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Liquid-Based Cytology and Human Papillomavirus Testing to Screen for Cervical Cancer: A Systematic Review for the U.S. Preventive Services Task Force FREE

Evelyn P. Whitlock, MD, MPH; Kimberly K. Vesco, MD, MPH; Michelle Eder, PhD; Jennifer S. Lin, MD, MCR; Caitlyn A. Senger, MPH; and Brittany U. Burda, MPH
[+] Article and Author Information

From the Oregon Evidence-based Practice Center, Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon.

Acknowledgment: The authors thank Daphne Plaut, MLS, for conducting the literature searches; Kevin Lutz, MFA, for editorial support; and Rebecca Holmes, MD, MS, and Sarah Zuber, MSW, for assistance in conducting the evidence review. They also thank the Agency for Healthcare Research and Quality and the USPSTF and Marc Arbyn, MD, MSc, DrTMH; Walter Kinney, MD; Mary Mitchell; Alan G. Waxman, MD, MPH; and Diana Petitti, MD, MPH, for their contribution to this evidence review.

Grant Support: This review was conducted by the Oregon Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (contract HHS-290-2007-10057-I, task order 3).

Potential Conflicts of Interest: Drs. Whitlock, Vesco, Eder, and Lin and Ms. Senger: Grant (money to institution): Agency for Healthcare Research and Quality; Support for travel to meetings for the study or other purposes (money to institution): Agency for Healthcare Research and Quality; Payment for writing or reviewing the manuscript (money to institution): Agency for Healthcare Research and Quality. Drs. Whitlock, Eder, and Lin and Ms. Senger: Provision of writing assistance, medicines, equipment, or administrative support (money to institution): Agency for Healthcare Research and Quality. Ms. Senger: Support for travel to meetings for the study or other purposes (money to institution): National Institutes of Health. Ms. Burda: Grant (money to institution): Agency for Healthcare Research and Quality; Support for travel to meetings for the study or other purposes (money to institution): Agency for Healthcare Research and Quality; Consultancy: Oregon Health & Science University. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1382.

Requests for Single Reprints: Reprints are available from the Agency for Healthcare Research and Quality Web site (www.preventiveservices.ahrq.gov).

Current Author Addresses: Drs. Whitlock, Vesco, Eder, Lin, and Senger and Ms. Burda: Center for Health Research, Kaiser Permanente Northwest, 3800 North Interstate Avenue, Portland, OR 97227.

Author Contributions: Conception and design: E.P. Whitlock, K.K. Vesco.

Analysis and interpretation of the data: E.P. Whitlock, K.K. Vesco, M. Eder, J.S. Lin.

Drafting of the article: E.P. Whitlock, K.K. Vesco, M. Eder, C.A. Senger.

Critical revision of the article for important intellectual content: E.P. Whitlock, K.K. Vesco, J.S. Lin, C.A. Senger.

Final approval of the article: E.P. Whitlock, K.K. Vesco, M. Eder, J.S. Lin.

Obtaining of funding: E.P. Whitlock.

Administrative, technical, or logistic support: C.A. Senger, B.U. Burda.

Collection and assembly of data: K.K. Vesco, M. Eder, J.S. Lin, C.A. Senger, B.U. Burda.


Ann Intern Med. 2011;155(10):687-697. doi:10.7326/0003-4819-155-10-201111150-00376
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This article has been corrected. The original version (PDF) is appended to this article as a supplement.

Background: Screening programs using conventional cytology have successfully reduced cervical cancer, but newer tests might enhance screening.

Purpose: To systematically review the evidence on liquid-based cytology (LBC) and high-risk human papillomavirus (HPV) screening for U.S. Preventive Services Task Force use in updating its 2003 recommendation.

Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, and PsycINFO from January 2000 through September 2010.

Study Selection: Two independent reviewers selected fair- to good-quality English-language studies that compared LBC or HPV-enhanced primary screening with conventional cytology in countries with developed population-based screening for cervical cancer.

Data Extraction: At least 2 independent reviewers critically appraised and rated the quality of studies and used standardized abstraction forms to extract data about test performance for detecting cervical intraepithelial neoplasia (CIN) and cancer and screening-related harms.

Data Synthesis: On the basis of 4 fair- to good-quality studies (141 566 participants), LBC had equivalent sensitivity and specificity to conventional cytology. Six fair- to good-quality diagnostic accuracy studies showed that 1-time HPV screening was more sensitive than cytology for detecting CIN3+/CIN2+ but was less specific. On the basis of 2 fair- to good-quality randomized, controlled trials (RCTs) (120 533 participants), primary HPV screening detected more cases of CIN3 or cancer in women older than 30 years. Four fair- to good-quality diagnostic accuracy studies and 4 fair- to good-quality RCTs showed mixed results of cotesting (HPV plus cytology) in women aged 30 years or older compared with cytology alone, with no clear advantage over primary HPV screening. Incomplete reporting of results for all screening rounds, including detection of disease and colposcopies, limits our ability to determine the net benefit of HPV-enhanced testing strategies.

Limitation: Resources were insufficient to gather unpublished data, short-term trial data showed possible ascertainment bias, and most RCTs used protocols that differed from current U.S. practice.

Conclusion: Evidence supports the use of LBC or conventional cytology for cervical cancer screening, but more complete evidence is needed before HPV-enhanced primary screening is widely adopted for women aged 30 years or older.

Primary Funding Source: Agency for Healthcare Research and Quality.

Context

  • Several techniques may be used to screen for cervical cancer.

Contribution

  • This systematic review focused on screening for women aged 30 years or older. Liquid-based cytology and conventional cytology had similar sensitivity and specificity for detecting cervical intraepithelial neoplasia. One-time human papillomavirus (HPV) testing was more sensitive but less specific than cytology. The overall harms and costs of work-up for false-positive HPV test results were unclear.

Implication

  • Liquid-based and conventional cytology seem interchangeable for cervical cancer screening. Substituting a strategy of HPV screening (with or without cytology triage for positive test results) seems promising but needs evaluation in long-term, large trials.

—The Editors


Cervical cancer screening programs that use conventional cytology every 1 to 5 years have demonstrated reductions in both cervical cancer incidence and mortality over time (1). Conventional cytology, however, is imperfectly sensitive and labor-intensive, leading to keen interest in new screening technologies serving as alternatives or adjuncts (2). Liquid-based cytology (LBC) offers potentially improved test specimen collection that can support cotesting (HPV plus cytology), but its effect on screening test performance remains uncertain (2). Other, newer technologies have been spurred by the scientific establishment of the causal role of various high-risk human papillomavirus (HPV) types in cancer of the cervix and other tissues (3).

Currently, 3 tests for high-risk HPV—Digene Hybrid Capture 2 (Qiagen, Germantown, Maryland), Cobas 4800 HPV (Roche Diagnostics, Indianapolis, Indiana), and Cervista HR HPV (Hologic, Bedford, Massachusetts)—are approved by the U.S. Food and Drug Administration (FDA) for patients with atypical squamous cells of undetermined significance (ASC-US) on cytology to determine referral for colposcopy, and for co-testing women aged 30 years or older as a risk assessment or patient management tool (45). A fourth test, Amplicor HPV (Roche Diagnostics), is awaiting FDA approval (6).

