Cervical Cancer Screening - HPV - www.jinekolojivegebelik.com

CERVICAL CANCER SCREENING: INCORPORATING HPV TESTING M.A. Bertrand, MD, FRCSC Professor & Head, Division of Gynecologic Oncology, University of Western Ontario, London, Ontario, Canada

Epidemiology – Cancer of the Cervix

370,000 cases estimated worldwide ’93; with 200,000 deaths;

3 rd most common cancer in women worldwide;

80% of all cases of cervical cancer occur in the developing countries;

Estimates of the prevalence of pre-invasive lesions range from 1.25 – 3 .0 million (USA)

Epidemiology – Cancer of the Cervix

Incidence rates (per 100,000 women)

Finland 4.3

Canada 7.6 (‘05 estimated rates)

France 9.8

Romania 23.9

Serbia 27.4

Ethiopia 35.5

Latin America 37

Cervical Cancer Update

Epidemiology – Cancer of the Cervix Canada

12 th most common cancer in women in Canada

2005 – estimated 1,350 new cases

approximately 400 deaths

The rate of decline in incidence has slowed in the last 20 years;

Trend of increasing incidence in white women < 50 yrs of age (USA & Europe)

Estimated Cervical Cancer Cases Canada, 2005

Number of new cases 1,350

Incidence rates * 7.6 ( ’77 – 15.4)

Number of deaths 400

Mortality rates * 2.0 (’77 – 4.8)

* rate per 100,000

National Cancer Institute of Canada: Canadian Cancer Statistics 2005

Cervical Cancer in Ontario 2004

New cases - 510

Number of Deaths - 150

Death to Case Ratio = 30/100

A reduction in incidence rates

From 21.6 /100,000 in 1969

to 7 in 2004

Canadian Cancer Statistics, National Cancer Institute of Canada, 2004

Cervical Cancer – Actual / Expected Number of Deaths (Canada)

Cervical Screening in Canada CCHOTA, May 2003, No response from PQ, NB, YK TBS 2001 N Y/N N NT/NV Mod. British N N Y BC TBS 2001 N N Y Alberta TBS 2001 N N Y Saskatchewan TBS 2001 N N Y Manitoba TBS 1991 N N Y PEI TBS 2001 N N Y Nova Scotia TBS 2001 On demand N Y Newfoundland TBS 2001 On demand Y Y Ontario Terminology HPV Testing Liquid Based Cytology Screening Program Province/ Territory

Ontario Cervical Screening Practice Guidelines Cervical Screening Guidelines Development Committee of the Ontario Cervical Screening Program and the Gynecology Cancer Disease Site Group of Cancercare Ontario

Guidelines Revision Process Ontario Cervical Screening Program Cancer Care Ontario Program in Evidence Based Care Cancer Care Ontario GYN Disease Site Group Screening Guidelines Development Committee QMPLS “ Weigh the Evidence”

LBC is the preferred method for cervical cytology screening; however conventional Pap smears remain an acceptable method.

A province wide cervical screening program with an adequate recall mechanism is recommended.

Initiation of Screening

Data on optimal age to begin screening is limited to HPV modeling and cancer rates

Minimal risk of significant lesion within 3-5 yrs of first HPV contact

Incidence of cervical cancer is low < 20 yrs

Potential harm to screening adolescent women

false positives, transient lesions, anxiety

Initiation of Screening ACOG, American College of Obstetricians & Gynecologists; ACS, American Cancer Society; CTFPHE, Canadian Task Force on the Periodic Health Examination; IARC, International Agency for Research on Cancer; NHS, National Health Service, NZGG, New Zealand Guidelines Group; USPSTF, United States Preventive Services Task Force. All sexually active women CTFPHE 20 years of age for sexually active women NZGG 21 year of age or within 3 years of first intercourse ACOG, ACS, USPSTF 25 years of age IARC, NHS

Initiation of screening

Cervical cytology screening should be initiated within three years of first vaginal sexual activity.

All women who are or have ever been sexually active should be screened.

Cessation of Screening ACOG, American College of Obstetricians & Gynecologists; ACS, American Cancer Society; CTFPHE, Canadian Task Force on the Periodic Health Examination; IARC, International Agency for Research on Cancer; NHS, National Health Service, NZGG, New Zealand Guidelines Group; USPSTF, United States Preventive Services Task Force. Not enough evidence ACOG Age 65 USPSTF Age 70 NZGG Age 65 NHS Age 70 ACS Age 65 IARC

Cessation of screening Screening may be discontinued after the age of 70 if there is an adequate negative screening history in the previous 10 years (i.e. 3-4 negative tests).

