer, screen indefinitely while in reasonably good health Increased risk for vaginal cancer Error on side of screening if accurate information unavailable ACOG Screening Guidelines: Screening Interval After age 30 & 3 consecutive normal smears, may screen every 2-3 years Unless new partner, HIV (+), DES, chronic steroid use, or immunocompromised Women w/ prior abnormal results not considered screening (surveillance group) May also combine with HPV testing ti to extend interval to 3 years 1 Frame PS. J Am Board Fam Pract 1998; 11: Sawaya GF. ASCCP March Abstract 7

8 Pap Diagnoses Preceding Histologic High-Grade Neoplasia LSIL 20% AGC 10% 39% ASC 31% HSIL Modified from Kinney W, et al. Obstet Gynecol. 1998;91: Natural History of HPV Infection 0 to 2 Year 0 to 3 Years Up to 20 Years Initial HPV Infection Continuing Infection CIN 1 CIN 2/3 or AIS E6 & E7 interference w/ p53 & prb Cervical Cancer Cleared HPV Infection Type Specific Immunity 8

HPV Clearance Most HPV infections are transient In women 15 25 years of age, ~80%

infections cleared within 1 year and 91% within 2 years 3 Median duration of

HPV 18) 1. Meijer CJLM, et al. Histopathology. 1998;33:83 6. 2.

9 HPV Clearance Most HPV infections are transient In women years of age, ~80% of HPV infections resolve spontaneously 1 In 608 college women, 70% of new HPV infections cleared within 1 year and 91% within 2 years 3 Median duration of infection = 8 months 3 Certain HPV types are more likely to persist (eg, HPV 16 and HPV 18) 1. Meijer CJLM, et al. Histopathology. 1998;33: Schiffman M, Kjaer SK. J Natl Cancer Inst Monogr. 2003;31: Ho GYF, et al. N Engl J Med. 1998;338:

30% ) Percentage HPV (+ 25% Any HPV High-risk HPV 20% 15% 10% 5% 0% 15 20

Cancer 2004:91:942-53 Combination HPV/Pap tests are approved for screening

3 years when both tests negative HPV prevalence ranges from 5-10% About

10 30% ) Percentage HPV (+ 25% Any HPV High-risk HPV 20% 15% 10% 5% 0% Age Group Peto et al Br. J. Cancer 2004:91: Combination HPV/Pap tests are approved for screening in women ages 30+ Minimize overtreatment and cost by screening only every 3 years when both tests negative HPV prevalence ranges from 5-10% About 60% have negative cytology Fetterman et al. JLGTD 2006;3:179; Cuzick et al. Lancet 2003;362:

11 11

Natural History of HPV 20514 women in Kaiser Permanente HPV 16+ Portland, OR followed HPV 18+ for 10 years Cumulative incidence rates of CIN3 HC2+ 17.2 % for HPV 16+ 13.6% for HPV 18+ 3.

12 Natural History of HPV women in Kaiser Permanente HPV 16+ Portland, OR followed HPV 18+ for 10 years Cumulative incidence rates of CIN3 HC % for HPV % for HPV % for 11/13 HC2+ 0.8% for HC2- HC2- From Khan MJ, et al. JNCI 2005; 97: HPV Seattle, Washington college students 36 month cumulative risk of CIN2-3 Any incident HPV 10% Incident HPV 16/18 27% Median time to detection of CIN2-3 was only 14 mo after HPV detection From Winer, et al. J Inf Diseases

13 HPV Vaccines HPV 16 and 18 Prevalence by Cytology Sentinel Surveillance ( ) Prevalence (%) Any abnormality ASCUS LSIL HSIL HPV 18 HPV 16 Centers for Disease Control and Prevention, preliminary/unpublished data. Modified from CIP. June Available at Accessed on March 3,

14 Most Prevalent HPV Types That Cause Cervical Squamous Cancer -infected patients (%) All HPV % 13% >70% of cases HPV 16 of cervical cancer HPV 18 are associated with HPV 16 or 18 HPV 45 HPV 31 HPV 33 5% 4% 3% 0 HPV 16 HPV 18 HPV 45 HPV 31 HPV 33 N=1918 patients. Munoz et al. N Engl J Med. 2003;348: Based on a worldwide survey. Most Prevalent HPV Types That Cause Cervical Adenocarcinoma ence of HPV type in adenocarcinonma (%) Preval cases of % 32% 8% 4% HPV 16 HPV 18 HPV 45 Multiple types HPV DNA was detected in 93% of patients with cervical adenocarcinoma. Castellsague X et al. J Natl Cancer Inst. 2006;98:

Prevalence of HPV in Genital Warts >90% of cases of genital warts are

4 Million annual visits to physicians 1. Brown DR et al.

Natural History of HPV Infection 0 to 2 Year 0 to 3 Years Up to 20 Years

15 Prevalence of HPV in Genital Warts >90% of cases of genital warts are associated with HPV types 6 and Million annual visits to physicians 1. Brown DR et al. J Clin Microbiol. 1999;37: Natural History of HPV Infection 0 to 2 Year 0 to 3 Years Up to 20 Years Initial HPV Infection Continuing Infection CIN 1 CIN 2/3 or AIS E6 & E7 interference w/ p53 & prb Cervical Cancer Cleared HPV Infection Type Specific Immunity 15

Immunization Against HPV Studies suggest type-specific immunity to HPV 1 Type-specific

that induce type-specific neutralizing antibodies 2 Self assembled L1 protein VLPs are

Cancer Epidemiol Biomarkers Prev. 2004;13:324-327. 2. Schiller JT et al.

