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Recent Updates in Cervical Cancer: Screening, Vaccine, and Conservative Management

This article highlights recent updates in cervical cancer, including advancements in screening techniques, the use of HPV vaccine after LEEP procedure, conservative management options for CIN 2/3, and the role of sentinel pelvic lymph nodes. It also discusses ongoing cervical cancer activities at KCH/Lilongwe.

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Recent Updates in Cervical Cancer: Screening, Vaccine, and Conservative Management

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  1. Recent updates in Cervical Cancer LameckChinula MD Obstetrician and Gynecologist Malawi Inaugural Cancer Symposium

  2. Outline • Introduction • Cervical cancer screening and what’s coming? • HPV vaccine after LEEP • Conservative management of CIN 2+: therapeutic vaccine and Imiquimod • Role of sentinel pelvic LNs • Cervical cancer activities • Conclusion

  3. Introduction • 4th commonest cancer in women globally • Most common cancer in women in Malawi

  4. Natural history and development of cervical cancer

  5. Characteristics of screening test • Cytology • VIA/VILI

  6. Cervical cancer screening • HPV DNA testing • Highly sensitive • Excellent negative predictive value • Combined HPV DNA/Cytology • Endorsed by ACS/ASCCP/ASCP, ACOG and USP-STP • HPV 16/18 genotyping • For triaging positive HPV/negative cytology • Joint European Cohort Study: • 24,295 women • 6-yr risk of CIN 3+ much lower ff a neg HPV than neg cytology (0.27% v 0.97%) • Katki et al: Lancet Onco 2011 • Retrospective study • 330,000 women 30yrs+ • Combined HPV DNA testing/cytology • Risk of CIN 3+ comparable in 3yrs cytology alone v 5 yrs combined HPV/cytology

  7. Screening: What’s coming? • Novel biomarkers: p16 and Ki-67 • Petry et al. Gynecol onco 2011: Triaging neg. cytology, pos. hr-HPV with novel p16 ki-67 dual-stained cytology • Dual-stained cytology for both markers is highly sensitive (91.9% and 96.4% for CIN 2 and CIN 3+) • Also highly specific (82.1% and 76.9% for CIN 2 and CIN 3) • Potentially useful in triaging for colposcopy for women with positive hr-HPV but negative cytology • HPV oncogene E6/7 mRNA testing • hr-HPV E6/7 proteins malignantly transform infected cells by inhibiting anticancer proteins, p53 and pRB • HPV E6/E7 mRNA demonstrates stronger correlation with cervical disease than HPV DNA • CLEAR trial: 11,000 women • As sensitive as HPV DNA based test and more specific • Reduces unnecessary colposcopies

  8. HPV vaccine after LEEP • W.D. Kang et al. / Gynecologic Oncology 130 (2013) 264–268 • Determine whether quadrivalent HPV vaccine after LEEP for CIN 2+ is effective in preventing recurrence of CIN 2-3 • 737 women 20-45yrs with CIN 2/3 treated with LEEP and followed up (HIV neg) • 360 vaccinated and 377 non-vaccinated • In HPV 16/18 infected, CIN 2/3 recurrence was higher in non-vaccinated arm (18/211 = 8.5% vs 5/197 =2.5%) p<0.01 • Multivariate analysis: risk of recurrence was higher for patients with no vaccination (HR = 2.84; 95% CI: 1,335-6.042; p<0.01), cone margin involvement (HR=4.869, p<0.01) and positive endocervical cytology (HR=3=102, p=0.01) • Conclusion: Quadrivalent HPV vaccine after treatment may be considered to prevent recurrence