Screening Interval ACOG, American College of Obstetricians & Gynecologists; ACS, American Cancer Society; CTFPHE, Canadian Task Force on the Periodic Health Examination; IARC, International Agency for Research on Cancer; NHS, National Health Service, NZGG, New Zealand Guidelines Group; USPSTF, United States Preventive Services Task Force. At least every 3 yrs USPSTF Every 3 yrs CTFPHE Every 3 yrs NZGG Every 3 yrs, age 25-50 then every 5 yrs NHS Annually under age 30 Every 2-3 yrs over age 30 ACOG, ACS Every 3 yrs, age 25-49 IARC

These recommendations do not apply to those women who have had previous abnormal Pap tests. Screening at a 3 year interval is recommended, supported by an adequate recall mechanism. Screening interval · Screening should be done annually until there are 3 consecutive negative Pap tests. · Screening should continue every 2 to 3 years after three annual negative Pap tests.

Women who have sex with women should follow the same screening recommendations as women who have sex with men. Pregnant women should be screened the same as women who are not pregnant . Discontinue cervical screening in women who have undergone total hysterectomy for benign causes. Immunocompromised or HIV positive women should receive annual screening.

These are minimum guidelines only. Certain clinical situations may require earlier follow-up/referral for colposcopy.

Any repeat Pap test should not be performed earlier than three months.

The Pap test should not be used in the assessment of a visible cervical lesion. These patients require biopsy for accurate diagnosis.

Other Timing Issues

These recommendations do not apply to those women who have had previous abnormal Pap tests or treatment for SIL

they should have at least yearly screening.

Screening at a three-year interval is recommended if there is an adequate recall mechanism in place.

Women who have not been screened in more than five years should be screened annually until there are three consecutive negative Pap tests.

HPV Testing ?

Human Papillomaviruses

HPV Genome : Double–stranded DNA virus

Management of cytologic abnormalities

ASCUS and LSIL Mimics

ASCUS

Risk of Harbouring HSIL

While most ASC-US patients will have no cervical abnormality

9% will have HSIL.

With LSIL.

up to 18.3% will have HSIL.

ASC-US & The ALTS Trial

A large USA RCT

Compared management options for women ASC-US and LSIL

Randomization was to one of three management arms:

repeat conventional cytology

reflex HPV DNA testing, or

immediate colposcopy.

Reflex HPV Testing

Can be subsequently be performed on the residual of cells of an LBC sample if ASC-US is diagnosed.

It is cost effective because a second sample (and clinic visit) is not necessary.

HPV Testing for ASC-US The ALTS Trial:

52% were HPV +ve

10 % of HPV +ve ASCUS had HSIL

48% were HPV –ve and spared colposcopy.

only 31% of women >28 years old had +ve HPV test and 69 % spared colposcopy.

a -ve HPV result = a 99.5% chance of not missing a significant lesion.

The ALTS Trial: HPV Testing for LSIL

83% of the women with LSIL were HPV positive.

This makes HPV testing for LSIL unnecessary

Most of these women will be referred to colposcopy any way.

The ALTS Trial

Therefore, HPV DNA testing for ASC-US:

was more sensitive in detecting CIN 3 than conventional cytology

resulted in fewer referrals for colposcopy among women over 29 years

conventional cytology alone provides adequate triage in women with LSIL.

Sherman ME, et al; Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study Group. Effects of age and human papilloma viral load on colposcopy triage: J Natl Cancer Inst. 2002;94:102-7.

HPV Testing & Costs

A 1999 assessment concluded that HPV testing in primary screening would not be cost-effective unless:

screening intervals be substantially lengthened for HPV –ve patients,

the age at which women are no longer need screening be lowered (e.g. 60) following a series of negative HPV tests.

Cuzick J, Beverley E, Ho L, Terry G, Sapper H, Mielzynska I et al. HPV testing in primary screening of older women. Br J Cancer 1999; 81(3):554-558.

HPV Testing & Costs

There will be a greater reduction in cancer

at less cost than annual conventional cytology

for women aged 30 years and more if:

Screening occurs every 2- or 3-years

reflex HPV testing is used for equivocal results

Goldie SJ, Kim JJ, Wright TC. Cost-effectiveness of human papillomavirus DNA testing for cervical cancer screening in women aged 30 years or more. Obstet Gynecol 2004; 103(4):619-631.

Ontario Guidelines ASC-US & HPV Testing

HPV DNA testing with cytology is therefore recommended for women aged 30 and older with ASCUS.

Lower false +ve rate

i.e. +HPV and –ve colpo

In women under the age of 30,

HPV testing is not recommended

Why 30?

The absolute benefit of HPV DNA testing is smaller in younger women than it is in older women because:

the high rate of transient HPV infections and

the very low incidence of cervical cancer.

The benefits of HPV DNA testing among women with ASCUS increase along a continuum with age,

The likelihood of harms from HPV DNA testing (unnecessary anxiety, treatment and cost) diminish as age increases.

The balance of benefits and potential harms, therefore, grows more favorable as women age.

