Dec 23, 2011 - 3Family Practice Unit, Women's College Hospital, Toronto ON. 4London Health .... the evidence base for guidelines in a Canadian province.
Gynaecology
Cervical Screening: A Guideline for Clinical Practice in Ontario Joan Murphy, MD,1 Erin B. Kennedy, MHSc,2 Sheila Dunn, MD,3 C. Meg McLachlin, MD,4 Michael Fung Kee Fung, MD,5 Danusia Gzik, MD,6 Michael Shier, MD,7 Lawrence Paszat, MD8 1
Division of Gynecologic Oncology, University Health Network, Toronto ON
2
Program in Evidence-based Care, Cancer Care Ontario and Department of Oncology, McMaster University, Hamilton ON
3
Family Practice Unit, Women’s College Hospital, Toronto ON
4
London Health Sciences Centre, London ON
5
Ottawa General Hospital, Ottawa ON
6
North Simcoe Muskoka Local Health Integration Network, Huntsville ON
7
Sunnybrook Health Sciences Centre, Toronto ON
8
Institute for Clinical Evaluative Sciences, Toronto ON
Abstract
Résumé
Objective: To develop guidelines to inform the Ontario Cervical Screening Program’s invitations to women in the target population, provide evidence-based clinical practice guidance for practitioners, and inform policy decisions.
Objectif : Élaborer des lignes directrices pour étoffer les invitations que le Programme ontarien de dépistage du cancer du col de l’utérus propose aux femmes de la population cible, fournir une orientation pratique clinique factuelle aux praticiens et éclairer les décisions en matière de politiques.
Methods: A systematic review was conducted of relevant websites, the Medline and EMBASE databases (2005 to November 2010), and the Cochrane Library (2005 to 2010). No guidelines or systematic reviews were located that addressed the topics of interest. The evidence base consisted of seven randomized controlled trials, three case–control studies, one cohort study, and one review article. A methodologist performed data identification and extraction. Review of the data and quality assessment was carried out by the authors, who have expertise in methodology, gynaecologic oncology, pathology, and family medicine. The systematic review methods and resulting recommendations were reviewed by an internal panel with clinical, methodological, and oncology expertise. External review was provided by Ontario clinicians and other experts. Conclusions: The guideline development process led to recommen dations for the optimal primary cervical screening method, screening interval, and age of screening cessation for Ontario women in the target population. There was insufficient evidence to provide a recommendation for age of initiation of cervical screening with HPV testing. The creation of an organized screening program in the province will allow the implementation of evidence-based recommendations. We provide interim recommendations for cervical screening until HPV testing has been funded.
Key Words: HPV testing, cervical cancer screening, cancer prevention Competing Interests: See Acknowledgements.
Méthodes : Nous avons mené une analyse systématique portant sur les sites Web pertinents, les bases de données Medline et EMBASE (de 1998 à juillet 2004) et la Cochrane Library (de 2005 à 2010). Aucune ligne directrice ni aucune analyse systématique traitant des sujets à l’étude n’ont pu être identifiées. La base factuelle consistait en sept essais comparatifs randomisés, en trois études cas-témoins, en une étude de cohorte et en un exposé de synthèse. Un spécialiste de la méthodologie a mené l’identification et l’extraction des données. L’analyse des données et l’évaluation de la qualité ont été menées par les auteurs, lesquels disposent d’une expertise en méthodologie, en gynécologie oncologique, en pathologie et en médecine familiale. Les méthodes d’analyse systématique et les recommandations formulées ont été analysées par un comité interne dont les membres disposaient d’une expertise clinique, méthodologique et oncologique. Une analyse externe a été menée par des cliniciens ontariens et d’autres spécialistes. Conclusions : Le processus d’élaboration des lignes directrices a mené à la formulation de recommandations visant la détermination de la méthode optimale de dépistage cervical primaire, de l’intervalle optimal de dépistage et de l’âge optimal pour l’abandon du dépistage chez les Ontariennes de la population cible. Nous ne disposions pas de données suffisantes pour formuler une recommandation quant à l’âge auquel le dépistage cervical au moyen du dépistage du VPH devrait être entamé. La création d’un programme de dépistage organisé dans la province permettra la mise en œuvre de recommandations factuelles. Nous fournissons des recommandations intérimaires pour ce qui est du dépistage cervical, et ce, jusqu’à ce que le dépistage du VPH ait été financé.
