The Ontario Cervical Screening Program (OCSP) is currently being relaunched to incorporate an organized call and recall component. This relaunch has necessitated a review of evidence related to the research questions listed above and an update of the relevant portions of the Program in Evidence-based Care (PEBC) May 2005 guideline Cervical Screening (1). The updated guideline will help the OCSP to realize its long-term goals of reducing the incidence of and mortality from cervical cancer through an organized screening program and improving the capacity of providers to engage in organized cervical screening. It will also address the 2011-2014 Ontario Cancer Plan (2) goal of creating evidence-based guidelines for cervical cancer screening.
Evidence clearly indicates that there is a role for HPV testing in primary screening, and, thus, the primary recommendations presented in Part 1 of this guideline are for HPVbased testing for women 30 years of age and over. The proposed algorithm (Figure 1) assumes the existence of an organized province-wide screening program.
There is lesser quality evidence at this time for the appropriate screening algorithm for women under 30. For this reason, and because HPV testing is not currently funded in the province and the components of an organized screening program are in the process of being put in place, a set of interim recommendations (Section 1, Part 2) are also provided that include the younger age group and acknowledge the current standard of cytology-based testing. The goal of the interim recommendations is to provide a bridge to the time when HPV testing for primary screening is funded in Ontario. Because screening for cervical cancer is a quickly evolving field, the HPV testing-based algorithm, the optimal age for screening initiation, and a method of screening for women younger than 30 years should be reviewed prior to implementation. A comparison of recommendations contained in this guideline and in the previous version published in 2005 is presented in Table 1. A table of screening test results terminology and a glossary of terms are provided in Appendices 1 and 2, respectively. For more information on HPV and the development of cervical cancer, details of the systematic review, and discussion of the impact of adoption of HPV testing for primary screening, please see Section 2 of this report. 

# RECOMMENDATION Primary Screening Test
HPV DNA testing of cells collected from the cervix is recommended for primary cervical screening. Cytology screening, which was recommended for primary screening in the previous version of this guideline, is now recommended only in the event of a positive HPV DNA test result (see HPV screening algorithm, Figure 1). Interim recommendations are provided in Section 1, Part 2 (Interim Recommendations), because HPV testing is not funded at this time for primary screening in Ontario.

# KEY EVIDENCE HPV testing
Seven randomized controlled trials (RCTs) (3)(4)(5)(6)(7)(8) have been conducted to assess the performance of HPV testing in primary screening. The trials assessed the rates of cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2 or CIN3), either at a baseline screening round or over two screening rounds. CIN2 is a useful indicator because it is often the threshold for clinical management. CIN3 is less likely than lower grades of CIN to regress or resolve without treatment and so is a useful predictor of the risk for cervical cancer. The results showed that:
- HPV testing consistently detected significantly more CIN2 and CIN3 in the baseline screening round than did cytology-based testing. HPV testing detected fewer CIN2 or more severe (CIN2+) cases in the subsequent screening round, indicating a lead time gain with HPV testing.  The one trial that had sufficient sample size to report incidence and mortality due to cervical cancer found a significant reduction with HPV testing but not with cytology testing, compared to standard care (9).  There was no significant difference in the number of invasive cancers detected in the baseline screening round in the New Technologies in Cervical Cancer trial (8) comparing HPV testing and cytology testing. In the subsequent screening round, no cases of cancer were found in the HPV-testing group, while nine cases were found in the cytology-testing group. A high number of the cancers detected in the second round in the cytology group were adenocarcinomas (10). This is consistent with previous reports that cytology is less effective in preventing adenocarcinomas than squamous cell carcinomas (approximately 20% of cervical cancers in Ontario are adenocarcinomas) (11).

# Cytology Triage of HPV Positive Results
- Due to the higher sensitivity of HPV testing compared to conventional cytology, the rate of colposcopy referral with HPV testing alone is higher than the rate with conventional cytology. For example, in the Canadian Cervical Cancer Screening Trial (CCCaST) RCT, the rate of referral to colposcopy after a positive HPV test alone was 6.1%, compared to a referral rate of 2.6% for conventional cytology results of atypical squamous cells of undetermined significance (ASCUS) (3).  A triage test can reduce the number of colposcopy referrals and increase the specificity of the screening algorithm. In CCCaST, HPV with Pap triage resulted in a 1.1% rate of referral based on ASCUS (3). The Finnish Public Health 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 (LSIL) and the HPV with cytology triage arm of their trial (12).

# QUALIFYING STATEMENT
- The recommendation for HPV testing is applicable only in the context of an organized screening program with an adequate database infrastructure that allows for an invitation to screening at recommended intervals, and a follow-up of women with abnormal test results.  HPV testing has been shown to be more effective for women 30 years of age and older (see Age of Screening Initiation below).  Women who have never been sexually active 1 do not require cervical screening.

# RECOMMENDATION Age of Screening Initiation
It is the opinion of the Cervical Screening Guideline Working Group (the Working Group) that there is insufficient evidence at this time to make a recommendation for the age at which to begin cervical screening using HPV testing as the primary screen. HPV testing performs better for women 30 and over compared to younger women because the rate of transient infections is higher in the younger age group; therefore, the screening algorithm in the following recommendation is presented for women 30-65 years of age.

