Cervical Screening and pre-cancer treatment: what are the options?

Cervical screening and

pre-cancer treatment:

What are the options?

Vivien Tsu, PhD, MPH

Comprehensive Cervical Cancer Prevention and

Control

UNFPA, Antalya, 18-20 May 2011

Overview

• Screening technologies

• Treatment options

• Program considerations

• Getting started

• Concluding thoughts

Source: Wright, TC and Schiffman, M. Adding a Test for Human Papillomavirus DNA to Cervical-Cancer

Screening. The New England Journal of Medicine 2003;348:489-490.

How cervical cancer develops

Long latent period allows screening to

detect precancer

Peak Ages: 15-25 25-35 45-50

Cervical cytology (Pap test)

Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix

in England: evaluation based on routinely collected statistics. The British Medical Journal. 1999; 318:904.

Cervical cancer incidence: England 1971-1995

Incidencia de cáncer cervical invasor

estandarizada por edad, Inglaterra 1975 -95

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1987

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Incidencia de cáncer cervical invasor

estandarizada por edad, Inglaterra 1975-95

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10

14

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1971

1975

1979

1983

1987

1991

1995

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Invasive cervical cancer

National call-recall introduced

Coverage

Why hasn’t cytologic screening (Pap

testing) worked for low-income areas?

• Low sensitivity and limited reproducibility

• Requires frequent visits and high coverage

• Requires quality controls and regular training

• Global costs of programs are very high

IARC MONOGRAPH: SCREENING FOR CERVICAL CANCER 2005

Combined

Seattle

Canada

HART

Jena

Tuebingen

Hannover

French Private

French Public

0% 10% 30% 50% 70% 90% 100%

CIN 2+

Sensitivity of Cytology: CIN2+

Cuzick et al., IJC, 2006

Mayrand et al., NEJM, 2007

Visual Inspection with Acetic Acid (VIA)

• Cervix washed with vinegar (3-5% acetic acid) and

inspected with naked eye 1 minute later

• HPV-infected cells appear more white (acetowhite)

than nearby normal tissues

• 5-day curriculum for nurses and midwives

• Equipment and supplies: speculum, cotton swabs,

vinegar, lamp or torch

• Immediate results

VIA: Normal result

Before acetic acid After acetic acid

VIA: Abnormal result

Before acetic acid After acetic acid

• ~31,000 women screened with VIA, ~30,000 in control group

• Incidence of cervical cancer ~25% lower, and mortality ~35% lower, after 1 round of VIA screening

• Among women 30-39 yrs, 38% reduction in incidence and 66% lower mortality

(Lancet, 2007)

VIA strengths and weaknesses

Strengths:

• Very well accepted by health workers and women.

• Simple; immediate result, very suitable for screen-and-treat (no

triage before treatment).

• Requires only acetic acid, a speculum, and a light source (torch).

• Can be performed by nurses and midwives with short training.

Weaknesses:

• Sensitivity is not optimal, but at least similar to or better than Pap.

HPV DNA testing

• Tests for HPV infection with oncogenic types

rather than cervical lesions

• Hybrid capture 2 (hc2) used in high-resource

countries as triage test for uncertain Pap

results (reflex testing)

• Being used as primary screening test in UK

and elsewhere

A new HPV DNA test for low-resource

settings

hc2

The

careHPVTM

test

START project:

-Developed the new test.

-Validated it with specimens from

China and India.

QIAGEN:

-Set up production in

China.

-Seeking regulatory approval in

China.

-CE Mark approval granted by EU

(consumer safety and health)

Comparison of HC2 and careHPV

Digene hc 2

(existing test)

QIAGEN careHPV

Test format Batch Rapid-batch

Time 7 hours Less than 3 hours

Detects HPV-DNA HPV-DNA

Test environment Fully functioning lab,

controlled temperature,

purified water, refrigeration,

skilled lab tech

Static or mobile clinic,

no temperature control,

no running water or

electricity, basic lab tech

Number of samples 96 well batch, or high

throughput

96 well batch; 24-well

planned

Number of oncogenic HPV types 13 All 13 + type 66

Target price per specimen Usually more than US$20 Less than US$8

Combined

HART

Jena

Tuebingen

Hannover

Canada

Seattle

French Private

French Public

0% 10% 30% 50% 70% 90% 100%

HPV sensitivity

CIN 2+

Cuzick et al., IJC, 2006

Mayrand et al., NEJM, 2007

HPV-DNA testing sensitivity

0%

5%

10%

15%

20%

25%

0.0 4.5 15.0 27.0 39.0 51.0 63.0 75.0 87.0 99.0 111.0 119.5

Follow-up (months)

Ac

um

ula

te In

cid

en

ce

≥C

IN3

HPV16+

HPV18+

HPV +

HPV-

Predictive value of HPV-DNA testing

Khan M, Castle PE, Lorincz AT, et al. The Elevated 10-Year Risk of Cervical Precancer and Cancer in Women With Human

Papillomavirus (HPV) Type 16 or 18 and the Possible Utility of Type-Specific HPV Testing in Clinical Practice. Journal of the

National Cancer Institute. 2005;97(14):1072-1079.

