Perfecting the Prevention of Cervical cancer. I have no financial interests in any product I will discuss today. Preview

Size: px

Start display at page:

Download "Perfecting the Prevention of Cervical cancer. I have no financial interests in any product I will discuss today. Preview"

Nathan Anthony
5 years ago
Views:

financial interests in any product I will discuss today.

1 Perfecting the Prevention of Cervical cancer Rebecca Jackson, MD Associate Professor Obstetrics, Gynecology & Reproductive Sciences and Epidemiology & Biostatistics I have no financial interests in any product I will discuss today. Preview Effectiveness of Cervical Cancer Screening Program in US - Can we do better? Effectiveness (and safety) of HPV vaccine 1

2 Cervical Cancer in the US Cervical Cancer in the US 3.5 million women have abnormal pap results in the US annually (about 7% of total paps performed); 4.4% of pap results are ASCUS 2006: 9700 new cases of invasive cervical cancer, 3700 deaths Pap screening is the most effective cancer screening program ever invented cervical cancer deaths have decreased 75% as a result of Pap screening 50% of women in the US with cervical cancer were never or rarely screened Risk Factors for Cervical Cancer Persistent high risk HPV infection Little or no history of Pap screening History of cervical dysplasia Smoking Parity Increasing age Immunosuppression Other sexually transmitted infections Failure to use condoms? Role of HPV in Cervical Cancer Nearly 100% of cervical cancer is due to HPV infection Specifically, it is due to persistent high risk HPV infection - Infections are sexually acquired in teens, twenties (40% prevalence within 2 yrs of sex) - Most HPV infections are transient (<2 yrs) In most cases, the body s s immune system eliminates HPV infection; rarely do symptoms occur 2

3 Do condoms prevent HPV? Natural History Risk FactorsF Frequency of condom use < 5% 5 49% 50 99% 100% Adj HR (95% CI) -- ( ) ( ) 0.9) ( ) 0.6) About 60% regress within 2-3 yrs Normal Cervix HPV-related Changes HPV Infection No. of new sex partner 0 1 More than 1 No. previous partners of sex partners 1+ or unknown None ( ) ( ) -- (0-0.2) 0.2) Low-Grade SIL (Atypia, CIN I) About 15% progress within 3-4 yrs High-Grade SIL (CIN II, III/CIS) 30% - 70% progress within 10 yrs Invasive Cancer Cofactors High-Risk HPV (Types 16, 18, etc.) Source: PATH Winer, NEJM : Factors Contributing to Cervical Cancer NIH Consensus Conference 50%-60% Never or Rarely Screened Uncommon CA difficult to detect False negative cytology test Cytology abnormal, lost to follow-up Cytology abnormal, mismanaged Rapidly progressive 9-12% 5-10% 5-10% 10-15% 10-15% 14%-22% not detectable by screening Improving cervical cancer screening Screen Screen unscreened women - Half of cancers occur in these women - Tend to be poor, uninsured, with lack of access to care Decrease false positives (and therefore unnecessary colposcopy) Decrease over-treatment treatment (and therefore unnecessary excision) Increase sensitivity of screening (5-10%) 3

4 Who does not get screened? Harms of over-treatment Group All women Insured Yes No Country of birth US born Foreign born in U.S. <10 yrs Race/Ethnicity Hispanic Non-Hispanic White Non Hispanic Black Asian Pap past 3 years 82% 85% 62% 83% 61% 77% 83% 84% 71% 30% of CIN3 and 60% of CIN2 regress spontaneously We have no tests to determine which will progress vs regress Excision of these lesions is by definition, over- treatment ASCCP has encouraged less aggressive treatment of certain groups (esp( adolescents) Swan J, Breen N, Coates RJ, Rimer BK, Lee NC. Progress in cancer screening practices in the United States: results from the 2000 National Health Interview Survey. Cancer. 2003;97: Potential adverse effects of LEEP Preterm delivery Low birth weight Preterm premature ROM 70% increase 82% increase 169% increase Preterm premature 169% increase No randomized trials. Lancet : Q1. A 22 year old woman, sexually active for 4 years, presents for an annual exam. What cervical cancer screening method will you use? 1.Do not screen at this time 2.Pap smear only 3.Liquid based cytology (LBC) only 4.Pap or LBC plus primary HPV testing 5.Pap or LBC plus reflex HPV testing for ASCUS 4

Positive predictive value using 1.6% prevalence: 43% (pretty good). Why does the pap smear work?