  9. Conservative management of CIN 2/3: Therapeutic DNA • RCT: assessed whether VGX-3100 would cause histopathological regression in women with CIN 2/3 • VGX-3100: synthetic plasmids targeting HPV 16/18 E6/7 oncoproteins • 167 randomized (3:1): 125 received VGX-3100 and 42 placebo given im at 0,4, 12wks • Per protocol analysis (all doses received): Histopath regression was higher in Rx arm {(49.5% vs 30.6%, % point difference 19 (95% CI 1.4-36.6)}; P=0.034 • Modified intention to treat analysis (atleast one dose): still higher regression in Rx arm {(48.2% vs 30%, % point difference 18.2 (95% CI: 1.3-34.3)}; p=0.034 • Conclusion: VGX-3100 first therapeutic vaccine to show efficacy against CIN 2/3 assoc with HPV 16/18 • VGX-3100 presents a non-surgical therapeutic option for CIN 2/3

  10. Conservative management of CIN 2/3: Imiquimod • Imiquimod • Topical immune response modulator that triggers immune response that results in HPV clearance • RCT: 59 hr-HPV, CIN 2/3, HIV neg women enrolled (Austria) • Self administered vaginal imiquimod • Results • High rate of regression/remission • High rates of HPV clearance • Microinvasive cancer in 3 patients (all in placebo arm)

  11. Sentinel node biopsy for LN staging of cervical cancer • S Kadkhodayan et al/EJSO 41 (2015)1-20 • Systematic review and meta-analysis • 67 studies included • Pooled detection rate was 89.2% (95% CI: 86.3-91.6) • Pooled sensitivity 90% (95% CI: 88-92) • Sentinel LN mapping and sensitivity were related to mapping method (blue dye, radiotracer or both) and Hx of preop neo-adjuvant chemotherapy • Sensitivity was higher in patients with bil. detected pelvic sentinel LNs cf unilateral nodes • Lymphatic mapping could identify sentinel nodes outside routine lymphadenectomy limit • Mapping useful in small tumor sizes and lower stage • Further studies need to be explore impact of sentinel nodes mapping in fertility sparing surgery and in pts with history of neo-adjuvant chemotherapy

  12. Cervical cancer activities at KCH/Lilongwe • Clinical services : KCH and Nkhoma Hospital • Research activities: UNC • Publications

  13. Colposcopy/LEEP clinic • KCH Department of Obstetrics and Gynecology • Weekly referral colposcopy clinic which provides diagnostic and LEEP services for the entire central region of Malawi • Previously hysterectomy with occasional Cold Knife Conization was largely the first line management for CIN 2+ • 10-15 patients seen in a week • Also a training base for residents and other interested clinician

  14. Surgical Gyn oncology Training with Groesbeck

  15. A Randomized, Phase II Trial to Compare an HPV Test-and-Treat Strategy to a Cytology-based Strategy for Prevention of CIN 2+ in HIV-infected Women • Hypothesis: In HIV-infected women with hr-HPV, immediate cryotherapy results in a lower probability of CIN II+ than a cytology-based strategy • Primary Objective: To evaluate the effectiveness of immediate cryotherapy in HIV-infected women with hr-HPV compared to a cytology-based strategy by comparing cumulative CIN II+ rates

  16. Retrospective cross-sectional study: • Assess the frequency of high-grade dysplasia (CIN2/3) and cervical cancer among women having diagnostic workup • Examine associations between HIV and age with CIN2+ (CIN2/3 or cancer) • CIN 2+ and cervical cancer were very common especially among HIV-positive women • 35% of cervical cancer cases &25% of CIN+ occurred in women falling outside the currently recommended ages for VIA screening

  17. Thermo-coagulation proved feasible and acceptable in this setting • Effective implementation requires comprehensive training and provider support, ongoing competency assessment, quality assurance and improvement audit • Thermo-coagulation offers an effective alternative to cryotherapy

  18. Conclusion • HPV vaccine and cervical cancer screening programmes remain the mainstay for cervical cancer prevention and control • Novel developments presented here are largely from high-income countries and have excluded HIV infected women • Need to think of how best generalizable data can be realized in Africa (Malawi) e.g. cancer consortium? International collaborations with universities? • Need for in-country/regional expertise and infrastructure for cancer research and practice

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