Benefits from screening rely primarily on histologic diagnosis and treatment of cervical intraepithelial neoplasia (CIN) (7) during the long preclinical period typical of cervical cancer (89). Although there are varying levels of CIN (1, 2, and 3), CIN3 is considered the only truly precancerous lesion because it includes carcinoma in situ (1011) and is more likely to progress to invasive cervical cancer (12). Although CIN2 is the usual treatment threshold, it is heterogeneous, equivocal in cancer potential, and more likely to regress than CIN3 (1011). Histologic diagnoses (CIN or cancer) are made from a biopsy specimen taken during colposcopy. In the United States, the cytologic threshold for immediate colposcopy referral is generally a low-grade squamous intraepithelial lesion (13). For abnormal screening test results that do not meet the immediate referral threshold, retesting at shorter intervals is recommended; colposcopy referral should be triggered for persistent or progressively abnormal results on retesting (1314).

In 2003, the U.S. Preventive Services Task Force (USPSTF) recommended cervical cancer screening in sexually active women with a cervix (grade A recommendation), but concluded that the evidence was insufficient to recommend for or against the routine use of LBC or HPV testing as alternatives or adjuncts to cytology screening. In support of its updated recommendation, the USPSTF commissioned a targeted systematic review (15) and a separate modeling exercise comparing the benefits and harms of various screening strategies (16). We summarize the evidence from our full report here and in our companion paper (17). This article addresses the following questions:

1. To what extent does LBC improve sensitivity, specificity, and diagnostic yield and reduce indeterminate results and inadequate samples compared with conventional cervical cytology?

2. What are the harms of LBC?

3. What are the benefits of using HPV testing as a screening test, either alone or in combination with cytology, compared with not testing for HPV in women aged 30 years or older?

4. What are the harms of using HPV testing as a screening test, either alone or in combination with cytology, in women aged 30 years or older?

We followed a standard protocol; search, selection, assessment, and synthesis methods, with evidence tables, which are detailed in our full report (15). This article summarizes the evidence about primary HPV screening in women aged 30 years or older. The full report also details the evidence for HPV screening in younger women and for HPV triage of ASC-US or low-grade squamous intraepithelial lesions on cytology (15).

Data Sources

We initially searched for systematic reviews, meta-analyses, and evidence-based guidelines on cervical cancer screening listed in the Database of Abstracts of Reviews of Effects, the Cochrane Database of Systematic Reviews, PubMed, and the Health Technology Assessment Database from 2000 through 2007. Two systematic reviews addressing LBC screening (1819) were used to identify primary studies before 2003. No systematic reviews on HPV testing that met our inclusion criteria were identified. We considered all studies in the previous USPSTF review (20) and conducted literature searches from 2003 through September 2010 by using MEDLINE, the Cochrane Central Register of Controlled Trials, and PsycINFO.

We conducted a targeted search for any studies related to the trials included in our review (published from September 2010 to 3 August 2011 in PubMed) to ensure that all relevant studies were captured in our previous literature searches. In addition, selected experts in the field were queried on 8 August 2011 to identify relevant publications. We found 9 additional studies including no additional reports from trials included the review: 4 contextually relevant (2122) or unrelated (2324) reports from previously identified cohorts, 1 performance study of a new HPV test (25), 2 unrelated reports from trial authors (2627), and 2 public health reports (2829). None added primary results to our key questions, but most added to our discussion (2123, 2627).

Study Selection

We evaluated 4262 abstracts and 641 full-text articles (Figure). Two reviewers evaluated abstracts and articles against prespecified inclusion criteria. Discrepancies were resolved by consensus. We included fair- to good-quality studies that provided evidence regarding test performance for detection of CIN2+ (CIN2, CIN3, or cancer) or CIN3+ (CIN3 or cancer), as well as harms. Included studies met design-specific quality standards that minimized the effect of verification bias and were conducted in routine screening populations in countries with developed population-based screening for cervical cancer. For question 3, we evaluated the evidence regarding the use of HPV testing in screening scenarios: primary screening with HPV testing alone, primary HPV testing with cytology triage of positive HPV (reflex cytology), primary HPV plus cytology screening (cotesting), and cytology testing with HPV triage of ASC-US or low-grade squamous intraepithelial lesion on cytology (reflex HPV). Cytology with reflex HPV is covered in our full report (15).

Grahic Jump Location
Figure.

Summary of evidence search and selection.

CC = conventional cytology; HPV = human papillomavirus; LBC = liquid-based cytology.

Grahic Jump Location
Data Extraction and Quality Assessment

At least 2 investigators critically appraised and independently rated the quality of all eligible studies by using criteria based on the USPSTF methods, supplemented by the National Institute for Health and Clinical Excellence criteria for quality of systematic reviews and the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) tool (3032). Good-quality studies generally met all design-specific criteria, whereas fair-quality studies did not meet all the criteria but had no fatal flaws in study design. Poor-quality studies had substantial flaws or lack of reporting that implied bias affecting interpretation of study results and were therefore excluded after agreement among reviewers. One investigator abstracted data from included studies into evidence tables, and a second reviewer verified these data.

Data Synthesis and Analysis

We performed qualitative data synthesis because heterogeneity in the samples, study designs, screening protocols, and instruments did not allow for quantitative synthesis. We synthesized results from diagnostic accuracy studies (to evaluate 1-time test performance) separately from randomized, controlled trials (RCTs). For RCTs of HPV screening, we report results for each round of screening, as well as cumulative results. In these RCTs, results were generally reported for women screened (rather than an intention-to-screen analysis). For consistency, we report the results for women screened (denominator) unless otherwise noted. We also synthesize results for both CIN2+ and CIN3+, even though many CIN2 lesions will regress.

Role of the Funding Source

The Agency for Healthcare Research and Quality funded this work, provided project oversight, and assisted with internal and external review of the draft evidence synthesis, but had no role in the design, conduct, or reporting of the review. The authors worked with 8 USPSTF members, who helped set the review scope and provided input into methodological issues during the conduct of the review.

Benefits and Harms of LBC Compared With Conventional Cytology

We identified 1 fair- and 1 good-quality RCT (3334) comprising 134 162 women exclusively or predominately aged 30 to 60 years. These trials compared relative detection of CIN3+ and CIN2+ and relative positive predictive value after a single screening with LBC or conventional cytology. We identified 2 fair-quality observational studies (3536) of 7404 similarly aged women that reported absolute sensitivity and specificity of both tests in primary care–applicable settings (Table 1).

