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Results of a Randomized Trial on the Management of Cytology Interpretations of ASCUS The ASCUS-LSIL Triage Study ALTS Gr

. 55 million Papanicolaou tests performed yearly in the US.5% interpreted as

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Results of a Randomized Trial on the Management of Cytology Interpretations of ASCUS The ASCUS-LSIL Triage Study ALTS Gr

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    1. Results of a Randomized Trial on the Management of Cytology Interpretations of ASCUS The ASCUS-LSIL Triage Study (ALTS) Group A Journal Club Presentation By: Elise Grenier, MD, MS University of California, San Francisco Department of Family and Community Medicine March 5, 2004

    2. 55 million Papanicolaou tests performed yearly in the US. 5% interpreted as atypical squamous cells of undetermined significance (ASCUS) and 3% as low-grade squamous intraepithelial lesion (LSIL) (3 million women in all). Total clinical management costs- several billion dollars per year

    3. Dilemma The need to find the small minority of women with cervical intraepithelial neoplasia (CIN) grade 3 or cancer vs. the very high prevalence of ASCUS and LSIL.

    4. The ASCUS-LSIL Triage Study (ALTS) Group Designed to compare alternative strategies for the initial management of common cytology (Pap smear) abnormalities. Current strategies rely on cytology and colposcopy guided biopsies. Virtually all cases of cervical cancer have infection with oncogenic types of HPV. Could HPV testing be incorporated into cervical cancer screening programs?

    5. The ASCUS-LSIL Triage Study (ALTS) Group 3488 women with community read cytology report of ASCUS (majority were conventional Paps). Randomized to 3 equal strategies: Immediate colposcopy (IC)- reference standard of sensitivity and safety. Cytology follow-up (CM)- Repeat cervical cytology at 6, 12, and 18 mo. More conservative and less invasive, also permitted regression of self-limited HPV infections. HPV Triage- colposcopy based on HPV DNA test results.

    6. The ASCUS-LSIL Triage Study (ALTS) Group A priori end point of CIN grade 3 by the pathology quality control group. Clinical end point of CIN grade 2 or 3 by pathologists at the four clinical centers.

    7. Allocation IC (n=1163) women referred for colposcopy regardless of enrollment test results. HPV Triage (n=1161) women sent to colposcopy if enrollment HPV results positive or missing or high-grade SIL (HSIL) found. CM (n=1164) women sent to colposcopy if HSIL found on enrollment, otherwise followed by repeat cytology.

    8. Patient Management All women at each visit received a pelvic exam and collection of two cervical specimens. ThinPrep method- used for cytology slide and HPV testing. 2 Cervigrams after rinsing with 5% acetate sol. Patients referred to colposcopy if HSIL found at any time. If colpo histology showed CIN grade 2 or 3 by clinical center, pt was referred to loop electrosurgical excision procedure (LEEP).

    9. Patient Management At exit- women with persistent low-grade lesions, (defined as CIN grade 1 histology and cytology results from at least one of the previous visits showed LSIL or HPV + ASCUS) were offered LEEP. Colpo at exit for 1) Pt safety and 2) to completely ascertain disease end-point. Colpo at exit for 1) Pt safety and 2) to completely ascertain disease end-point.

    10. ASCUS Referral (total enrollment = 3488) Exit LEEP- numbers are subdivided in parentheses by the indication triggering the procedure: persistent low-grade disease vs presence or suspicion of high-grade disease, respectively. Exit LEEP- numbers are subdivided in parentheses by the indication triggering the procedure: persistent low-grade disease vs presence or suspicion of high-grade disease, respectively.

    11. Results 93% of women had at least one follow-up visit, with 85% having an exit visit. Retention did not differ by study arm. Virtually all women referred to colpo did attend, and those referred to LEEP received treatment. Referral to colpo during the follow-up study period depending on HSIL cytology were low and not significantly different between study arms.

    12. Results Approx. 1/5 of women had LEEP during the course of the study, but this did not vary by study arm. But the timing of LEEP did vary, correlating to the time of detection of disease. 2/3 of the LEEPs in the IC and HPV triage groups were performed during the enrollment period.