Received on December 23, 2011 Accepted on February 8, 2012
J Obstet Gynaecol Can 2012;34(5):453–458
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INTRODUCTION
T
he purpose of cervical screening is to reduce the risk of cervical cancer through the detection and treatment of lesions that have the potential to become malignant. This should be accomplished while minimizing side effects and harms such as anxiety and unnecessary treatment. Many guidelines exist for cervical screening in North America, Europe, and elsewhere. All recommend a cytology-based primary screen, either conventional (i.e., the Papanicolaou smear test) or liquid-based. The previous Ontario guideline, published in 2007, recommended initial screening with liquid-based cytology within three years of initiation of sexual activity, to be repeated yearly for three years, then if results are normal, every two to three years until age 70 (Table 1).1 The characteristics of a screening program can influence guideline recommendations. In the past, recommendations took into account the opportunistic nature of cervical screening in Ontario, and called for frequent screening intervals and a young age of initiation to compensate for a lack of follow-up, feedback, and communication of results.2,3 Currently, the program is being organized to include a systematic invitation and recall component, and feedback to women and practitioners. Unfortunately, the decline in cervical cancer incidence in Ontario, largely attributed to cytology-based screening, has plateaued. These factors have necessitated an update to Ontario’s cervical screening guidelines to incorporate recent advancements in the understanding of the natural history of HPV and in HPV testing as a method of screening. To our knowledge, this is the first time that the results of randomized controlled trials of HPV testing for primary screening beyond baseline testing have been included in the evidence base for guidelines in a Canadian province. These guidelines will be used to inform the Ontario Cervical Screening Program’s invitations to women in the target population, provide evidence-based clinical practice guidance for practitioners, and inform policy decisions. Guideline Scope and Research QUESTIONS
This guideline provides recommendations for cervical screening in the general population of asymptomatic women in Ontario who have been sexually active. The
ABBREVIATIONS ASCUS atypical squamous cells of undetermined significance CIN
cervical intraepithelial neoplasia
PEBC
Program in Evidence-based Care
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target users are family physicians, other primary care providers, and gynaecology specialists involved in screening women for cervical cancer and its precursors. The recommendations assume an organized screening program, including a central database infrastructure that allows invitations for screening to be sent at appropriate times, as well as communication of abnormal results and feedback to women and practitioners. Four research questions regarding screening method, age range, and interval are addressed (Table 2). In 2007, Ontario introduced an HPV vaccination program for girls in Grade 8. Specific recommendations for the vaccinated cohort are not being made at this time, although in the future it may be appropriate to target specific recommendations to this sub-group. Recommendations for other special populations or further testing in the event of abnormal results are beyond the scope of this guideline. GUIDELINE DEVELOPMENT
This guideline was initiated by the Ontario Cervical Screening Program in conjunction with the Program in Evidence-based Care, an initiative of Cancer Care Ontario. The PEBC produces evidence-based guidelines, using the methods of the Practice Guidelines Development Cycle.4 A Cervical Screening Guideline Working Group was struck to lead the process of guideline development and included representatives with expertise in gynaecologic oncology, family medicine, pathology, and methodology. Literature Search Strategy
A systematic review was conducted of websites of international guideline developers, Canadian provincial and national cancer agencies, cancerviewcanada.ca,5 and Medline and EMBASE (2005 to November 2010, text words and medical subject headings: “cervix,” “cervical,” “cancer,” “carcinoma,” “screening,” and “mass screening”). Reference lists of included articles were scanned for additional citations. The Cochrane Library was searched for topic-specific reviews from 2005 to 2010. Eligible sources included English language practice guidelines, systematic reviews, and randomized trials for the primary screening question. For the screening age and interval questions, observational studies were also considered. Guidelines were excluded if they did not include a systematic review (item 7 of the AGREE II Rigour of Development domain).6 Costing analyses were not considered. Literature Search Results