Table Jump PlaceholderTable 1. Results of Liquid-Based Cytology Studies 

On the basis of these studies, LBC and conventional cytology did not differ substantially in relative detection or absolute sensitivity or specificity for detection of CIN2+/CIN3+ at any cytologic threshold (Table 1). Although the fair-quality NTCC (New Technologies for Cervical Cancer Screening) trial reported lower relative positive predictive value for LBC than for conventional cytology (33), its findings are inconsistent with the good-quality NETHCON (Netherlands ThinPrep Versus Conventional Cytology) trial (34) and with both observational studies (3536). The limitations of the NTCC trial, including the newness of LBC reading in many centers and lack of blinding, could have influenced these results. In terms of specimen adequacy, most of the evidence indicated a lower proportion of unsatisfactory slides for LBC than for conventional cytology (0.4% vs. 1.1% in NETHCON; 2.6% vs. 4.1% in NTCC). Technical issues probably explain disparate findings in smaller observational studies (15). Although we found no studies that directly addressed harms of LBC testing, we would not expect to find differential patient effects because LBC differs from conventional cytology primarily in specimen preparation and handling (3738).

Benefit and Harms of HPV Testing in Women Aged 30 Years or Older as an Alternative or Adjunct to Conventional Cytology Screening

We included 6 diagnostic accuracy studies, 6 RCTs of comparative effectiveness, and 4 studies on psychological harms of HPV screening. The volume (and quality) of evidence varied among 3 HPV screening strategies (Tables 2 and 3 and Appendix Table) (3951). For primary HPV screening compared with cytology, we found 1 RCT (NTCC phase 2; 49 196 participants) (39) and 6 diagnostic accuracy studies (comprising 37 431 participants) (36, 4044). For HPV screening followed by cytology triage compared with cytology alone, we found 1 Finnish RCT (71 337 participants) (45). For HPV and cytology cotesting, we found 4 RCTs (NTCC phase 1, POBASCAM [Population Based Screening Study Amsterdam Program], Swedescreen, and ARTISTIC [A Randomised Trial in Screening to Improve Cytology]; comprising 127 149 participants) (4649) and 4 diagnostic accuracy studies (comprising 21 739 participants) (36, 4143).

Table Jump PlaceholderTable 2. Absolute Test Performance of Primary Screening With HPV Testing Alone and Combination HPV and Cytology Screening in Developed Countries in Women Aged 30 Years or Older 
Table Jump PlaceholderTable 3. Results From Randomized, Controlled Trials of HPV Screening Strategies in Cervical Cancer Screening in Women 30 Years or Older 
Table Jump PlaceholderAppendix Table. Characteristics of Randomized, Controlled Trials of HPV Screening Strategies for Cervical Cancer Screening 

Studies of HPV-enhanced primary cervical cancer screening primarily evaluated Hybrid Capture 2, whereas a few used polymerase chain reaction testing. We report results for women aged 30 years or older to reflect the age bracket for FDA-approved use of Hybrid Capture 2 as an adjunct to cytology (45) and the reduced prevalence of high-risk HPV in women as they age (17, 52). For results in younger women, please see our full report (15).

Primary HPV Screening Alone Compared With Cytology Alone

In 6 fair- or good-quality diagnostic accuracy studies, 1-time HPV testing was more sensitive but less specific than cytology. For CIN3+ outcomes, point estimates for sensitivity ranged from 86% to 97% for HPV testing versus 46% to 50% for cytology at a colposcopy referral threshold of ASC-US. For CIN2+ outcomes, sensitivity ranged from 63% to 98% for HPV testing versus 38% to 65% for cytology (Table 2). However, specificity for CIN2+ and CIN3+ was consistently 3 to 5 percentage points lower for HPV testing than for cytology (Table 2).

In phase 2 of the NTCC, a fair-quality Italian RCT comparing Hybrid Capture 2 HPV screening with cytology in 35 471 women aged 35 to 60 years, about twice as many cases of CIN3+ were detected in the HPV testing group after a single round, with relatively fewer cases detected in the second screening round (relative detection ratio, 0.23 [95% CI, 0.07 to 0.82]) (Table 3) (39). After the second screening round (using cytology only in both groups) and a median of 3.5 years of follow-up from baseline, the cumulative relative detection of CIN3+ still increased in the HPV testing group (1.57 [CI, 1.03 to 2.40]). Because women with a positive HPV result or ASC-US on cytology were immediately referred for colposcopy, many baseline colposcopies were done overall but many more were done in the HPV testing group than in the cytology group (5.8% vs. 2.5%).

Trial investigators pooled cumulative cases of invasive cancer from the primary Hybrid Capture 2 screening strategy (NTCC phase 2) (39) with the Hybrid Capture 2–cytology cotesting strategy (NTCC phase 1) (46), citing insignificant statistical heterogeneity between the trials. Pooled results suggested decreased cumulative cases of invasive cancer after HPV screening, compared with cytology (6 vs. 15; P = 0.052) in women aged 35 years or older. These findings are preliminary because these cancer outcomes were based on pooling noncomparable screening strategies and also did not reflect similar opportunities for diagnosis in both strategies. More valid studies would ensure or control for similar delivery of colposcopy or provide longer follow-up with registry linkages to allow disease ascertainment outside the screening program.

Phase 2 of NTCC referred many women for colposcopy who would instead have been retested in the United States. The Appendix Table details other interpretation and quality issues with NTCC phase 2. Determination of benefits and burdens or harms of HPV testing and cytology screening is impossible because neither cumulative colposcopy results nor cumulative relative positive predictive value over both screening rounds were reported.

Primary HPV Screening Followed by Cytology Triage Compared With Cytology Alone

A large, fair-quality Finnish trial (59 757 women aged 35 to 65 years) compared primary Hybrid Capture 2 screening (with cytology triage for positive HPV test results) with cytology screening alone (45). Women with minimally abnormal results had repeated testing recommended. After a single screening round, Hybrid Capture 2 testing with cytology triage compared with cytology alone increased relative CIN2+ detection (1.36 [CI, 0.98 to 1.89]); effects on relative detection of CIN3+ were less clear because of the small sample size and wide CIs (1.38 [CI, 0.81 to 2.36]) (Table 3). Colposcopy referrals were modest in women older than 35 years and similar between HPV screening (0.9%) and cytology alone (1.0%); however, these probably include only immediate colposcopy referrals, because retesting was recommended for slightly more women who received HPV testing than who received cytology (7.2% vs. 6.6%). Extended follow-up (mean, 3.3 years; maximum, 5.0 years) with linkage to registry data in 38 670 screened women aged 30 to 60 years found significantly increased relative detection of CIN3+ (and cancer) after a single round of HPV screening (1.77 [CI, 1.16 to 2.74]) (51). Among women with positive results in either group, most were retested to confirm abnormalities before colposcopy referral. Women with negative results on initial HPV testing tended toward a lower cumulative 5-year CIN3+ rate than women with negative results on initial cytology, although the CI for this estimate was wide (0.28 [CI, 0.04 to 1.17]) (data not shown).