5 Is the pap smear a good test? It is far from perfect! It is acceptable about about 90% of women in the US are screened It is not very sensitive, specificity range is wide - Sensitivity: about 80% (as low as 50%) - Specificity: about 98% (as low as 78%) Positive predictive value using 1.6% prevalence: 43% (pretty good). Why does the pap smear work? Sensitivity and specificity not so great BUT Natural history is favorable (precursor exists and is detectable and 100% treatable; time course is long) Thus, there are many opportunities to detect dysplasia: even if one test is false negative, get another chance It is cost-effective because many many years of life are saved because cancer is actually prevented. Improving sensitivity: Liquid based cytology? For years, LBC (Thin-Prep) advertised as: more sensitive similarly or slightly less specific fewer unsatisfactory readings These conclusions based on observational studies. Now, 3 RCT s s completed. 2 smaller, 1 very large (45,000) Obwegeser Acta Cyto 2001, Taylor Int J Cancer Ronco BMJ 2007 Improving sensitivity: Liquid based cytology? RCT results Obwegeser: : No difference sensitivity or specificity, more unsatisfactory tests in LBC Taylor: : Sensitivity 5% lower for LBC, specificity similar, more unsatisfactory tests in LBC Ronco (n=45,000): Increased rate of ASCUS, increased sensitivity for CIN1 but not CIN2+, decreased specificity, fewer unsatisfactory tests Obwegeser Acta Cyto 2001, Taylor Int J Cancer Ronco BMJ

6 Decreased specificity of LBC: RCT results Decreased specificity= more false positive results, more unnecessary work-ups. With LBC, more colposcopies done and more CIN 1 found, but no difference in CIN 2+ or CIN 3+ detected. 855 (3.8%) vs 1434 (6.3%) colposcopies performed Bottom line: LBC similar sensitivity, worse specificity, more expensive Ronco BMJ 2007 Improving sensitivity/specificity: HPV testing 1. HPV triage for ASCUS (ie( if HPV+, then colpo.. If negative, 1 yr re-screen) 2. HPV co-test: HPV plus cytology (aka primary HPV screening) Hybrid Capture-2 2 used (13 HR HPV types) HPV triage of ASCUS ALTS: immediate colpo vs reflex testing with HPV vs repeat cytology. (but repeat cytology arm only got colpo for hsil or greater not current practice) Immediate colposcopy not typically used in practice. Typical choice is repeat cytology with colpo if >ASC vs HPV triage of ASCUS Using HPV reflex decreases colpo by 55% compared to immediate colpo (but unknown rate of colpo for repeat cytology as practiced today) Unclear what to do with HPV +, colpo negative (40%) Bottom line: HPV triage may decrease number of colpos but this has not been studied in an RCT Am J Obstet Gynecol 2003;188:

7 Primary screening with HPV Useful if it can reliably distinguish women who need either more or less intensive pap testing 2 new RCT s s comparing pap vs LBC+HPV, one in >35 and one in <35. Similar results: increased sensitivity (relative sensitivity 1.47), decrease PPV (relative PPV 0.55) more colpo! Unclear what to do with HPV+, pap- (10%) ACOG, ACS say ok to use q 3yr for >30 yo only (due to low specificity in <30). USPSTF: insufficient evidence Ronco, Lancet Oncol Jul;7(7):547-55, Ronco : J Natl Cancer Inst Jun 7;98(11): Bottom line: Cervical cancer screening Cervical cancer screening very effective. To improve: screen the un-screened or poorly screened (60% of cases) and encourage adequate follow-up (10-15%) 15%) Improving sensitivity will only impact 5-10% 5 of cases ( cases per year) - Liquid based cytology not the answer - Double screen with HPV plus cytology maybe, but lose specificity. Improving specificity is also important in order to decrease needless colposcopies and treatments Q1. A 22 year old woman, sexually active for 4 years, presents for an annual exam. What cervical cancer screening method will you use? 1.Do not screen at this time 2.Pap smear only 3.Liquid based cytology (LBC) only 4.Pap or LBC plus primary HPV testing 5.Pap or LBC plus reflex HPV testing for ASCUS Part 2 Effectiveness and safety of HPV vaccine 7

