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STD AIDS Control Division

STD AIDS Control Division. Can women screen themselves for cervical cancer? The evidence regarding self sampling for Human Papillomavirus. Gina Ogilvie MD MSc Associate Director, STD/AIDS Control University of British Columbia. STD AIDS Control Division. CERVICAL CANCER and HPV

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STD AIDS Control Division

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  1. STD AIDS Control Division Can women screen themselves for cervical cancer? The evidence regarding self sampling for Human Papillomavirus Gina Ogilvie MD MSc Associate Director, STD/AIDS Control University of British Columbia

  2. STD AIDS Control Division CERVICAL CANCER and HPV • Widely accepted that human papillomavirus, a sexually transmitted virus, is the major precipitant in the evolution from squamous metaplasia to dysplasia in the transition zone of the cervix • HPV is the necessary but insufficient cause of cervical cancer

  3. STD AIDS Control Division • HPV genomes are found in 99% of premalignant and malignant squamous cell cancer cases worldwide (Walboomers, 2001) • Presence of high risk HPV (HR-HPV) types (16,18,31,33,34,35,39,45,51,52,56,58,59,66,68,70) are generally recognized as the major risk factor for development of cervical cancer

  4. STD AIDS Control Division PREVALENCE OF HUMAN PAPILLOMAVIRUS • Prevalence estimates of HPV in women conducted in Ontario, Newfoundland and Baffin Island • Range from 11% to 26% • Prevalence decreases from more than 20% in women under 25 to less than 5% in women over 40

  5. STD AIDS Control Division NATURAL HISTORY OF HPV • HPV can be cleared from the cervix • Median time to HPV clearance is 9.8 months for HR-HPV types and 4.3 months non-HR types • However, not cleared in all women and it is in this cohort that cervical cancer develops after viral incorporation • Recent study found 45% of women with persistent HR-HPV infections developed high grade cervical lesions

  6. STD AIDS Control Division DETECTION OF HPV • Human Papillomavirus is detected by nucleic acid and signal amplification techniques including PCR and Hybrid-Capture II method • Many labs are able to conduct their own PCR • Methods are commercially available for HC-II and soon developed for PCR

  7. STD AIDS Control Division • Potential advantage of specimen collection for HPV compared to Pap tests is that women may be able to obtain their own swabs • Can use cotton swabs, tampons, cervico-vaginal lavage, and cytobrushes • Can insert these swabs intravaginally themselves and obtain their own samples to be processed for analysis • Offer tremendous opportunities, particularly for isolated communities and women who have difficulty obtaining Pap smears

  8. STD AIDS Control Division CURRENT ISSUES WITH CERVICAL CANCER SCREENING IN CANADA • In Canada, a large proportion of cases of cervical cancer are found in women who have not attended or not received adequate screening with Pap smear • Variety of barriers exist for Pap testing, including access to medical care and personal/psychological/cultural barriers to pelvic examination and Pap testing • Less educated, immigrant, aboriginal, non-native English or French speaking and low income women are less likely to have received a Pap smear

  9. STD AIDS Control Division • Also, recent studies have provided data confirming the limitations of Pap testing, including limited sensitivity (50-60%) and poor to fair agreement on interpretation (κ =0.46) among pathologists

  10. STD AIDS Control Division • Looking towards recent developments and advances in our understanding of the pathogenesis of cervical cancer to attempt to improve access and uptake of screening • Use new knowledge of the role of HPV in causing cervical cancer to potentially address some of the current challenges with Pap testing

  11. STD AIDS Control Division • However, currently little consensus regarding the diagnostic accuracy of self collected samples for HPV • Range of studies with differing estimates • Unable to generate summary recommendations because of the varied nature of the findings

  12. STD AIDS Control Division • How good are patient collected HPV-DNA samples compared to clinician collected HPV-DNA samples? • How good are patient collected HPV-DNA samples at diagnosing potentially malignant lesions?

  13. STD AIDS Control Division • To determine the answer to these questions, we conducted a diagnostic meta-analysis of the accuracy of patient collected specimens compared to two different reference standards • Clinician obtained HPV specimen • Colposcopic (with histologic where available) diagnosis of CIN2/3

  14. STD AIDS Control Division • Derive summary estimates for the self collected sample of: • Sensitivity • Specificity • Receiver Operating Characteristic Curves • Area under the Curve

  15. Methods STD AIDS Control Division • Used methods recommended for diagnostic systematic reviews as outlined by the Cochrane Collaboration • Data Source: • MEDLINE, EMBASE, Cochrane Database of Abstracts of Reviews of Effectiveness, Cochrane Database of Systematic Reviews and Cochrane Central Registry of Controlled Trials

