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

1. 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

2. Overview
• Screening technologies
• Treatment options
• Program considerations
• Getting started
• Concluding thoughts

3. How cervical cancer develops
Peak Ages: 15-25 25-35 45-50
Long latent period allows screening to
detect precancer
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.

4. Cervical cytology (Pap test)

5. Cervical Incidencia deincidence: England
cancer cáncer cervical invasor
1971-1995
estandarizada por edad, Inglaterra 1975 -95
1975-95
18 100
Coverage 90
80
Incidence rate / 100,000
14 70
Percentage
Invasive cervical cancer 60
50
40
10
30
National call-recall introduced 20
10
6
0 0
71
75
79
83
87
91
95
19
19
19
19
19
19
19
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.

6. 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

8. Sensitivity of Cytology: CIN2+
CIN 2+
HART
Tuebingen
Hannover
Jena
French Public
French Private
Seattle
Canada
Combined
0% 10% 30% 50% 70% 90% 100%
Cuzick et al., IJC, 2006
Mayrand et al., NEJM, 2007

9. 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

10. VIA: Normal result
Before acetic acid After acetic acid

11. VIA: Abnormal result
Before acetic acid After acetic acid

12. • ~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)

13. 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.

14. 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

15. A new HPV DNA test for low-resource
settings
START project:
-Developed the new test.
hc2
-Validated it with specimens from
China and India.
QIAGEN:
-Set up production in
The
China. careHPVTM
-Seeking regulatory approval in test
China.
-CE Mark approval granted by EU
(consumer safety and health)

16. Comparison of HC2 and careHPV
Digene hc 2 QIAGEN careHPV
(existing test)
Test format Batch Rapid-batch
Time 7 hours Less than 3 hours
Detects HPV-DNA HPV-DNA
Test environment Fully functioning lab, Static or mobile clinic,
controlled temperature, no temperature control,
purified water, refrigeration, no running water or
skilled lab tech electricity, basic lab tech
Number of samples 96 well batch, or high 96 well batch; 24-well
throughput planned
Number of oncogenic HPV types 13 All 13 + type 66
Target price per specimen Usually more than US$20 Less than US$8

17. HPV-DNA testing sensitivity
CIN 2+
HART
Tuebingen
Hannover
Jena
French Public
French Private
Seattle
Canada
Combined
0% 10% 30% 50% 70% 90% 100%
HPV sensitivity
Cuzick et al., IJC, 2006
Mayrand et al., NEJM, 2007

18. Predictive value of HPV-DNA testing
25%
20% HPV16
+
Acumulate Incidence ≥CIN3
HPV18
+
15%
10%
5%
HPV
+
0%
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) HPV-
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.

19. 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.

20. 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.

21. START-UP* project - careHPV™
QIAGEN
*Screening Technologies to Advance Rapid Testing for Cervical Cancer
Prevention – Utility and Program Planning.

22. Nicaragua
PATH: Jose Jeronimo PATH: Jose Jeronimo
PATH: Jose Jeronimo PATH: Jose Jeronimo

23. Hyderabad, India
PATH: Jose Jeronimo

25. careHPV: preliminary results
Self-sampling: 86 percent of women accepted self-collecting the sample and
there were no problems.
Screening method Sensitivity* Specificity*
(95% CI) (95% CI)
Vaginal careHPV™ (1.0 cutoff) 79.3% 91.6%
(69.6, 87.1) (90.7, 92.3)
Cervical careHPV™ (1.0 cutoff) 85.9% 93.2%
(77.0, 92.3) (92.4, 913.9)
VIA 71.7% 81.6%
(61.4, 80.6) (80.4, 82.7)
Pap smear (ASCUS+) 64.1% 97.4%
(53.5, 73.9) (96.9, 97.8)
*Clinical sensitivity and specificity estimates.
Based on results from women with screening and final diagnosis completed.
92 cases of CIN2+.

26. Screening for pre-cancerous lesions:
What to use?
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.

27. Triage with colposcopy?
Logistic issues: Performance issues:
• Lack of trained • Poor correlation between
providers. colposcopic criteria and
final histological diagnosis.
• Cost and limited (Massad, JLGTD. 2009
Jul;13(3):137-44)
availability of
equipment. • Colposcopy criteria not
reproducible (Jeronimo, J
Obstet Gynecol 2007 Oct;110(4):
• Delay of evaluations. 833-40)

28. 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 2 68
(26.3%) (2.1%) (71.6%) 95

29. Cryotherapy:
Simple Treatment
• Metal probe applied to the
cervix 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

30. 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

31. PROGRAM CONSIDERATIONS

32. 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+

33. 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%

34. 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

35. 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

36. 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

37. Screen and treat algorithm
Community
mobilization
SCREENING
VIA or Molecular test (HPV DNA)
Negative Positive Suspicious
for cancer
Recall VIA for cryo eligibility Refer for diagnosis
VIA: 3-5 years
& treatment
HPV: 5-10 years
Cryotherapy Refer for LEEP

38. 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

39. 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

40. 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?)

41. Phasing-in strategies
• Cascade down • Multi-level wedge
Good because it:
•Spreads across country at start Good because it:
•Trains trainers first •Generates referral patients
BUT: from screening
•Can take a long time to trickle •Models whole system at start
down BUT:
•Takes longer to generate •Limited coverage at first
referred patients

42. 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

43. Thank you!
Vivien Tsu, PHD, MPH
Director, HPV Vaccines Project
vtsu@path.org