No guidelines that included a systematic review of the HPV testing literature were identified. Results from seven randomized trials,7–13 three case–control studies,14–16 two cohort studies,17,18 one pooled cohort study,19 and a review
Cervical Screening: A Guideline for Clinical Practice in Ontario
Table 1. Summary of 2005 versus 2011 key recommendations for cervical screening in Ontario Primary screening test
Age of screening initiation
Evidence- and consensus-based (2006 to 2010)
Women 30 to 65: HPV testing; Women < 30: to be determined
To be determined
Every five years with a negative HPV test result
65
Evidence-based (up to 2005)
Cytology testing
Within three years of initiation of sexual activity
Annually until three negative tests, then every two to three years
70
Year
Evidence base
2011
20051
Screening interval
Age of screening cessation*
*Provided that there is an adequate, up-to-date negative screening history.
Table 2. Literature search results (March 2005 to October 2010) Question
Studies
Quality of evidence
What is the optimal primary cervical screening method (i.e., HPV DNA testing and/or cytology testing)?
Seven randomized controlled trials7–13
High
What is the most appropriate age for the initiation of cervical screening?
Three case–control studies14–16
Low
What is the most appropriate interval for cervical screening?
Two cohort studies17,18 One pooled cohort study19 One review article20
Moderate
What is the most appropriate age for the cessation of cervical screening?
No studies found
Low
article20 were identified (Table 2). The results of the systematic review for HPV testing in primary screening are published separately.21
a small number of content experts, and a professional consultation that was intended to facilitate dissemination of the final guidance to Ontario practitioners.
Synthesis of the Evidence and Development of Recommendations
Targeted peer review
Data were extracted by a methodologist, then verified by a research assistant and reviewed by the working group. Evi dence quality was assessed on the basis of study design and volume of evidence (Table 2). Recommendations were drafted by the working group on the basis of published evidence or by consensus where high quality evidence was not available.
During the development process, three clinical and/or methodological experts identified by the working group were approached and agreed to participate. The draft report and an evaluation questionnaire were sent via email on July 7, 2011. Written comments were invited. Reminders were sent at two weeks and at four weeks. The working group reviewed the peer review results and made changes to the draft guideline accordingly.
Internal Review
Professional consultation
The recommendations drafted by the working group were circulated to the Cervical Screening Expert Panel, made up of individuals from Cancer Care Ontario’s Gynecologic Cancer Disease Site Group (5 reviewers) and Cervical Clinical Advisory Committee (5 reviewers). The report was also reviewed by the PEBC Report Approval Panel, a threeperson panel with clinical, methodological, and oncology expertise. Internal review comments were incorporated by the working group into the guideline draft. External Review by Ontario Clinicians and Other Experts
The external review process included a targeted peer review to obtain direct feedback on the draft report from
Four hundred thirteen Ontario practitioners from the areas of family medicine or primary care, gynaecology, gynaecologic oncology, and those with an interest in HPV testing and/or screening were surveyed. One hundred six responses were received (23%), the majority of which were from family medicine specialists (52%). Participants were asked to rate the quality of the guideline, whether they would use and/or recommend it, whether they perceived barriers or enablers to implementation, and for other comments. The consultation period lasted from July 7, 2011, to August 23, 2011. The working group reviewed the results of the survey and revised the draft accordingly. MAY JOGC MAI 2012 l 455
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Primary cervical screening with HPV testing (women 30 to 65) HPV DNA testing in women 30 to 65 years of age
Negative
Positive
Cytology Triage of HPV Positive Results
Cytology test Repeat HPV DNA testing at 5-year intervals until age 65 years
Positive (≥ ASCUS)
Negative
Repeat HPV testing at 12 months
Negative
Colposcopy
Positive
Adapted with permission of Elsevier from Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand MH, et al. Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries. Vaccine 2008;26(Suppl 10):K29–41.20
CLINICAL RECOMMENDATIONS AND EVIDENCE BASE What is the Optimal Primary Cervical Screening Method?