  16. STD AIDS Control Division • MeSH (Medical Subject Headings) of • Human papillomavirus and HPV • Cervix neoplasms and cerivcal dysplasia and cervical intraepithelial neoplasia Were exploded and combined with self$ Limited to English Language Consult experts in field for missed studies

  17. STD AIDS Control Division • Criteria for inclusion • Consecutively/randomly recruited women • Reference standard of colposcopy +/- biopsy OR clinician obtained HPV specimen applied uniformly or randomly • PCR or Hybrid Capture II of HPV specimen • Blinded analysis of sample

  18. STD AIDS Control Division Two study authors (GO and DP) identified and reviewed studies to be included Agreement on inclusion/exclusion was calculated using Cohen’s kappa () Disagreements were resolved by consensus

  19. STD AIDS Control Division • Data that were abstracted from each study: • Number of patients • Clinical setting • Recruitment • Sample type • Diagnostic method • Oncogenic vs Non-oncogenic HPV Author contacted if unable to construct 2X2 table from available data

  20. STD AIDS Control Division • Heterogeneity of the OR determined by 2 • Presence or absence of a threshold effect determined by Spearman’s  • Summary estimates of sensitivity and specificity generated using the DerSimonian and Laird random effects model • Summary ROC curves were generated with Meta-test software [Joseph Lau, MD New England Medical Centre, 2003] • Area under the curve was calculated for each summary ROC curve

  21. STD AIDS Control Division • Subgroups of interest identified prior to conducting search • Hybrid Capture II • PCR • Abnormal Pap smears • Colposcopy or referral clinics • Dacron/Cotton swabs for obtaining sample

  22. Results STD AIDS Control Division • 821 studies identified in the search • 106 included either clinician or self collected specimen for HPV-DNA • No additional studies identified by expert in the field • Agreement for inclusion was  = 0.98 [95% CI 0.96-1.00] • Disputed study was include after review of the abstract

  23. STD AIDS Control Division • Patient collected HPV and Clinician collected HPV • Sixteen studies deemed acceptable to combine • On review, one study found to be a case control study and thus excluded • Six studies did not provide raw data needed for calculations • Three study authors provided original data • Remaining two authors of three studies did not provide original data • Thus, twelve studies included in HPV vs HPV

  24. STD AIDS Control Division • 2 for heterogeneity of odds ratio was conducted for overall and subgroups • All were significant (p<0.01) except in studies enrolling only women with abnormal Pap smears and in studies enrolling at colposcopy clinics • Indicating the need to use REM and SROC

  25. Study Subgroups Number of studies (n) Range (Sensitivity) Range (Specificity) Pooled Sensitivity (95% CI) Pooled Specificity (95% CI) AUC† AUC‡ Overall 12 (4212) 0.56-1.00 0.79-1.00 0.81 (0.71-0.88) 0.88 (0.83-0.91) 0.90 0.89 Overall* 11 (3018) 0.56-1.00 0.79-1.00 0.79 (0.68-0.86) 0.87 (0.83-0.90) 0.92 0.89 Women with ABN pap smear 8 (1014) 0.63-1.00 0.79-1.00 0.80 (0.7-0.87) 0.88 (0.82-0.93) 0.93 0.92 Conducted at referral clinic 7 (921) 0.63-1.00 0.79-1.00 0.82 (0.71-0.89) 0.89 (0.81-0.94) 0.94 0.93 Dacron / cytobrush / cotton Swab used for self sample* 6 (2537) 0.56-0.90 0.79-0.94 0.74 (0.61-0.84) 0.88 (0.83-0.92) 0.91 0.89 HC-II technique* 4 (1955) 0.56-0.90 0.79-0.91 0.78 (0.54-0.91) 0.86 (0.79-0.9) 0.89 0.88 PCR technique 7 (1063) 0.63-1.00 0.80-1.00 0.79 (0.66-0.88) 0.88 (0.81-0.93) 0.93 0.90 STD AIDS Control Division Summary Estimates from Meta-analysis (HPV vs HPV)

  26. STD AIDS Control Division

  27. STD AIDS Control Division Patient collected HPV vs Clinician collected HPV • Sensitivity ranged from 0.56-1.00 • Pooled sensitivity was 0.79 [95% CI 0.68-0.86] • Specificity ranged from 0.79-1.00 • Pooled specificity was 0.87 [95% CI 0.83-0.90]

  28. Summary ROC Curves (HPV vs HPV) STD AIDS Control Division Overall 1.0 0.8 0.6 Sensitivity 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 False Positive Rate

  29. 1.0 0.8 Sensitivity 0.6 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 False Positive Rate STD AIDS Control Division OVERALL Outlier Removed APS COLPO PCR HC DAC