    13. Clinical Center Enrollment ThinPrep vs. HPV DNA test results Although all these women were referred for ASCUS Pap smear interpretations in the community, the clinical center interpretations of the enrollment ThinPrep slides, taken on average 2mo later were heterogeneous. Only 32.4% were again interpreted as ASCUS. There was a significant trend between the severity of the ThinPrep interpretations and HPV DNA positivity (Ptrend<.001). Overall 50.7% of women with ASCUS cytology were HPV DNA positive.Although all these women were referred for ASCUS Pap smear interpretations in the community, the clinical center interpretations of the enrollment ThinPrep slides, taken on average 2mo later were heterogeneous. Only 32.4% were again interpreted as ASCUS. There was a significant trend between the severity of the ThinPrep interpretations and HPV DNA positivity (Ptrend<.001). Overall 50.7% of women with ASCUS cytology were HPV DNA positive.

    14. Results Although all these women were referred for ASCUS Pap smear interpretations in the community, the clinical center interpretations of the enrollment ThinPrep slides showed only 32.3% with ASCUS. There was a significant trend between the severity of the ThinPrep interpretations and HPV DNA being positive (P trend<.001). Overall 50.7% of women with ASCUS cytology were HPV DNA positive.

    15. Results Overall, cumulative percentages of CIN 3, the a priori study endpoint, did not vary significantly by study arm- IC (8.3%) HPV (8.9%) CM (9.3%) Cumulative percentages of CIN 2 did vary by study arm, with significantly fewer diagnoses of CIN 2 in CM arm (4.7%) compared to (IC = 7.9%, HPV = 7.3%) (p=.005). Most likely due to the regression of missed CIN 2 in CM arm.

    17. Results Diagnosis of CIN 3 was latest in the CM arm (p<.001), and marginally earlier in the HPV triage arm then in the IC arm (Ptrend=0.06). 38.9% of the CIN 3 was diagnosed at exit in the CM arm. Findings from the clinical endpoint of CIN 2 and 3 mirrored that of the study in percent distribution of time of diagnosis.

    18. Performance of management strategies for detection of cumulative histologic diagnoses of CIN 3 by pathology QC group This table compares the alternative management strategies on the basis of the sensitivity for the detection on CIN 3 and the percentage of women requiring colpo.This table compares the alternative management strategies on the basis of the sensitivity for the detection on CIN 3 and the percentage of women requiring colpo.

    19. Results HPV triage- detected 72.3% of cases during enrollment period compared to 53.6% in IC. CM detected 54.6% of cases over the enrollment and follow-up period.

    20. Results: Triage test performance Of the women in the ALTS trial with ASCUS and who were ultimately found to have CIN grade 3: Enrollment HPV testing would have properly triaged 92.4% (CI = 88.7-95.2) and referred 53.1% of women to colpo. Repeating cytology twice at the ASCUS level (as in the CM group) would provide comparable sensitivity (95.4%) for the detection of CIN3. But doing so would refer more women (67.1%) to colpo.

    21. Bottom Line: For women with ASCUS cytology interpretations, this data demonstrates that HPV DNA testing triage is at least as sensitive as immediate colposcopy in the detection of CIN grade 3, while nearly halving the number of women referred to colposcopy. Repeat cytology with a colposcopy visit is also as sensitive in detecting CIN 3 but requires many more visits for Papsmear and more colposcopy exams than does a single HPV test.

    22. Bottom Line: Immediate colposcopy has been assumed to be the safest option with the disadvantage of high cost and potential over treatment. The sensitivity of a single repeat conventional Pap is relatively low, so a program of repeat cytology has been proposed. Also several studies have been evaluating the performance of HPV testing and have reported the sensitivity to be 83-100%.

    23. Bottom Line: SO The ALTS data suggest that HPV triage is the most effective strategy for management of women with ASCUS. It may also soon be proven to be more cost effective as well.

    24. Was this a good study? Evaluation of a randomized clinical trail. There were equal number of women in each arm of the study randomized to each group for a prospective study over two years. Referral to colpo at enrollment was based on the randomization arm (IC) and initial test result (HPV and CM)- this was the only management decision that differed. The study had excellent retention and compliance with recommended interventions thus did not influence the outcome of the study.

    25. FYI: The other parts of the ALTS group: LSIL- best managed by immediate colposcopy, because there is no useful triage strategy identified. LSIL results are fairly reproducible on cytology and most are HPV positive (80%). HPV testing had the highest sensitivity for CIN3 (66%) compared to IC (56%) and CM (48%) groups. (Pvalue= .16) among women with LSIL. But almost similar number of women were sent to colpo (85%) compared to IC (100%). So HPV testing is at least as sensitive but not as effective as IC.

    26. Thank you David Thom, MD, PhD Julie Haugen, MLIS

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