HPV and Cervical Cancer: Review Cervical cancer is due to

other high risk HPV types (30s, 40s, 50s) - Infections are sexually

yrs) Genital warts: caused by HPV 6 & 11 Gardasil Merck Gardasil

(Cervarix Cervarix is HPV 16/18, GlaxoSmithKline, not yet FDA

8 HPV and Cervical Cancer: Review Cervical cancer is due to persistent high risk HPV infection - 67%: HPV types 16 & 18-33%: other high risk HPV types (30s, 40s, 50s) - Infections are sexually acquired in teens, twenties - Most HPV infections are transient (2 yrs) Genital warts: caused by HPV 6 & 11 Gardasil Merck Gardasil quadravalent vaccine active against HPV 6,11,16,18. (Cervarix Cervarix is HPV 16/18, GlaxoSmithKline, not yet FDA approved) Approved by FDA 2006 Contains virus-like particles (not live virus) 3 doses: 0, 2, 6 months 8

9 Discovery of association between HPV and cervical cancer 1983 HPV vaccine timeline HPV Vaccine developed st Large RCT Published (FUTURE 1) 2002 FDA Approval 2006 Q2. A 22 year old woman, sexually active for 6 years with 7 lifetime partners, presents for an annual exam. What will you recommend regarding HPV vaccination? 1.Do not recommend because of low efficacy in sexually active women 2.Do not recommend b/c >18 yo 3.Do not recommend b/c of other reason 4.Don Don t t bring it up unless she requests it herself then give after discussing risks/benefits and efficacy 5.Discuss risks/benefits and let patient decide 6.Recommend it CDC vs ACS Guidelines CDC Routine vaccination with 3 doses for females yo Can be started as young as 9 years of age Catch-up vaccination for females yo Ideally, vaccine should be administered before potential exposure to HPV ACS Same Catch-up in years old - not yet enough information to recommend vaccinating women yo,, so these women should discuss vaccination with their doctor. Evidence of efficacy: Gardasil 4 RCT s. Largest= FUTURE I and II. All Merck sponsored. Pooled results recently published (Lancet) Multinational study sites; 20,541 women enrolled year old women, majority sexually active, <4 4 lifetime partners Planned follow-up 4 years. Interim results from both FUTURE studies published prior to study end ( year follow-up) Ault, Lancet

Efficacy in girls Recommended to girls aged 9-12.

term UNKNOWN: length of immunity to vaccine, especially if no exposure to HPV UNKNOWN: Efficacy for decreasing dysplasia in this age group (no reason to think it won t t be efficacious if immunity

10 Efficacy in girls Recommended to girls aged Newly sexually active women most at risk of HPV acquisition so want to protect them No efficacy studies in this population Instead, immunogenicity studies that show immunity to hpv 16/18 most short term UNKNOWN: length of immunity to vaccine, especially if no exposure to HPV UNKNOWN: Efficacy for decreasing dysplasia in this age group (no reason to think it won t t be efficacious if immunity sustained) Little known fact: FUTURE I & II not yet complete Future II Future I Both with 3 yrs f/u instead of the planned 4 yrs Gardasil Study Design 3 subgroups studied 1. susceptible per protocol group: virus naïve at start and throughout the vaccination period, received all doses 2. unrestricted susceptible per protocol : virus naïve at start but may have become positive during vaccination period, received all doses 3. general population impact ie an intention to treat (ITT) group: virus naïve or exposed at start or during, protocol violators Main outcome HPV 16/18 associated dysplastic lesions (CIN1+) Secondary outcome of total dysplasia regardless of HPV type is reported for some but not all of subgroups above 10

11 Gardasil: : Pooled RCT results HPV16/18 assoc CIN2+ Gardasil: : Pooled RCT results All CIN2+ (not just HPV 16/18 assoc) Efficacy against 16/18 lesions at 3-44 years** RR (1-efficacy) ARR NNT Per Protocol & virus naïve (best case scenario) 0.01 (0-0.07) 0.07) 9.8 per 1000 ( per 1000) 102 ITT*and not virus naïve (sex active) 0.56 ( ) 0.69) 11 per 1000 (25 14 per 1000) 92 Efficacy against all CIN2+ at 3-43 years** RR (1-efficacy) ARR NNT Per Protocol & virus naïve (best case scenario) Not given Not given Not given ITT*and not virus naïve (sex active) 0.82 ( ) 0.93) 8.6 per 1000 (47 38 per 1000) 116 * ITT=intention to treat **CIN 2/3 and AIS lesions caused by HPV 16/18 only * ITT=intention to treat **CIN 2/3 and AIS lesions regardless of HPV type ITT: Reduction in CIN2/3 + AIS HPV 16/18 lesions Lesions due to any HPV type Other expected benefits Reduce incidence of abnormal Paps and cost of subsequent work up (via reduction in transient HR-HPV HPV infections that cause abnormal Paps) Reduce occurrence of genital warts and cost of treatment (quadrivalent( vaccine) Reduce need for treatment of CIN and its sequelae Reduce cervical cancer death among unscreened and rarely screened women 11