Under 30 –HPV Testing for ASC-US Not Recommended

The majority of patients with ASC will be HPV+ve

Most of these are transient infections

Lasting no more than 4 to 8 months

Therefore HPV testing is not helpful in triage

The risk of missing a cancer is extremely low

Therefore…Under 30

Repeat Pap test in 6 months is recommended.

If that Pap test is again abnormal,

refer for colposcopy.

If that Pap test is normal,

repeat cytology in another 6 months.

Once a woman has had 2 negative Pap tests results, she should return to routine screening.

HPV Testing in 30+ with ASC-US

If HPV positive - refer for colposcopy

If HPV negative - repeat LBC in 12 months

Once a woman has had two negative LBC Pap tests,

she should then return to routine screening.

In the Absence of HPV Testing in 30+ with ASC-US

A repeat Pap test in six months is recommended.

If the Pap test is again abnormal,

refer for colposcopy.

If the Pap test is normal,

repeat the Pap in another six months.

Once there has been 2 negative Pap tests at 6 mo intervals, then return to routine screening.

Qualifying Statements

These are minimum guidelines only.

Certain clinical situations may require earlier follow-up/referral for colposcopy.

A repeat Pap test should not be performed earlier than 3 months following the original.

A Pap test should not be used as the sole assessment of a visible cervical lesion.

These patients require a biopsy for accurate diagnosis.

The Big Question…

Will HPV testing help sort out Pap smear problems?

Yes….and…..

No

In fact, it adds new problems…

Benefits of Testing for HPV

Will reduce referrals to colpo clinic for ASC-US HPV –ve patients.

reduces the false +ve rate of cytology alone

HPV +ve patients can be followed at defined intervals so that any SIL (10% risk of HSIL) is detected early and treated.

Woman with negative results on both HPV and cytology testing have very low risk of developing a high-grade lesion over an extended interval.

Sherman ME, Lorincz AT, Scott DR, Wacholder S, Castle PE, Glass AG et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst 2003; 95(1):46-52.

Problems with HPV Screening

ASC-US HPV + pts referred to Colpo:

Many will a normal cervix on colposcopic examination

Patients will struggle with being told their cervix is colposcopically normal but they have an oncogenic virus infection

only about 10% will develop HSIL

We must resist the urge, or, being urged to, treat the cervix in the absence of biopsy proven LSIL or HSIL.

A recent randomized trial from the U.K. (HART) and the ASCCP Guidelines recommend

repeat Pap & HPV testing at 12 month intervals indefinitely

Cuzick J, et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet 2003; 362(9399):1871-1876.

Women with mildly abnormal smear results & are HPV +ve experience:

high levels of anxiety

exacerbated by an inability to understand the meaning of the results

resulting in an fear of cancer far above the risk associated with ASCUS/LSIL

Those who were HPV –ve were no less anxious than HPV +ve women.

There is a dearth of research on the merits and consequences of conveying this information.

Esther Maissi et al. Psychological impact of HPV testing in women with borderline or mildly dyskaryotic cervical smear test results. British Medical Journal 2004; 328: 1293-6

Women struggle to balance:

the anxiety of knowing that HPV infection causes cervical cancer

with

the fact that HPV infection often regresses without treatment.

They are also confused that cytology results are normal in the presence of HPV infection.

Anhang R, Wright TC, Jr., Smock L, Goldie SJ. Women's desired information about human papillomavirus. Cancer 2004; 100(2):315-320.

Negative Outcomes with HPV Testing

HPV testing in screening may shift the overall societal perspective of cervical cancer.

The link between STD and cervical cancer was always present but now it will be explicit.

This may lead to decreases in screening due to stigma of screening participants.

Compliance with follow up visits also remains a concern.

HPV Education

For adolescents and young adults, media sources, parents and friends play a more important role in HPV education than health professionals

Adolescents have indicated that, compared with other STIs, they know and were taught the least about HPV

If not carefully delivered, negative outcomes including

stigma,

decreased screening,

and anxiety following a positive test,

New Health Technology - Beneficial

Improved disease outcome;

Reduction in use of invasive procedures or side-effects;

Reduction in costs

Improved disease outcome

The object of cervical cancer screening is to prevent the development and death from cancer of the cervix;

No studies to show reduction in invasive cancer of the cervix through the use of HPV testing in screening or triage;

Studies have shown that it is possible to find more high grade lesions when HPV testing is added to cytology;

Whether this leads to meaningful improvement in disease control is unclear

In BC, most cancers of the cervix arise not from technical deficiencies of Pap Smears, but from insufficient screening from the general population , it is unlikely that adding HPV screening would improve in outcomes.