# RECOMMENDATION Screening Interval (Women 30-65)
Screening interval recommendations are according to the algorithm presented in Figure 1. For women aged 30-65, HPV DNA testing is to occur at five-year intervals after an initial negative result, which is a change from the recommendation for repeat cytology testing every two to three years contained in the 2005 version of this guideline. HPV-positive tests should be assessed with cytology testing and not referred directly to colposcopy. Repeat HPV testing for results of HPV positive/cytology negative should be conducted after one year. 

# KEY EVIDENCE
The proposed HPV testing algorithm is based on a combination of evidence from cohort studies, the natural history of HPV infections, and the consensus of the Working Group.

# Five-Year Interval after HPV Negative Results
- Six years after a negative HPV test, pooled cohort data found a cumulative incidence rate for CIN3+ of 0.27% (95% CI, 0.12 to 0.45), which was lower than the rate after three years with a negative cytology test (0.51%; 95% CI, 0.23 to 0.77) (14). This indicates that retesting at five-year intervals would entail a low level of risk.  The risk of CIN3+ after a negative HPV test is low: in a Danish cohort study 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%) (15). 

# One-Year Interval with HPV Positive/Cytology Negative Results
The short-term persistence of HPV infection for at least one year is an important predictor of CIN2+ (16). In women who tested HPV positive at enrolment and negative after about one year (nine-21 months), the cumulative incidence of CIN2+ after three years was 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) (16). Consequently, referral to colposcopy after two consecutive positive HPV tests occurring a year apart is recommended, even in the event of initially negative cytology results.

# QUALIFYING STATEMENTS
The screening algorithm (Figure 1) should be reviewed for currency prior to implementation.
A variation on this algorithm includes genotyping for HPV 16 and/or HPV 18 immediately after a positive HPV test and cytology results of normal, ASCUS or LSIL, based on the rationale that HPV 16 has been shown to be more persistent and more often associated with high-grade lesions, and HPV 18 is more often associated with difficult to detect lesions in the endocervical canal (13). Positivity for either of these types may require immediate colposcopy.

# RECOMMENDATION Age of Screening Cessation
Screening may be discontinued after the age of 65 provided there is an adequate negative screening history in the previous 10 years (i.e., two or more negative tests) and a final negative HPV test at age 65. Women who do not meet these requirements should continue with screening at recommended intervals. This is a change from the previous recommendation of cessation at age 70 (1).

# KEY EVIDENCE
This recommendation is the consensus of the authors, taking into account the low rate of cervical cancer in this age group among women who have previously been adequately screened, the potential discomfort of the procedure, and difficulties with visualization of the squamocolumnar junction in older women.

# PART 2: INTERIM RECOMMENDATIONS (TO BE FOLLOWED UNTIL HPV TESTING IS FUNDED) INTERIM RECOMMENDATION Primary Screening Test
On an interim basis, the authors endorse the recommendation contained in the 2005 version of this guideline: primary screening with cytology testing (1).

# KEY EVIDENCE
This recommendation is the opinion of the authors based on the systematic review conducted for the previous version of this guideline (1).

# QUALIFYING STATEMENTS
- Women with Pap tests that lack transformation zone components (i.e., endocervical and/or metaplastic cells) may continue screening at the regular intervals recommended by the guideline. Repeated samples lacking transformation zone may require further investigation.  The above statement does not include women with test results of "unsatisfactory", who should undergo repeat screening in three months. This qualifying statement is the opinion of the Working Group based on the clinical experience that a shorter waiting period may result in the detection of reactive changes as a result of the first screening test.  The Working Group maintains the recommendations for screening of special populations contained in the 2005 guideline:  Immunocompromised women (e.g., those currently taking long-term immunosuppressants, those who are HIV positive) should receive annual screening.  Screening can be discontinued in women who have undergone a total hysterectomy for benign causes with no history of cervical dysplasia or HPV. Women who have undergone subtotal hysterectomy (with an intact cervix) should continue screening according to the guidelines.  Indications for screening frequency for pregnant women should be the same as for women who are not pregnant. Manufacturers' recommendations for the use of individual screening tools in pregnancy should be considered.  Women who have sex with women should follow the same cervical screening regimen as women who have sex with men.

# INTERIM RECOMMENDATION Age of Screening Initiation
Cytology testing should commence at 21 years of age for sexually active women.

