How cervical cancer develops Peak Ages: 15-25 25-35 45-50 Long latent period allows screening to detect precancerSource: Wright, TC and Schiffman, M. Adding a Test for Human Papillomavirus DNA to Cervical-CancerScreening. The New England Journal of Medicine 2003;348:489-490.
Cervical Incidencia deincidence: England cancer cáncer cervical invasor1971-1995 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 19Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervixin England: evaluation based on routinely collected statistics. The British Medical Journal. 1999; 318:904.
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 highIARC MONOGRAPH: SCREENING FOR CERVICAL CANCER 2005
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, 2006Mayrand 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 weaknessesStrengths:• 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-resourcesettingsSTART project:-Developed the new test. hc2-Validated it with specimens fromChina and India.QIAGEN:-Set up production in TheChina. careHPVTM-Seeking regulatory approval in testChina.-CE Mark approval granted by EU(consumer safety and health)
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 plannedNumber of oncogenic HPV types 13 All 13 + type 66 Target price per specimen Usually more than US$20 Less than US$8
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 sensitivityCuzick et al., IJC, 2006Mayrand et al., NEJM, 2007
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.
Risk of CIN 3+ after a negative HPV resultDillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, et al. Long term predictive values ofcytology and human papillomavirus testing in cervical cancer screening: joint European cohort study.British Medical Journal. 2008; 337:a1754.
Accuracy of careHPVTM test, hc2 test, andVIA 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 99.9n=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™ QIAGEN*Screening Technologies to Advance Rapid Testing for Cervical CancerPrevention – Utility and Program Planning.
Nicaragua PATH: Jose Jeronimo PATH: Jose Jeronimo PATH: Jose Jeronimo PATH: Jose Jeronimo
careHPV: preliminary resultsSelf-sampling: 86 percent of women accepted self-collecting the sample andthere 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+.
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.
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)
Limitations of colposcopy: Experiencefrom 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
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
What to use when cryotherapy is notsuitable• 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
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 for cryo eligibility Refer for diagnosis VIA: 3-5 years & treatment HPV: 5-10 years 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 issuesFollow-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 clinicCounseling 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 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
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