Low-Grade Squamous Intraepithelial Lesion - LSIL

Low Grade SIL

Management of LSIL

ALTS - LSIL – 83% HPV positive

Therefore HPV triage was abandoned

The CIN 3 follow up rate of LSIL was similar to ASCUS/ HPV +

BUT – There were concerns that in Ontario recommending colposcopy for all women with LSIL would overwhelm the colposcopy system

Management of LSIL

Age is a factor since many young women with LSIL have transient lesions

Spitzer, ASCCP - “ Even though adolescents have a high incidence of LSIL, they have a very low incidence of developing rapid onset cervical cancer. For selected adolescents, acceptable options for follow-up consist of repeat cervical cytologic analysis at 6 and 12 months”

BUT no evidence to support a specific age

High-Grade squamous Intraepithelial Lesion - HSIL

Women with AGC should also receive endocervical and endometrial sampling, where appropriate. High grade SIL, ASC-H, Atypical Glandular cells Colposcopy

Potential Use of HPV Testing

Primary screening tool for women over 30;

Triage tool for women over 30 with a mild atypia that are recommended for 6 month repeat smear;

As a risk assessment tool for women over 30 with high risk flag whose last smear was negative.

Next…

HPV Vaccines !

HPV Vaccines

Who?

When?

Cross-protection?

Alterations in Cervical Cancer Screening?

Conclusion

Cancer of the cervix is a relatively less common cancer;

The goal of screening is the prevention of cancer of the cervix;

Conclusion

Overall, the great majority of women referred for colposcopy still do not develop CIN 2-3 and very few will develop cancer;

Critical to optimize postcolposcopy management to detect initially missed CIN 2-3 while avoiding overtreatment of the many women referred .

Conclusion

The role of HPV testing within a cervical screening program has yet to be fully understood;

HPV vaccines have the potential to eliminate Cancer of the Cervix…

Prudence must be used when introducing the HPV vaccine within the context of an existing Cervical Cancer Screening Program

Conclusion

Other issues that have yet to be addressed:

Patient preference

Convenience

Quality of life

Cost – effectiveness

Thank you for your attention

Question?

Sensitivity for CIN 3

Negative Predictive Value

Cervical Cancer Screening Programs and Practices, Canada 2001

What is the optimal cervical screening tool?

Do organized cervical screening programs reduce the incidence / mortality of cervical cancer compared to spontaneous cervical screening?

What is the most appropriate time for initiation and cessation of cervical screening?

At what time interval should women be screened?

How should women in special circumstances be screened?

What is the optimal management for women with abnormal cytology (up to but not including colposcopy/management)?

Project Objectives

ALTS Trial -ASCUS Triage As compared to prevalence of CIN 3 in immediate colposcopy arm – 11.4% 96% 99% NPV for CIN 3 17% 20% PPV for CIN 3 58% 53% Referred to colp 83.4% 92.4% Sensitivity – CIN 3 ASCUS / ASCUS ASCUS / HPV +

Next Steps

Draft revision

Stakeholder Review

Final revision

Approval – OCSCG, PEBC, GYN DSG

Publication / Education

Next steps

Implementation

Management guidelines

ALTS – Results by age % Referred to Colp Sensitivity for CIN 3 50% 64% Cytology follow up 31% 65% HPV testing 91% 88% Cytology follow up 94% 96% HPV testing Age >= 29 years Age 23-28 years

CYTOLOGY COLPO .>MOD REPEAT @ 6 MONTHS PERSISTENT OF MILD FOR 2 YRS OR > MOD Recall @ 24 months Neg Mild PRIMARY SCREENING FOR WOMEN OVER 30 Current Practice : Women over 30, 3 consecutive negatives, not high risk, recall @ 24 m .

PRIMARY SCREENING FOR WOMEN OVER 30 HPV: Screen every 3 years HPV Cytology Colpo + > Or = mild Recall @ 36 m Neg Repeat @ 12 m. HPV & cytology Neg

TRIAGE of MILD DYSPLASIA for WOMEN OVER 30 Current Practice: Women > 30 years, last smear mild Repeat cytology @ 6 months COLPO > Mod or 3rd consec. mild Recall @ 6 months Mild Recall @ 12 months Neg

TRIAGE of MILD DYSPLASIA for WOMEN OVER 30 HPV Testing: Use at 6 months Mild repeat @ 6 months HPV Cytology Colpo Repeat @ 12 m. HPV & Cytology Neg > Mild Pos Recall @ 24 months Neg

TRIAGE of High Risk WOMEN OVER 30 Current Practice: High risk flag set, last smear Neg (72,000 women) High Risk Cytology Repeat Cytology @ 6 months Mild Colpo > Mod Recall @ 12 months Neg

TRIAGE of High Risk WOMEN OVER 30 HPV Testing: Use at 6 months High Risk HPV Cytology Colpo Recall @ 12 months HPV & Cytology Neg > Mild + Turn High Risk & recall @ 24 months Neg

Ontario HPV Pilot Project Cancer Care Ontario and Ministry of Health