HPV DNA testing for high risk strains (HPV testing) is recommended for primary cervical screening. If HPV screening is positive, cytology screening is recommended as a triage test to reduce the number of colposcopy referrals and increase the specificity of the screening algorithm (Figure 1). This recommendation is based both on the results of RCTs with a low risk of bias and the consensus of the working group. HPV Testing for Primary Screening
Across RCTs,7–13 HPV testing detected significantly more cervical intraepithelial neoplasia grade 2 and grade 3 in the baseline screening round than did cytology-based testing. Fewer CIN2 or more severe (CIN2+) cases were detected in the HPV group in the subsequent screening round, indicating earlier detection of cytologic abnormality with HPV testing. One trial found a significant reduction with HPV testing, but not with cytology testing, compared with standard care in cervical cancer incidence and mortality.13 In another trial, there was no significant 456 l MAY JOGC MAI 2012
difference in the number of invasive cervical cancers detected in the baseline screening round comparing HPV testing and cytology testing.10 In the subsequent screening round, no cases of cancer were found in the HPV-testing group, and nine cases were found in the cytology-testing group (P = 0.03). A high number of the cancers detected in the second round in the cytology group were adenocarcinomas. Due to higher sensitivity, the rate of colposcopy referral after HPV testing alone can be higher than after conventional cytology. In one trial, the referral rate after a positive HPV test alone was 6.1%, compared with a rate of 2.9% after conventional cytology showing atypical squamous cells of undetermined significance. HPV with cytology triage resulted in a 1.1% rate of referral based on ASCUS.12 Another trial found the frequency of colposcopy referrals was 1.2% in both the conventional cytology arm at a threshold of low-grade squamous intraepithelial lesions and the HPV with cytology triage arm of their trial.22 Cytology testing is recommended as the triage test, but there are other potential options include incorporating testing for HPV 16 or HPV 18, which are associated with a greater risk of carcinogenicity.17 What is the Most Appropriate Age for the Initiation of Cervical Screening?
It is the opinion of the working group that there is insufficient evidence at this time to make a recommendation regarding age of screening initiation with HPV-based testing. Low-quality evidence (case–control studies with some risk of bias, confounding, or results due to chance) was available for this question. The results of the studies were mixed, with a trend towards higher efficacy of screening for older women.14–16 No studies directly assessed the optimal age of initiation of cervical screening with HPV testing as the primary screen. At What Interval Should Women Be Screened?
Rescreening should be conducted according to the algorithm presented in the Figure. HPV testing performs better for women aged 30 and older than for younger women because the rate of transient infections is lower in that older age group23; therefore, the screening algorithm is presented for women 30 to 65 years of age. Moderate quality evidence from observational studies was combined with the opinion of the guideline development group to formulate the screening interval recommendations.
Cervical Screening: A Guideline for Clinical Practice in Ontario
Five-year interval after HPV negative results
Six years after a negative HPV test, the cumulative incidence rate for CIN3+ was 0.27% (95% CI 0.12 to 0.45), which was not significantly different from the rate after three years with a negative cytology test (0.51%; 95% CI 0.23 to 0.77).19 The risk of CIN3+ after a negative HPV test is low: the 12-year absolute risk of CIN3+ after a negative HPV DNA test in women with normal cytology was 3.0% (95% CI, 2.5 to 3.5%).18 One-year interval after HPV positive/cytology negative results
Persistent lesions have a higher likelihood of progressing to cervical cancer. Short-term persistence of HPV infection for at least one year is an important predictor of CIN2+: women who tested HPV positive at enrolment and negative after approximately one year had a cumulative incidence of CIN2+ after three years of 1.2% (95% CI −0.2 to 2.5). The three-year cumulative incidence of CIN2+ in women who tested positive for carcinogenic HPV at study enrolment and again after approximately one year was 17.0% (95% CI 12.1 to 22.0).17 Qualifying statement
Based on consensus, colposcopy for ASCUS or more serious lesions among the HPV positive is recommended here, although management of abnormal results was not included in the scope of the systematic review. What is the Most Appropriate Age for Stopping Cervical Screening?