# KEY EVIDENCE
Lower quality evidence was available for the questions regarding the age of initiation of cervical screening. Three case-control studies were found that addressed the questions of initiation (17)(18)(19). The results of these studies were mixed, with a trend towards higher efficacy of screening for older women. There were no studies found that directly assessed the optimal age of initiation of cervical screening with HPV testing as the primary screen.
- After weighing the available evidence, the authors of this guideline have concluded that the harms of screening women under 21 years of age significantly outweigh the benefits.
In the opinion of the authors, the potential for adverse reproductive outcomes with treatment, anxiety related to the testing procedure, and the anxiety and potential stigma associated with positive test results considerably outweigh the benefits of screening in women younger than 21 years of age (20)(21)(22)(23), given the relatively high rate of HPV infection (24), rarity of cervical cancer in women under 25 years, and the up to decadeslong time period of progression from HPV infection to cervical cancer (25).  In the opinion of the Working Group, evidence regarding the necessity, utility, and/or effectiveness of screening in women 21 to 24 years is not as clear; the authors of this guideline are not convinced that the harms outweigh the benefits of screening for these women. Therefore, the consensus is that lesions in these women should be detected and treated where appropriate in order to minimize the potential for their progression to cervical cancer.  The guideline authors do recognize that there is also a potential for harm with screening. The potential harms related to treatment of CIN are adverse reproductive outcomes, including premature rupture of membranes, low birth weight, and preterm delivery (22). The early detection and treatment of CIN3 in young women, however, might prevent some cancers developing to a stage where treatment could result in compromised fertility. Based on the information available at this time, the authors of this guideline consider that the benefit of eliminating potential cases of invasive cervical cancer in women 21-24 years of age outweighs the reproduction-related harms, as well as the potential anxiety, fear, and uncertainty related to abnormal screening tests, intensified screening, colposcopy, biopsy, and treatment for CIN.

# QUALIFYING STATEMENTS
- Women who are not sexually active 3 by age 21 may delay cervical screening.  Women who have never been sexually active do not require cervical screening.  The interim recommendation to begin screening at 21 years of age should be reviewed within 24 months of the publication of this guideline.  As HPV-vaccinated women reach the age of screening initiation, there may be impact on the screening recommendations.

# KEY EVIDENCE
The key evidence for this recommendation is presented in Section 2 (systematic review section) of the 2005 PEBC guideline Cervical Screening (1).

# INTERIM RECOMMENDATION Screening Interval
Women should be screened every three years.

# KEY EVIDENCE
The previous guideline recommended three annual negative screens before lengthening the screening interval to two to three years. Evidence presented in the previous version of this guideline showed that the excess risk with screening every three years compared to annually was approximately three additional cases of cervical cancer per 100,000 women (26).
A modelling study conducted in Australia found that increasing the recommended screening interval from two years to three years with cytology-based testing would result in no substantial change to incidence and mortality due to cervical cancer (27).

# INTERIM RECOMMENDATION Age of Screening Cessation
The authors endorse the age of cessation of cytology-based testing presented in the 2005 version of this guideline:  Screening may be discontinued after the age of 70 if there is an adequate negative cytology screening history in the previous 10 years (i.e., three to four negative cytology tests).

# KEY EVIDENCE
Key evidence for this recommendation is presented in Section 2 (systematic review section) of the 2005 PEBC guideline Cervical Screening (1).

# Recommended Management for Women with Abnormal Cytology
Management recommendations were not included in the scope of the current guideline. The algorithm for the management of abnormal results from the previous version of this guideline has been appended, however, as its recommendations still apply to the interim cytology-based guidelines provided here. Please see Appendix 3 (Section 1, page 19). If the evidence base for these recommendations is required, please email ccopgi@mcmaster.ca.

# FUTURE RESEARCH
Results from further screening rounds of several of the RCTs included in the evidence base for this guideline are anticipated (Table 2). These results should further inform the optimal screening algorithm for women 30 years of age and older and the optimal age for commencing cervical screening. An international agreement has been reached to conduct future meta-analyses of the HPV screening trials and to synthesize evidence on new methods for cervical cancer prevention (28). 

# NTCC (ISRTCN81678807) February 2002 December 2004
Yes; A cost-benefit analysis is underway (10). Also, the group is updating the follow-up of a third screening round (personal communication, Guglielmo Ronco, May 2011).

# ARTISTIC (ISRCTN25417821) June 2001 November 2009
Yes; the ARTISTIC trial is continuing to follow women while maintaining the randomised concealment of HPV testing results for a further three-year round of screening (29). The HPV FOCAL study (Trial Registration No. ISRCTN79347302) is being conducted by the BC (British Columbia) Cancer Agency, in collaboration with the BC Centre for Disease Control, the University of British Columbia, McGill University, and healthcare providers in Metro Vancouver and Greater Victoria. In a Canadian context, this study aims to establish the efficacy of human HPV testing as a stand-alone screening test with cytology triage of HPV positive women, establish an appropriate screening interval for HPV negative women, and determine cost-effectiveness of HPV testing as a primary screening test.
Other HPV testing strategies under study are based on molecular markers and include viral load, genotyping, testing for the RNA of the viral oncogenes E6 and E7, and testing for the overexpression of the p16-INK4A protein (31).
As research continues into the risk factors for cervical cancers and the different typespecific and other tests evolve, screening algorithms will become increasingly more complex. In response to this, a group is developing a tool to predict the risk for a woman of having or developing cervical precancer. These risk estimates could be used to make referral and screening interval decisions (32) and may be considered for implementation in future update of this guideline. Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

# RELATED GUIDELINES