In the Finnish trial, issues with interpretation and quality primarily reflect its incomplete reporting and implementation to date and the attributes of a pragmatic trial. As with many other trials, data for cumulative colposcopies, adherence to colposcopy, and retesting referrals for the entire first screening round are not yet reported. A second screening round at 3 years is planned. As more data from this trial are reported, differences with practice in the United States will also need to be considered.

Combination HPV and Cytology Screening (Cotesting) Compared With Cytology Alone

Four diagnostic accuracy studies (comprising 21 739 participants) reported the absolute test performance of HPV–cytology cotesting (Table 2). Two studies reporting sensitivity and specificity for Hybrid Capture 2–cytology cotesting among 17 885 women aged 30 to 60 years (36, 41) used a positive result from either test so that all HPV-positive patients met the threshold. For the detection of CIN3+/CIN2+, Hybrid Capture 2 testing plus cytology (either test positive) was more sensitive but less specific than cytology alone (Table 2). The combination of Hybrid Capture 2 plus cytology did not differ in performance from Hybrid Capture 2 alone. Two smaller studies (36, 43), comprising 3852 participants, reported positive cotesting results only if results of both tests were positive, unless a relatively high cytology threshold (that is, high-grade squamous intraepithelial lesion) was met, similar to some cotesting trials. Wide CIs limit sensitivity comparisons, although specificity with this type of cotesting was clearly better than that of Hybrid Capture 2 alone (Table 2).

Four large, fair-quality RCTs compared cotesting with cytology screening alone in European women aged 30 to 64 years (Table 3) (4649). These 4 studies included NTCC phase 1, POBASCAM, Swedescreen, and ARTISTIC, and comprised 82 390 participants. In contrast to HPV screening alone, cotesting did not detect more CIN3+ after 2 screening rounds than cytology alone (Table 3). Round-specific screening results were not completely consistent. Generally, cotesting detected relatively more CIN2+ (and sometimes CIN3+) after 1 screening round, compared with cytology alone. Cotesting identified less CIN3+ (and, where reported, cancers) after the second round, tending toward fewer cancers cumulatively. Interpreting these mixed results is complicated by uncertainty about the completeness of outcome ascertainment for cancers and high-grade precancers due to between-trial differences in duration and completeness of follow-up for the entire screened population and screening episode (15); lack of consensus on the appropriate surrogate outcome (15), with possible asymmetry bias due to limited long-term follow-up (1); and screening protocol differences (Table 3 and Appendix Table) between trials and with U.S. practice.

Only 1 trial, NTCC phase 1 (46), found a relative increase in any cumulative CIN measure after cotesting. This test, however, used a lower threshold for immediate colposcopy than the other trials. Women aged 35 years or older were referred for colposcopy with either a cytology threshold of ASC-US or a positive HPV result regardless of cytology. This strategy increased detection of both CIN2+ and CIN3+ after 1 screening round and cumulative CIN2+ detection overall (RR, 1.50 [CI, 1.13 to 1.98]) compared with cytology alone; however, it did not substantially decrease cases of CIN3+ in the second round or affect cumulative CIN3+ detection. More cases of invasive cancer occurred in the cytology-only group than in the cotesting group (10 vs. 2). On the basis of indirect comparisons between NTCC phases 1 and 2, cotesting offers no additional CIN3+ detection above primary HPV screening alone but may yield more false-positive results.

In the other 3 trials, high-grade squamous intraepithelial lesion was the referral threshold for colposcopy, with colposcopy referral for HPV-positive results only after repeated testing revealed persistent HPV positivity or abnormal cytology (4749). These trials have not completely reported second-round detection outcomes for a substantial proportion of trial participants (47), the complete follow-up period (49), or both (48). Data from a third screening round reported in 2011 from ARTISTIC do not correct all of these reporting deficiencies but provide 6-year cumulative rates of CIN2+ and CIN3+ development by baseline screening test results (53).

Only 2 trials (4748) have reported cumulative colposcopies. These were slightly higher in the cotesting group than in the cytology group of POBASCAM (3.4% vs. 2.8%), although both groups received HPV testing with polymerase chain reaction in the second round. For women aged 30 to 64 years, cumulative colposcopy referrals after 2 screening rounds in ARTISTIC were 6.0% in the cotesting group compared with 4.9% in the LBC-only group (48). However, ARTISTIC varied somewhat from other trials in several round-specific findings, so the relative colposcopy requirement between groups is probably not applicable to trials with different protocols and CIN detection results. Although the interpretation and quality issues vary between cotesting trials, reporting on colposcopy referrals, adherence, referrals for retesting, CIN treatments, and related harms was insufficient across all trials. Cotesting trials also generally represent approaches to managing abnormal screening results that differ from current U.S. recommendations.

Harms of HPV Testing

Human papillomavirus testing could increase harms relative to cytology by increasing the number of unnecessary colposcopies and downstream consequences related to diagnosis and treatment. These concerns cannot be completely addressed due to incomplete reporting, but are considered further elsewhere (9, 21). To evaluate the potential psychological effects of HPV testing, we found 4 fair-quality observational studies (5457) that used mailed questionnaires to examine the immediate and short-term effects of HPV testing in 4104 women in the United Kingdom or Australia. Levels of immediate anxiety and distress were increased in women who tested positive for HPV compared with those who tested negative. These differences, however, were resolved by 6-month follow-up. Data on other psychosocial outcomes and longer-term follow-up were sparse.

Substantial new evidence has become available since the previous USPSTF review and recommendation and continues to accrue. Large RCTs clearly establish that for cytology-based screening, LBC does not differ from conventional cytology in sensitivity, specificity, or relative CIN detection but may yield a lower proportion of unsatisfactory slides. Cost, overall screening strategy, and other considerations may also pertain to local decisions on which approach to use for conducting cytology screening.

Numerous studies have confirmed that HPV testing is more sensitive than cytology, but with a tradeoff in terms of reduced specificity. Thus, although HPV-enhanced screening strategies offer a potential cancer prevention benefit compared with cytology alone, test performance studies alone are insufficient to justify substituting HPV testing for cytology (58). Diagnostic work-up for false-positive results and diagnosis of regressive or nonprogressive histologic predisease could result in harms from unnecessary procedures or overtreatment. Understanding the tradeoff from reduced specificity is critical, particularly given the relatively low incidence of cervical cancer and the established practice of repeated cervical cancer screening (17). Thus, experts agree that large, pragmatic, comparative RCTs of repeated screening rounds are necessary, with increasing emphasis on the need to confirm the effect not just on surrogates (such as CIN) but also on cancer incidence and mortality (27).

On the basis of large RCTs, primary HPV screening seems very promising, particularly when coupled with reflex cytology to triage positive results before colposcopy. Screening with HPV testing enhances the detection of CIN3+ compared with cytology alone but also increases CIN2+ detection and immediate colposcopy referrals. All CIN lesions, even CIN3, have some potential for overdiagnosis and therefore potential harms (26). Thus, the net effect of primary HPV screening needs to be determined through the completion of ongoing trials and more detailed reporting of potential harms and benefits from completed trials. An ongoing trial in Canada will also provide new evidence that directly compares primary HPV screening and cytology triage with cytology screening and HPV triage in a protocol more similar to U.S. practice than the European trials (59); a collaborative pooling of European trial results is also expected (60).