Castle PE, Sideri M, Jeronimo J. Risk assessment to guide the prevention of cervical cancer. American Journal of Obstetrics &

Gynecology. 2007;197(4):356.e1-356.e6.

Risk of CIN 3+ after a negative HPV result

Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, et al. Long term predictive values of

cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study.

British Medical Journal. 2008; 337:a1754.

Accuracy of careHPVTM test, hc2 test, and

VIA in China

Sensitivity Specificity PPV NPV

careHPVTM cervical samples 89.7 84.2 14.7 99.6

careHPVTM vaginal samples 81.4 82.4 11.9 99.3

HPV DNA Hybrid Capture 2 (hc2) 97.1 85.7 16.6 99.9

n=2,382 (Shanxi Province, China)

Reference standard: directed, four-quadrant biopsy and ECC (>CIN 2) externally read.

Qiao YL et al. Lancet Oncol. 2008 Oct;9(10):929-36.

START-UP* project - careHPV™

*Screening Technologies to Advance Rapid Testing for Cervical Cancer

Prevention – Utility and Program Planning.

QIAGEN

PATH: Jose JeronimoPATH: Jose Jeronimo

PATH: Jose JeronimoPATH: Jose Jeronimo

Nicaragua

PATH: Jose Jeronimo

Hyderabad, India

careHPV: preliminary results

Screening method Sensitivity*

(95% CI)

Specificity*

(95% CI)

Vaginal careHPV™ (1.0 cutoff) 79.3%

(69.6, 87.1)

91.6%

(90.7, 92.3)

Cervical careHPV™ (1.0 cutoff) 85.9%

(77.0, 92.3)

93.2%

(92.4, 913.9)

VIA 71.7%

(61.4, 80.6)

81.6%

(80.4, 82.7)

Pap smear (ASCUS+) 64.1%

(53.5, 73.9)

97.4%

(96.9, 97.8)

*Clinical sensitivity and specificity estimates.

Based on results from women with screening and final diagnosis completed.

92 cases of CIN2+.

Self-sampling: 86 percent of women accepted self-collecting the sample and there were no problems.

Test should be

• acceptable to women and providers.

• able to detect pre-cancer and cancer with high

sensitivity.

• feasible to implement at low levels of the health care

system.

• able to offer high protection with few screenings in

women’s life.

• ideally, able to be done with self-collected samples.

Screening for pre-cancerous lesions:

What to use?

Triage with colposcopy?

Logistic issues:

• Lack of trained

providers.

• Cost and limited

availability of

equipment.

• Delay of evaluations.

Performance issues:

• Poor correlation between

colposcopic criteria and

final histological diagnosis.

(Massad, JLGTD. 2009

Jul;13(3):137-44)

• Colposcopy criteria not

reproducible (Jeronimo, J

Obstet Gynecol 2007 Oct;110(4):

833-40)

Limitations of colposcopy: Experience

from Start-Up Project

Colposcopic diagnosis in women with final histological

diagnosis of CIN2+

Normal CIN 1 CIN 2+ Total

25

(26.3%)

2

(2.1%)

68

(71.6%) 95

Cryotherapy:

Simple Treatment

• Metal probe applied to thecervix to freeze (-50o C) the abnormal area for total of 6 minutes

• Does not require electricity; uses low-cost CO2 or N2O gas

• 80-90% effective in ablating even high-grade precancerous lesions (CIN 2 or 3)

• Ideal for nurses to perform at district hospitals and maybe even in health centers

• Appropriate for most lesions, except very large ones and those involving the endocervical canal

What to use when cryotherapy is not

suitable

• Loop electrosurgical excision procedure

(LEEP)

– Loop of wire used to excise a piece of the cervix

– Provides a biopsy specimen

– Must be done by well-trained provider

– Risk of bleeding

– Equipment is expensive and requires electricity

• Cone biopsy

– Useful when lesion extends into endocervical canal

– Requires anesthesia

• Hysterectomy – last resort for pre-cancer

PROGRAM CONSIDERATIONS

Target age for screening

• WHO recommends 30 as lower limit (except HIV+)