Screening may be discontinued after the age of 65 among the HPV negative. This recommendation is the opinion of the guideline development group. No evidence meeting our inclusion criteria was found. Age 65 is recommended provided that there is an adequate negative screening history in the previous 10 years (i.e., two or more negative tests) and a final negative test at age 65. Otherwise, women should continue with screening at recommended intervals. The consensus is based on the low rate of cervical cancer in this age group among women who are HPV negative or have had negative triennial cytology for many years. DISCUSSION
Ontario is implementing an organized cervical screening program, with ongoing process and outcome evaluations, which will allow the implementation of evidence-based recommendations. The screening algorithm presented here represents a shift towards better identification of risk. In the meantime, interim guidelines recommend that screening by cytology should commence at no earlier than
age 21, that it should be performed every three years, and that it should continue until age 70. The working group for this guideline is aware that recommendations for lengthened screening intervals can be difficult to implement.24 Our practitioner consultation provided some insight into why this may be so in Ontario: a false sense of security provided by frequent cervical screening, lack of awareness or understanding of new guidelines, using cervical screening as an opportunity to discuss unrelated concerns or health issues, static alignment of physician incentives, and a general resistance to change on the part of both practitioners and patients. There is also evidence to suggest that some women derive peace of mind from frequent Papanicolaou smear tests and that physicians may reinforce this perception.25,26 Potential harms of screening include adverse reproductive outcomes with treatment for lesions that would have regressed on their own and anxiety associated with positive test results.27 A major challenge will be to educate women and practitioners and to refrain from treating HPV-positive women who do not have obvious long-term persistence of high-risk HPV or serious lesions.28 Although the development process for these guidelines was rigorous and transparent, there were some limitations. Because of time and infrastructure constraints, the process did not include a patient/consumer representative or a period of public consultation. Also, while we have provided an informal rating of the evidence used to develop recommendations, we have chosen not to provide a rating for individual recommendations, but rather to explicitly state the evidence or consensus base for each recommendation. The literature regarding HPV testing and follow-up is evolving; therefore, the algorithm recommended here should be reviewed for currency before implementation. A recommendation for age of initiation was not made in this version of the guideline. The appropriate age should become clearer as further research results are published, and it will be affected by the increasing number of Ontario women who have been vaccinated against HPV. This guideline will be reviewed for currency within three years of publication, according to the policy of the PEBC. These recommendations should prompt an examination of the most appropriate setting in which to provide cervical screening services. The link between contraceptive care, screening for sexually transmitted infections, and cervical screening may well be an outdated paradigm. Provincial incentives for screening will need to be responsive to changes in guideline recommendations. Education regarding the roles of cytology and HPV testing is needed so that the new recommendations are perceived as an improvement in effective screening and not as a MAY JOGC MAI 2012 l 457
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cost-cutting measure, and so that women understand their risk of cervical cancer, the risks associated with treatment, and how frequently they should be screened.
11. Kitchener HC, Almonte M, Thomson C, Wheeler P, Sargent A, Stoykova B, et al. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Lancet Oncol 2009;10:672–82.