The FDA has already approved screening with cytology plus HPV testing (cotesting) in women aged 30 years or older (45). Our report found that cotesting was much more sensitive than cytology alone but may represent a strategy that adds little when compared with primary HPV screening. On the basis of test performance data and indirect comparisons between trials, 1-time HPV–cytology cotesting was very similar to HPV testing alone for the detection of CIN2+ or CIN3+, with similar (or slightly reduced) specificity. However, incomplete reporting complicates the interpretation of cotesting trials, because most lack cumulative outcome reporting for their entire study populations, and all lack data on cumulative colposcopies and related harms. A large observational study (61) conducted in the United States (331 818 participants) reported high clinician and patient acceptance of cotesting in women aged 30 years or older, with rescreening deferred until 3 years after negative results in an HMO setting. The cumulative 5-year incidence of CIN3 and cervical cancer from this cotested cohort suggests that primary HPV testing, particularly if followed by cytology triage, would efficiently detect more cases of CIN3+ and cancer, particularly adenocarcinoma (78% vs. 15%), than cytology alone, with a very high negative predictive value for cancer after negative HPV test results (21). Data on the proportion of cumulative cases of cancer among HPV-negative/Papanicolaou-positive women and their relative stages at diagnosis would clarify any safety tradeoffs in moving away from cotesting.

A major benefit of HPV-enhanced primary screening could be identification of a low-risk cohort in whom a prolonged screening interval would be appropriate. As discussed in our full report, mounting evidence suggests that the cumulative risk for CIN3+ is very low for 5 or more years in women after negative results on HPV testing (15, 22, 47, 49, 51, 53, 6264). Risk-stratifying approaches, whereby the rescreening interval is prolonged on the basis of initial screening results, have not been directly incorporated into trials to date, and safety data on prolonged screening intervals in low-risk women based on baseline HPV testing (with or without cytology) seem promising but are still accruing. Such an approach could potentially reduce screening demands for many women; for example, in cotesting trials, 78% to 93% of tested women had negative results on both tests initially (15). Besides safety, feasibility or acceptability may affect adoption of a risk-stratified policy on cervical cancer screening because primary care physicians may not currently be extending the screening interval to 3 years after negative cotesting results (65). For women with positive as well as negative results on HPV screening, ongoing research into HPV subtypes (22), HPV-related biomarkers, and other factors (such as screening history [23]), will probably advance effective and efficient risk stratification necessary for appropriately targeted screening.

The most thoroughly studied HPV test for use in cervical cancer screening or triage is Hybrid Capture 2. In the absence of adequate RCT data, those planning substitution of other types of HPV testing in cervical cancer screening programs based on these studies should carefully consider clinical test performance when directly compared with Hybrid Capture 2, evidence of test–retest and interlaboratory test reliability, other quality control issues, and cost (66).

The main limitations of our review and of this body of evidence follow. Our search may have missed smaller European studies published in national journals only. Most studies used colposcopy or biopsy as the reference standard, neither of which is 100% sensitive for detecting preinvasive disease (67). Trials that do not have full or complete ascertainment for undetected disease can inaccurately reflect sensitivity or true disease detection. Longer follow-up after multiple screening rounds, ideally combined with methods of creating equal probability of cervical lesion detection in all participants, gives a truer picture of the relative effect of different screening strategies on disease (1). Linking screening trial results with outside data, including registries, can help overcome possible ascertainment biases that are particularly likely to distort screening comparisons with relatively short-term results. Most trials did not report results by using an intention-to-screen analysis, in which all women in the randomized group are in the denominator of all calculations.

Finally, the data from trials involving HPV testing are reported in many publications, with updated results being published over time. Despite our efforts to search for additional data from studies with incomplete reporting, some missing data may have been available through more extensive author requests (which were beyond our resource capabilities) or could soon be published. Thus, our findings will probably need rapid updating as more data from completed and ongoing trials become available. In addition, none of the trials included the effect of HPV vaccines on screening, which will be critical in the future.

Liquid-based cytology and conventional cytology perform interchangeably in terms of newer screening technologies for cervical cancer screening. Compared with cytology, HPV testing offers a tradeoff between increased sensitivity and decreased specificity. Because cervical cancer screening is repeated over time, results from RCTs should inform a proposed change in screening approach. Substituting a strategy of primary HPV screening (with or without cytology triage) for one of cytology alone in women aged 30 years or older is appealing, but important details remain unclear, including how much early disease detection is improved, whether such a strategy would have a beneficial effect on invasive cervical cancer, and what other effects it would have in terms of burden and diagnosis- and treatment-related harms.

International Agency for Research on Cancer. Cervix Cancer Screening. IARC Handbook of Cancer Prevention, vol. 10. Lyon, France: IARC Pr; 2005.
 
Arbyn M, Antilla A, Jordan J, Ronco G, Schenck U, Segnan N, et al. European Guidelines for Quality Assurance in Cervical Cancer Screening. 2nd ed. Luxembourg: Office for Official Publications of the European Communities; 2008.
 
Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006; 24:Suppl 1S1-15.
PubMed
CrossRef
 
Center for Devices and Radiological Health.  Approval Letter: Digene Hybrid Capture 2 High-Risk HPV DNA Test-P890064/S009. Rockville, MD: U.S. Food and Drug Administration; 2003. Accessed at www.accessdata.fda.gov/cdrh_docs/pdf/p890064s009a.pdf on 25 September 2011.
 
Center for Devices and Radiological Health.  Summary of Safety and Effectiveness Data. Rockville, MD: U.S. Food and Drug Administration; 2002. Accessed at www.accessdata.fda.gov/cdrh_docs/pdf/p890064s009b.pdf on 25 September 2011.
 
Arney A, Bennett KM. Molecular diagnostics of human papillomavirus. Lab Med. 2010; 41:523-30.
CrossRef
 
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 99: management of abnormal cervical cytology and histology. Obstet Gynecol. 2008; 112:1419-44.
PubMed
 
Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993; 12:186-92.
PubMed
 
Richart RM. Cervical intraepithelial neoplasia. Pathol Annu. 1973; 8:301-28.
PubMed
 
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007; 370:890-907.
PubMed
CrossRef
 
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. J Low Genit Tract Dis. 2007; 11:223-39.
PubMed
 
McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008; 9:425-34.
PubMed
CrossRef
 
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007; 197:346-55.
PubMed
 
ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin no. 109: Cervical cytology screening. Obstet Gynecol. 2009; 114:1409-20.
PubMed
 
Vesco KK, Whitlock EP, Eder M, Lin J, Burda BU, Senger CA, et al. Screening for Cervical Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Report no. 86. AHRQ Publication no. 11-05156-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
 
Kulasingam S, Havrilesky L, Ghebre R, Myers ER. Screening for Cervical Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. AHRQ Publication no. 11-05157-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
 
Vesco KK, Whitlock EP, Eder M, Burda BU, Senger CA, Lutz K. Risk factors and other epidemiologic considerations for cervical cancer screening: a narrative review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011; 155:698-705.
 