• Upper age depends on resources, test

• HPV test not suitable for women <30, too many

women positive with transient infections that will

mostly resolve spontaneously

• VIA test less suitable for older women (post-

menopause) since transformation zone less visible

after 50 yrs old

– Cremer et al, 2011, found about 70% of women 50-59 had

adequate VIA exam, 50% of women 65+

Screening frequency considerations

• Depends on test

– HPV test: high sensitivity means high negative

predictive value, interval of 6-10 years effective

– VIA test and Pap: lower sensitivity means women

missed by one test may be identified by repeat in 3-

5 years before progression to cancer

• Depends on resources

– More benefit from covering all women once than

repeating smaller population more frequently;

increase frequency only after coverage reaches at

least 80%

Program design: new approaches

• Traditional management strategy:– Positive screening test (Pap) diagnostic step (colposcopy

and biopsy); wait for results of biopsy before treatment

– Multiple visits and delays (with loss to follow-up at each step)

– Dependent on highly skilled personnel to read Pap and biopsy

• Ways to reduce loss to follow-up

– Screen and treat approach

– Single visit approach

Screen and treat

• Definition: no diagnostic step after screening

test result; treatment based on screening

result

• Rationale:

– screening tests are accurate “enough”

– treatment is benign and inexpensive

– avoids loss to follow-up and high cost of skilled

(and scarce) personnel

• Risks: some unnecessary treatment, may miss

(and mistreat) some cancers

Single visit approach

• Definition: screening and treatment provided

on same day in same place

• Rationale: reduce loss to follow up

• Risks: same as screen and treat

• Feasibility issues:

– Capital costs to put cryo equipment at all screening facilities

– Logistic challenges of maintaining gas supplies at all facilities

– Sufficient patient load to maintain cryo skills

– Nurses sometimes not allowed to do cryo; doctor not available

at lowest level facilities

– Transportation costs and staffing if done as mobile outreach

– Even when available, many women prefer to return later

Screen and treat algorithm

Community

mobilization

SCREENING

VIA or Molecular test (HPV DNA)

Negative Positive Suspicious

for cancer

Recall

VIA: 3-5 years

HPV: 5-10 years

Refer for diagnosis

& treatment

VIA for cryo eligibility

Cryotherapy Refer for LEEP

Screen, triage, and treat algorithm

• After VIA or HPV positive test, triage test

can be done

– Triage can reduce treatment of false positives

– VIA for HPV+ women; if no visible lesion, recall in

6-12 months for repeat HPV test

– Pap for HPV+ women; if negative, recall in 6-12

months for repeat HPV test

– Pap for VIA+ women

– Triage with VIA or Pap risks loss of women with

real disease due to lower sensitivity

Other program issues

Follow-up after pre-cancer treatment

• Timing: 1-3 months later to check for healing; usually 1 year after

to check for cure

• Method:

– VIA: easy to do at local facility; immediate result; may miss lesion

– HPV DNA test: high sensitivity (misses very few lesions); no

immediate result; may have to go to secondary level facility

– Colposcopy: requires referral facility and specialist

– Pap: requires lab; no immediate result; misses many lesions

• Tracking system: reminder for woman; active outreach by clinic

Counseling and educational materials for

patients and the community

Getting started

• Do the numbers!– How many women in the target age?

– How many facilities capable of screening?

– How many women/week/facility if all screened in first year?

How many if spread over 5 years? 10 years? What is

feasible?

– If ~15% are screen-positive, how many cryos/week?

• Phase-in strategies– Gradual build up to steady state with re-screening at desired

intervals

– Campaign style with big push up front, then drop-off of

demand (and drop-off of skills?)

Phasing-in strategies

• Cascade down • Multi-level wedge

Good because it:

•Spreads across country at start

•Trains trainers first

BUT:

•Can take a long time to trickle

down

•Takes longer to generate

referred patients

Good because it:

•Generates referral patients

from screening

•Models whole system at start

BUT:

•Limited coverage at first

Concluding thoughts

• Think long-term; program will change over time

• Pick screening test that will allow greatest coverage,

including in lowest resource areas

• Build monitoring and quality improvement in from the

start

• Minimize any barriers to pre-cancer treatment; without

treatment, screening is wasted

• Vaccination now will bring down future screening

costs; 50% fewer screen-positive women needing

treatment and follow-up

Thank you!

Vivien Tsu, PHD, MPH

Director, HPV Vaccines Project

[email protected]