ACKNOWLEDGEMENTS
12. Mayrand M, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 2007;357:1579–88.
The work of the Program in Evidence-based Care is supported by the Ontario Ministry of Health and LongTerm Care through Cancer Care Ontario, and is editorially independent from its funding source. Sheila Dunn reported involvement in a clinical trial on this topic. Laurence Paszat reported grant support from the Canadian Institutes of Health Research for research on a related topic. Michael Shier reported receiving consulting fees, honoraria, and/or other support from GlaxoSmithKline and Graceway Pharmaceuticals and contributing to several publications on this topic in the past five years. REFERENCES 1. McLachlin CM, Mai V, Murphy J, Fung-Kee-Fung M, Chambers A, Oliver TK, et al. Ontario cervical cancer screening clinical practice guidelines. J Obstet Gynacol Can 2007;29:344–53. 2. Miller AB, Anderson G, Brisson J, Laidlaw J, Le Pitre N, Malcolmson P, et al. Report of a National Workshop on Screening for Cancer of the Cervix. 1991;145:1301–25. 3. Moscicki AB. Cervical cytology testing in teens. Curr Opin Obstet Gynecol 2005;17:471–5. 4. Browman GP, Levine MN, Mohide EA, Hayward RSA, Pritchard KI, Gafni A. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13:502–12. 5. cancerviewcanada.ca [website]. Toronto, ON: Canadian Partnership Against Cancer; updated 2011. Available at: http://www.cancerview.ca. Accessed March 13, 2012. 6. Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: Advancing guideline development, reporting, and evaluation in health care. Prev Med 2010;51:421–4. 7. Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007;357:1589–97. 8. Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370:1764–72. 9. Anttila A, Kotaniemi-Talonen L, Leinonen M, Hakama M, Laurila P, Tarkkanen J, et al. Rate of cervical cancer, severe intraepithelial neoplasia, and adenocarcinoma in situ in primary HPV DNA screening with cytology triage: randomised study within organised screening programme. BMJ 2010;340:c1804. 10. Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 2010;11:249–57.
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13. Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh AM, et al. HPV screening for cervical cancer in rural India. N Engl J Med 2009;360:1385–94. 14. Andrae B, Kemetli L, Sparen P, Silfverdal L, Strander B, Ryd W, et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst 2008;100:622–9. 15. Crocetti E, Battisti L, Betta A, Palma PD, Paci E, Piffer S, et al. The cytological screening turned out effective also for adenocarcinoma: a population-based case–control study in Trento, Italy. Eur J Cancer Prev 2007;16:564–7. 16. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case–control study of prospectively recorded data. BMJ 2009;339:b2968. 17. Castle PE, Rodriguez AC, Burk RD, Herrero R, Wacholder S, Alfaro M, et al. Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study. BMJ 2009;339:b2569. 18. Kjaer SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst 2010;102:1478–88. 19. 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. BMJ 2008;337:a1754. 20. Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand MH, et al. Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries. Vaccine 2008;26(Suppl 10):K29–K41. 21. Murphy J, Kennedy EB, Dunn S, McLachlin M, Fung Kee Fung M, Gzik D et al. HPV testing in primary cervical screening: a systematic review and meta-analysis. J Obstet Gynaecol Can 2012;34(5):443–52. 22. Leinonen M, Nieminen P, Kotaniemi-Talonen L, Malila N, Tarkkanen J, Laurila P, et al. Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst 2009;101:1612–23. 23. Bartholomew DA. Human papillomavirus infection in adolescents: a rational approach. Adolesc Med Clin 2004;15:569–95. 24. Roland KB, Soman A, Benard VB, Saraiya M. Human papillomavirus and Papanicolaou tests screening interval recommendations in the United States. Am J Obstet Gynecol 2011;205:447.e1–e8. 25. Sirovich BE, Woloshin S, Schwartz LM. Screening for cervical cancer: will women accept less? Am J Med 2005;118:151–8. 26. Zhang Y, Borders TF, Rohrer JE. Correlates of intent to seek unnecessary pap tests among elderly women. Womens Health Issues 2007;17:351–9. 27. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006;367:489–98. 28. Schiffman M, Wentzensen N, Wacholder S, Kinney W, Gage JC, Castle PE. Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst 2011;103:1–16.