Medical Services Advisory Committee. Liquid Based Cytology for Cervical Screening. MSAC Reference 12a. Canberra, Australia: Australia Department of Health and Aging; 2002.
 
Noorani HZ, Brown A, Skidmore B, Stuart GCE. Liquid-based cytology and human papillomavirus testing in cervical cancer screening. Technology Report no. 40. Ottawa: Canadian Coordinating Office of Health Technology Assessment; 2003.
 
Hartmann KE, Hall SA, Nanda K, Boggess JF, Zolnoun D. Screening for Cervical Cancer. Systematic Review no. 25. Rockville, MD: Agency for Healthcare Research and Quality; 2002.
 
Katki HA, Kinney WK, Fetterman B, Lorey T, Poitras NE, Cheung L, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011; 12:663-72.
PubMed
 
Schiffman M, Glass AG, Wentzensen N, Rush BB, Castle PE, Scott DR, et al. A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study. Cancer Epidemiol Biomarkers Prev. 2011; 20:1398-409.
PubMed
 
Castle PE, Fetterman B, Poitras N, Lorey T, Shaber R, Schiffman M, et al. Variable risk of cervical precancer and cancer after a human papillomavirus-positive test. Obstet Gynecol. 2011; 117:650-6.
PubMed
CrossRef
 
Littell RD, Kinney W, Fetterman B, Cox JT, Shaber R, Poitras N, et al. Risk of cervical precancer and cancer in women aged 30 years and older with an HPV-negative low-grade squamous intraepithelial lesion screening result. J Low Genit Tract Dis. 2011; 15:54-9.
PubMed
CrossRef
 
Castle PE, Gutierrez EC, Leitch SV, Maus CE, McMillian RA, Nussbaumer WA, et al. Evaluation of a new DNA test for detection of carcinogenic human papillomavirus. J Clin Microbiol. 2011; 49:3029-32.
PubMed
CrossRef
 
Kotaniemi-Talonen L, Malila N, Anttila A, Nieminen P, Hakama M. Intensified screening among high risk women within the organised screening programme for cervical cancer in Finland. Acta Oncol. 2011; 50:106-11.
PubMed
CrossRef
 
Anttila A, Pokhrel A, Kotaniemi-Talonen L, Hakama M, Malila N, Nieminen P. Cervical cancer patterns with automation-assisted and conventional cytological screening: a randomized study. Int J Cancer. 2011; 128:1204-12.
PubMed
CrossRef
 
Arbyn M, Castellsagué X, de Sanjosé S, Bruni L, Saraiya M, Bray F, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011..
PubMed
 
Franceschi S, Denny L, Irwin KL, Jeronimo J, Lopalco PL, Monsonego J, et al. Eurogin 2010 roadmap on cervical cancer prevention. Int J Cancer. 2011; 128:2765-74.
PubMed
CrossRef
 
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al, Methods Work Group, Third US Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001; 20:21-35.
PubMed
CrossRef
 
National Institute for Health and Clinical Excellence. The Guidelines Manual. London: National Institute for Health and Clinical Excellence; 2006.
 
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003; 3:25.
PubMed
CrossRef
 
Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ. 2007; 335:28.
PubMed
CrossRef
 
Siebers AG, Klinkhamer PJ, Grefte JM, Massuger LF, Vedder JE, Beijers-Broos A, et al. Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA. 2009; 302:1757-64.
PubMed
CrossRef
 
Taylor S, Kuhn L, Dupree W, Denny L, De Souza M, Wright TC Jr. Direct comparison of liquid-based and conventional cytology in a South African screening trial. Int J Cancer. 2006; 118:957-62.
PubMed
CrossRef
 
Coste J, Cochand-Priollet B, de Cremoux P, Le Galès C, Cartier I, Molinié V, et al, French Society of Clinical Cytology Study Group. Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening. BMJ. 2003; 326:733.
PubMed
CrossRef
 
Hologic.  ThinPrep Pap Test Quick Reference Guide: Endocervical Brush/Spatula Protocol. Marlborough, MA: Hologic; 2004. Accessed at www.thinprep.com/pdfs/pap_quick_reference.pdf on 25 September 2011.
 
TriPath Imaging.  SurePath Technology Is Changing Cervical Cancer Screening for the Better. Burlington, NC: TriPath Imaging; 2004. Accessed at www.nlma.nf.ca/documents/health_promotion/health_promotion_8.pdf on 25 September 2011.
 
Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al, New Technologies for Cervical Cancer screening (NTCC) Working Group. 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.
PubMed
 
Cárdenas-Turanzas M, Nogueras-Gonzalez GM, Scheurer ME, Adler-Storthz K, Benedet JL, Beck JR, et al. The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings. Cancer Epidemiol Biomarkers Prev. 2008; 17:2865-71.
PubMed
CrossRef
 
Petry KU, Menton S, Menton M, van Loenen-Frosch F, de Carvalho Gomes H, Holz B, et al. Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients. Br J Cancer. 2003; 88:1570-7.
PubMed
CrossRef
 
Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al, Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007; 357:1579-88.
PubMed
CrossRef
 
Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002; 288:1749-57.
PubMed
CrossRef
 
Bigras G, de Marval F. The probability for a Pap test to be abnormal is directly proportional to HPV viral load: results from a Swiss study comparing HPV testing and liquid-based cytology to detect cervical cancer precursors in 13,842 women. Br J Cancer. 2005; 93:575-81.
PubMed
CrossRef
 
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.
PubMed
CrossRef
 
Ronco G, Segnan N, Giorgi-Rossi P, Zappa M, Casadei GP, Carozzi F, et al, New Technologies for Cervical Cancer Working Group. Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst. 2006; 98:765-74.
PubMed
CrossRef
 
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.
PubMed
CrossRef
 
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.
PubMed
 
Naucler P, Ryd W, Törnberg 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.
PubMed
CrossRef
 
Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst. 2009; 101:88-99.
PubMed
CrossRef
 
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.
PubMed
CrossRef
 
Datta SD, Koutsky LA, Ratelle S, Unger ER, Shlay J, McClain T, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003-2005. Ann Intern Med. 2008; 148:493-500.
PubMed
 
Kitchener HC, Gilham C, Sargent A, Bailey A, Albrow R, Roberts C, et al. A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: extended follow up in the ARTISTIC trial. Eur J Cancer. 2011; 47:864-71.
PubMed
CrossRef
 
McCaffery K, Waller J, Forrest S, Cadman L, Szarewski A, Wardle J. Testing positive for human papillomavirus in routine cervical screening: examination of psychosocial impact. BJOG. 2004; 111:1437-43.
PubMed
CrossRef
 