12 Catch-up vaccination? Modest benefit (RRR = 18%) in young (<26) sexually active (<4 partners) women CDC, ACOG, Kaiser recommend recommend up to age 24 or 26. Nothing yet from USPSTF. ACS up to 18 b/c of lack of efficacy in older women What about a risk based approach? Can we better target women who will most benefit rather than using an age based cutoff? Subgroup analysis may help: by age, by yrs since first intercourse, by number sex partners (none( published yet) Difficult for adolescents to be truthful about sexual activity (especially if need parental permission for vaccine!) Pain Swelling Erythema Pruritus Fever Is it safe? Gardasil (N=5,088) 83.9% 25.4% 24.6% 3.1% 10.3% Placebo: Al 75.4% 15.8% 18.4% 2.8% Al (N=3,470) Gardasil (N=5,088) Placebo: NaCl 48.6% 7.3% 12.1% 0.6% NaCl (N=320) PBO (N=3,790) 8.6% Few subjects (0.1%) discontinued due to adverse experiences. Increased risk of anomalies? High rate of pregnancy (15%) even though contraception was recommended No overall increased risk of congenital anomalies However, in those vaccinated within 30 days of conception, statistically significant increased risk of anomalies: 7.1% vs 0 %. - Anomalies common and unrelated so likely not due to vaccine - 0% in placebo group less than expected 2-3% 2 rate in population Should we strongly recommend contraception pending further results? 12

13 The multi-million million dollar question: Will it decrease cervical cancer rates? For the vaccine to reduce rates of cervical cancer, we need to vaccinate women not currently being adequately screened. - Won t t these same women have trouble accessing the vaccine (poor, uninsured, recent immigrants)? - Targeting adolescent population difficult b/c no annual health exams Will vaccination decrease screening rates? Women need to continue routine screening to detect the 30% of non-16/18 dysplasia. In women being adequately screened, main benefit will be in reducing dysplasia, its work-up and treatment. A few more issues High cost - $360 for the 3-dose 3 series - What is being traded off? Replacement of HPV 16/18 with other HPV types - Will HPV 16/18 simply be replaced by other high risk HPV types thereby reducing vaccine effectiveness? - The rate of overall dysplasia not given in virus naïve group why not? Social concerns - Parental objections due to discomfort with sex - Pressure of Merck on legislators to mandate the vaccine Education - Lack of public knowledge about HPV - Potential for miscommunication about HPV risks, vaccine impact, need for Pap screening Q2. A 22 year old woman, sexually active for 6 years with 7 lifetime partners, presents for an annual exam. What will you recommend regarding HPV vaccination? 1. Do not recommend because of low efficacy in sexually active women 2. Do not recommend b/c >18 yo 3. Do not recommend b/c of other reason 4. Give only if patient requests it herself and after discussing risks/benefits and efficacy 5. Discuss risks/benefits and let patient decide 6. Recommend it Summary: HPV vaccine Very efficacious in virus naïve women Modestly efficacious in sexually active women Caveats: Studies not yet complete No studies on efficacy in girls <15 yo Don t t know duration of action Some evidence of harm (anomalies) (recommend contraception?) 13

First do no harm Preventative interventions require a very high standard of evidence for efficacy and safety - A large number of healthy people is invited in to receive an intervention.

14 First do no harm Preventative interventions require a very high standard of evidence for efficacy and safety - A large number of healthy people is invited in to receive an intervention. That intervention had better be beneficial. - Many examples of screening and prevention harms due to implementation prior to strong RCT data of net benefit First do no harm What is the urgency for HPV vaccine now? Why not wait until studies are complete, until we have studied efficacy in the recommended target population, until we have clarified the birth defect question? 14

Objectives. I have no financial interests in any product I will discuss today. Cervical Cancer Screening Guidelines: Updates and Controversies

Objectives. I have no financial interests in any product I will discuss today. Cervical Cancer Screening Guidelines: Updates and Controversies Cervical Cancer Screening Guidelines: Updates and Controversies I have no financial interests in any product I will discuss today. Jody Steinauer, MD, MAS University of California, San Francisco Objectives