16 Immunization Against HPV Studies suggest type-specific immunity to HPV 1 Type-specific neutralizing antibodies 2 Virus-like particles (VLPs) are recombinant viral capsids that induce type-specific neutralizing antibodies 2 Self assembled L1 protein VLPs are highly immunogenic 2 Photo courtesy of Margaret Stanley. 1. Viscidi RP et al. Cancer Epidemiol Biomarkers Prev. 2004;13: Schiller JT et al. Nat Rev Cancer. 2004;2: Quadrivalent L1 VLP Vaccine Prevention of HPV 6/11/16/18 Infection & Disease 16

Prevention of HPV 16/18-related Abnormal

Vaccine (Women 16 26 years) 100% 75% 50% 93%

85-97 25% 0% N (Vaccine)= 1021 N (Placebo)=

17 Prevention of HPV 16/18-related Abnormal Cervical Cytology by Quadrivalent L1 VLP Vaccine (Women years) 100% 75% 50% 93% 8 cases Vaccine 108 cases Placebo 95% CI % 0% N (Vaccine)= 1021 N (Placebo)= 1023 ASC-US (positive by high risk probe), LSIL, or worse 17

18 Reduction in Any Abnormal Pap tests Regardless of Causal HPV type by Quadrivalent L1 VLP Vaccine % 16% 35% 43% 0 ASC-US HR + LSIL ASC-H HSIL Cases Placebo Cases Vaccine W Huh, SGO 2008 Adverse Events in HPV 6/11/16/18 Studies Injection-site reactions (pain, redness, swelling) most common Most common general adverse events were fever and nausea No difference between vaccine & placebo SAEs occurred in <0.1% of both groups Among women becoming pregnant on trial Incidence fetal loss similar between groups (38% vs. 40%) Incidence congenital anomalies similar (15 vs. 16) includes pyloric stenosis, congenital megacolon, congenital hydronephrosis, hip dysplasia, and club foot 18

19 Gardasil Vaccine Reports to VAERS Guillain-Barré Syndrome (GBS) GBS occurs in 1-2 out of every 100,000 people in their teens There has been no indication that Gardasil increases the rate of GBS in girls and women above the rate expected in the general population Blood Clots Rarely, people have reported blood clots after Gardasil Most had a risk of getting blood clots, such as taking oral contraceptives Deaths As of December 31, 2008, there have been 32 U.S. reports of death among females who have received the vaccine There was no common pattern to the deaths that would suggest that they were caused by the vaccine Page last reviewed: March 29, 2009 Page last updated: March 3, 2009 Content source: Immunization Safety Office, Office of the Chief Science Officer Subjects Exposed to Any Vaccine HPV Type at Enrollment Efficacy Studies Combined Population Baseline HPV Status Naïve to all 4 types Positive to 1 type Positive to 2 types Positive to 3 types 73% 20% 6% 93% of subjects were naïve to 3 vaccine HPV types (6, 11, 16, or 18) at enrollment. Positive to 4 types 1.2% 0.1% Among subjects who were positive to a vaccine HPV type, most were positive to only 1 type. Exclusion criteria: 6 or more sexual partners 19

20 Indications and Use: Quadrivalent L1 VLP Vaccine Indicated in girls and women 9 to 26 years of age for the prevention of the diseases caused by HPV types 6, 11, 16, and 18: Cervical cancer Genital warts (condyloma acuminata) Dysplastic lesions: Cervical AIS CIN grades 2 and 3 VIN grades 2 and 3 VAIN grades 2 and 3 CIN grade 1 Gardasil Package Insert * 3 IM injections: 0, 2 and 6 months Shots for Girls Stir Early-Sex Concerns - June 2006 The Tennessean I would love to hear how to separate out the moral issues to a nine year old who is questioning why she needs such a vaccine. The laws and commands of God cannot and should not be separated for any reason. We have forgotten that He gave us laws and commands for our own good! Dr. Khabele failed to consider there would be little need for this vaccine if we taught biblical principles of sex. 20

21 Where can we intervene to close the gaps? BEDSIDE (Patient and Provider) Access to Care Education and Awareness Knowledge, Attitudes and Beliefs RESEARCH Clinical Trials Health Services and Health Outcomes Research Bench Research COMMUNITY (Policy & Public Health) Health Access to Care Education and Awareness Knowledge, Attitudes and Beliefs Conclusions 1. Management guidelines exist for cervical cancer screening 2. HPV vaccines have been developed to protect against the most common HPV types 1. Quadrivalent vaccine protects against HPV 6, 11, 16, Bivalent vaccine protects against HPV 16, A multi-pronged approach is needed to reduce disparities in cervical cancer screening, prevention, incidence and mortality 21

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