Kitchener HC, Fletcher I, Roberts C, Wheeler P, Almonte M, Maguire P. The psychosocial impact of human papillomavirus testing in primary cervical screening-a study within a randomized trial. Int J Gynecol Cancer. 2008; 18:743-8.
PubMed
CrossRef
 
McCaffery KJ, Irwig L, Turner R, Chan SF, Macaskill P, Lewicka M, et al. Psychosocial outcomes of three triage methods for the management of borderline abnormal cervical smears: an open randomised trial. BMJ. 2010; 340:b4491.
PubMed
CrossRef
 
Maissi E, Marteau TM, Hankins M, Moss S, Legood R, Gray A. Psychological impact of human papillomavirus testing in women with borderline or mildly dyskaryotic cervical smear test results: cross sectional questionnaire study. BMJ. 2004; 328:1293.
PubMed
CrossRef
 
Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? Ann Intern Med. 2006; 144:850-5.
PubMed
 
Ogilvie GS, van Niekerk DJ, Krajden M, Martin RE, Ehlen TG, Ceballos K, et al. A randomized controlled trial of human papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL Trial). BMC Cancer. 2010; 10:111.
PubMed
CrossRef
 
Arbyn M, Rebolj M, De Kok IM, Fender M, Becker N, O'Reilly M, et al. The challenges of organising cervical screening programmes in the 15 old member states of the European Union. Eur J Cancer. 2009; 45:2671-8.
PubMed
 
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; 103:368-83.
PubMed
 
Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, et al, Joint European Cohort Study. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008; 337:a1754.
PubMed
CrossRef
 
Sherman ME, Lorincz AT, Scott DR, Wacholder S, Castle PE, Glass AG, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003; 95:46-52.
PubMed
CrossRef
 
Kjaer S, Høgdall E, Frederiksen K, Munk C, van den Brule A, Svare E, et al. The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period. Cancer Res. 2006; 66:10630-6.
PubMed
CrossRef
 
Saraiya M, Berkowitz Z, Yabroff KR, Wideroff L, Kobrin S, Benard V. Cervical cancer screening with both human papillomavirus and Papanicolaou testing vs Papanicolaou testing alone: what screening intervals are physicians recommending? Arch Intern Med. 2010; 170:977-85.
PubMed
CrossRef
 
Kinney W, Stoler MH, Castle PE. Special commentary: patient safety and the next generation of HPV DNA tests. Am J Clin Pathol. 2010; 134:193-9.
PubMed
CrossRef
 
Stoler MH, Vichnin MD, Ferenczy A, Ferris DG, Perez G, Paavonen J, et al, FUTURE I, II and III Investigators. The accuracy of colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials. Int J Cancer. 2011; 128:1354-62.
PubMed
CrossRef
 

Figures

Grahic Jump Location
Figure.

Summary of evidence search and selection.

CC = conventional cytology; HPV = human papillomavirus; LBC = liquid-based cytology.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1. Results of Liquid-Based Cytology Studies 
Table Jump PlaceholderTable 2. Absolute Test Performance of Primary Screening With HPV Testing Alone and Combination HPV and Cytology Screening in Developed Countries in Women Aged 30 Years or Older 
Table Jump PlaceholderTable 3. Results From Randomized, Controlled Trials of HPV Screening Strategies in Cervical Cancer Screening in Women 30 Years or Older 
Table Jump PlaceholderAppendix Table. Characteristics of Randomized, Controlled Trials of HPV Screening Strategies for Cervical Cancer Screening 

Videos

Video News Release - Editor, Christine Laine, Explains Results of Women's Cancer Studies

References

International Agency for Research on Cancer. Cervix Cancer Screening. IARC Handbook of Cancer Prevention, vol. 10. Lyon, France: IARC Pr; 2005.
 
Arbyn M, Antilla A, Jordan J, Ronco G, Schenck U, Segnan N, et al. European Guidelines for Quality Assurance in Cervical Cancer Screening. 2nd ed. Luxembourg: Office for Official Publications of the European Communities; 2008.
 
Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006; 24:Suppl 1S1-15.
PubMed
CrossRef
 
Center for Devices and Radiological Health.  Approval Letter: Digene Hybrid Capture 2 High-Risk HPV DNA Test-P890064/S009. Rockville, MD: U.S. Food and Drug Administration; 2003. Accessed at www.accessdata.fda.gov/cdrh_docs/pdf/p890064s009a.pdf on 25 September 2011.
 
Center for Devices and Radiological Health.  Summary of Safety and Effectiveness Data. Rockville, MD: U.S. Food and Drug Administration; 2002. Accessed at www.accessdata.fda.gov/cdrh_docs/pdf/p890064s009b.pdf on 25 September 2011.
 
Arney A, Bennett KM. Molecular diagnostics of human papillomavirus. Lab Med. 2010; 41:523-30.
CrossRef
 
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 99: management of abnormal cervical cytology and histology. Obstet Gynecol. 2008; 112:1419-44.
PubMed
 
Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993; 12:186-92.
PubMed
 
Richart RM. Cervical intraepithelial neoplasia. Pathol Annu. 1973; 8:301-28.
PubMed
 
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007; 370:890-907.
PubMed
CrossRef
 
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. J Low Genit Tract Dis. 2007; 11:223-39.
PubMed
 
McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008; 9:425-34.
PubMed
CrossRef
 
Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007; 197:346-55.
PubMed
 
ACOG Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin no. 109: Cervical cytology screening. Obstet Gynecol. 2009; 114:1409-20.
PubMed
 
Vesco KK, Whitlock EP, Eder M, Lin J, Burda BU, Senger CA, et al. Screening for Cervical Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Report no. 86. AHRQ Publication no. 11-05156-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
 
Kulasingam S, Havrilesky L, Ghebre R, Myers ER. Screening for Cervical Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. AHRQ Publication no. 11-05157-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
 
Vesco KK, Whitlock EP, Eder M, Burda BU, Senger CA, Lutz K. Risk factors and other epidemiologic considerations for cervical cancer screening: a narrative review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011; 155:698-705.
 
Medical Services Advisory Committee. Liquid Based Cytology for Cervical Screening. MSAC Reference 12a. Canberra, Australia: Australia Department of Health and Aging; 2002.
 
Noorani HZ, Brown A, Skidmore B, Stuart GCE. Liquid-based cytology and human papillomavirus testing in cervical cancer screening. Technology Report no. 40. Ottawa: Canadian Coordinating Office of Health Technology Assessment; 2003.
 
Hartmann KE, Hall SA, Nanda K, Boggess JF, Zolnoun D. Screening for Cervical Cancer. Systematic Review no. 25. Rockville, MD: Agency for Healthcare Research and Quality; 2002.
 