  30. STD AIDS Control Division Patient collected HPV sample vs CIN2/3 • Twelve studies deemed eligible • One study determined to be case control and thus excluded • One used CIN1/2/3 as reference standard • Original data contributed by three authors requested • Thus, ten studies combined

  31. STD AIDS Control Division • 2 for heterogeneity of odds ratio was conducted for overall and subgroups • All were significant (p<0.01) • Indicating the need to use random effects model to combine data and present a summary ROC curve

  32. Study Subgroups Number of studies (n) Range (Sensitivity) Range (Specificity) Pooled Sensitivity (95% CI) Pooled Specificity (95% CI) DOR AUC† AUC‡ Overall 10() 0.49-0.92 0.54-1.00 0.73 (0.64-0.81) 0.77 (0.68-0.83) 10.34 0.84 0.84 Women with abnormal Pap smear 7() 0.49-0.92 0.54-1.00 0.74 (0.59-0.85) 0.68 (0.59-0.76) 6.97 0.83 0.83 Dacron / cytobrush / cotton Swab used for self sample* 6() 0.58-0.86 0.54-0.89 0.74 (0.64-0.81) 0.79 (0.70-0.85) 11.87 0.83 0.83 HC-II technique* 5 () 0.66-0.92 0.54-0.89 0.79 (0.69-0.86) 0.77 (0.66-0.85) 14.33 0.86 0.86 PCR technique 5() 0.49-0.86 0.72-1.00 0.62 (0.49-0.73) 0.73(0.69-0.78) 5.54 0.78 0.78 STD AIDS Control Division Summary Estimates from Meta-Analysis (HPV vs CIN 2/3)

  33. STD AIDS Control Division

  34. Patient collected HPV sample vs CIN2/3 STD AIDS Control Division • Sensitivity ranged from 0.49-0.92 • Pooled sensitivity was 0.73 [95% CI 0.64-0.81] • Specificity ranged from 0.54-1.00 • Pooled specificity was 0.77 [95% CI 0.68-0.83]

  35. STD AIDS Control Division Summary Receiver Operating Curve for HPV vs CIN2/3

  36. STD AIDS Control Division Summary Estimates from Subgroups

  37. Implications STD AIDS Control Division • Self collected samples for HPV have poorer sensitivities (0.79, 0.73) and specificities (0.87, 0.77) than reference standards of clinician collected HPV and CIN2/3 • Not currently able to universally recommend self sampling of HPV as primary method for screening for cervical cancer

  38. Implications STD AIDS Control Division • However, still potential uses for self sampling • Women who live in isolated communities and do not have access to practitioners • Women who do not have or find it difficult to attend primary clinicians • Women who have difficulty undergoing a pelvic examination • Women who live in less resourced settings

  39. Implications STD AIDS Control Division • Need to ensure that these women are aware that these samples would be more accurate if the clinician obtained these samples • However, in some cases, this may increase the uptake of Pap testing • In these settings, could ask women to take samples repeatedly, to improve to detection rate • Also, consider self sampling for HPV as triage

  40. Implications STD AIDS Control Division • Sensitivity of Pap test (Nanda 2000) for CIN2/3 was 47% (using LSIL as a cut off) • Sensitivity of HPV test (Belinson 2001) obtained by clinician for CIN2/3 was 95%

  41. Future Directions STD AIDS Control Division • Attempt to generate estimates for women over the age of 30, screening setting • Continued development of self collected samples as they offer potential to address some of the barriers with Pap testing • Determine the acceptability of self sampling compared to clinician sampling in groups that traditionally do not access Pap testing

  42. Future Directions STD AIDS Control Division • Conduct cost/benefit analysis to describe the increased uptake with self sampling vs the loss of diagnostic accuracy • Determine the consequences of ‘losing the Pap smear’ both from a clinical examination and health education perspective

  43. Future Directions STD AIDS Control Division • Need to ensure that studies have obtained relevant reference standard and are compared to current standards (ie clinician obtained Pap) • Include new advances, such as liquid based cytology

  44. STD AIDS Control Division Acknowledgements David Patrick Mark FitzGerald Richard White Mark Schulzer Martin Petric John Sellors Keith Chambers Michael Rekart

  45. Verification Bias STD AIDS Control Division • Occurs when reference standard is not conducted on every or randomly selected study participant(s) • Without reference standard, tend to overestimate the sensitivity of the test, as only those needing the reference standard (and thus higher pretest probability of having disease) are offered the test

  46. Verification Bias STD AIDS Control Division • In only one study (Belinson, 2001) did all participants receive a biopsy as the reference standard • 2000 women each received 4 biopsies • Compared patient collected HPV to CIN2/3 • Sensitivity of 83% • Specificity of 86%

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