Katki HA, Kinney WK, Fetterman B, Lorey T, Poitras NE, Cheung L, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011; 12:663-72.
PubMed
 
Schiffman M, Glass AG, Wentzensen N, Rush BB, Castle PE, Scott DR, et al. A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study. Cancer Epidemiol Biomarkers Prev. 2011; 20:1398-409.
PubMed
 
Castle PE, Fetterman B, Poitras N, Lorey T, Shaber R, Schiffman M, et al. Variable risk of cervical precancer and cancer after a human papillomavirus-positive test. Obstet Gynecol. 2011; 117:650-6.
PubMed
CrossRef
 
Littell RD, Kinney W, Fetterman B, Cox JT, Shaber R, Poitras N, et al. Risk of cervical precancer and cancer in women aged 30 years and older with an HPV-negative low-grade squamous intraepithelial lesion screening result. J Low Genit Tract Dis. 2011; 15:54-9.
PubMed
CrossRef
 
Castle PE, Gutierrez EC, Leitch SV, Maus CE, McMillian RA, Nussbaumer WA, et al. Evaluation of a new DNA test for detection of carcinogenic human papillomavirus. J Clin Microbiol. 2011; 49:3029-32.
PubMed
CrossRef
 
Kotaniemi-Talonen L, Malila N, Anttila A, Nieminen P, Hakama M. Intensified screening among high risk women within the organised screening programme for cervical cancer in Finland. Acta Oncol. 2011; 50:106-11.
PubMed
CrossRef
 
Anttila A, Pokhrel A, Kotaniemi-Talonen L, Hakama M, Malila N, Nieminen P. Cervical cancer patterns with automation-assisted and conventional cytological screening: a randomized study. Int J Cancer. 2011; 128:1204-12.
PubMed
CrossRef
 
Arbyn M, Castellsagué X, de Sanjosé S, Bruni L, Saraiya M, Bray F, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011..
PubMed
 
Franceschi S, Denny L, Irwin KL, Jeronimo J, Lopalco PL, Monsonego J, et al. Eurogin 2010 roadmap on cervical cancer prevention. Int J Cancer. 2011; 128:2765-74.
PubMed
CrossRef
 
Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al, Methods Work Group, Third US Preventive Services Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001; 20:21-35.
PubMed
CrossRef
 
National Institute for Health and Clinical Excellence. The Guidelines Manual. London: National Institute for Health and Clinical Excellence; 2006.
 
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003; 3:25.
PubMed
CrossRef
 
Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ. 2007; 335:28.
PubMed
CrossRef
 
Siebers AG, Klinkhamer PJ, Grefte JM, Massuger LF, Vedder JE, Beijers-Broos A, et al. Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA. 2009; 302:1757-64.
PubMed
CrossRef
 
Taylor S, Kuhn L, Dupree W, Denny L, De Souza M, Wright TC Jr. Direct comparison of liquid-based and conventional cytology in a South African screening trial. Int J Cancer. 2006; 118:957-62.
PubMed
CrossRef
 
Coste J, Cochand-Priollet B, de Cremoux P, Le Galès C, Cartier I, Molinié V, et al, French Society of Clinical Cytology Study Group. Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening. BMJ. 2003; 326:733.
PubMed
CrossRef
 
Hologic.  ThinPrep Pap Test Quick Reference Guide: Endocervical Brush/Spatula Protocol. Marlborough, MA: Hologic; 2004. Accessed at www.thinprep.com/pdfs/pap_quick_reference.pdf on 25 September 2011.
 
TriPath Imaging.  SurePath Technology Is Changing Cervical Cancer Screening for the Better. Burlington, NC: TriPath Imaging; 2004. Accessed at www.nlma.nf.ca/documents/health_promotion/health_promotion_8.pdf on 25 September 2011.
 
Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al, New Technologies for Cervical Cancer screening (NTCC) Working Group. 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.
PubMed
 
Cárdenas-Turanzas M, Nogueras-Gonzalez GM, Scheurer ME, Adler-Storthz K, Benedet JL, Beck JR, et al. The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings. Cancer Epidemiol Biomarkers Prev. 2008; 17:2865-71.
PubMed
CrossRef
 
Petry KU, Menton S, Menton M, van Loenen-Frosch F, de Carvalho Gomes H, Holz B, et al. Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients. Br J Cancer. 2003; 88:1570-7.
PubMed
CrossRef
 
Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al, Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007; 357:1579-88.
PubMed
CrossRef
 
Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002; 288:1749-57.
PubMed
CrossRef
 
Bigras G, de Marval F. The probability for a Pap test to be abnormal is directly proportional to HPV viral load: results from a Swiss study comparing HPV testing and liquid-based cytology to detect cervical cancer precursors in 13,842 women. Br J Cancer. 2005; 93:575-81.
PubMed
CrossRef
 
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.
PubMed
CrossRef
 
Ronco G, Segnan N, Giorgi-Rossi P, Zappa M, Casadei GP, Carozzi F, et al, New Technologies for Cervical Cancer Working Group. Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst. 2006; 98:765-74.
PubMed
CrossRef
 
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.
PubMed
CrossRef
 
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.
PubMed
 
Naucler P, Ryd W, Törnberg 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.
PubMed
CrossRef
 
Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst. 2009; 101:88-99.
PubMed
CrossRef
 
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.
PubMed
CrossRef
 
Datta SD, Koutsky LA, Ratelle S, Unger ER, Shlay J, McClain T, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003-2005. Ann Intern Med. 2008; 148:493-500.
PubMed
 
Kitchener HC, Gilham C, Sargent A, Bailey A, Albrow R, Roberts C, et al. A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: extended follow up in the ARTISTIC trial. Eur J Cancer. 2011; 47:864-71.
PubMed
CrossRef
 
McCaffery K, Waller J, Forrest S, Cadman L, Szarewski A, Wardle J. Testing positive for human papillomavirus in routine cervical screening: examination of psychosocial impact. BJOG. 2004; 111:1437-43.
PubMed
CrossRef
 
Kitchener HC, Fletcher I, Roberts C, Wheeler P, Almonte M, Maguire P. The psychosocial impact of human papillomavirus testing in primary cervical screening-a study within a randomized trial. Int J Gynecol Cancer. 2008; 18:743-8.
PubMed
CrossRef
 
McCaffery KJ, Irwig L, Turner R, Chan SF, Macaskill P, Lewicka M, et al. Psychosocial outcomes of three triage methods for the management of borderline abnormal cervical smears: an open randomised trial. BMJ. 2010; 340:b4491.
PubMed
CrossRef
 
Maissi E, Marteau TM, Hankins M, Moss S, Legood R, Gray A. Psychological impact of human papillomavirus testing in women with borderline or mildly dyskaryotic cervical smear test results: cross sectional questionnaire study. BMJ. 2004; 328:1293.
PubMed
CrossRef
 
Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? Ann Intern Med. 2006; 144:850-5.
PubMed
 
Ogilvie GS, van Niekerk DJ, Krajden M, Martin RE, Ehlen TG, Ceballos K, et al. A randomized controlled trial of human papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL Trial). BMC Cancer. 2010; 10:111.
PubMed
CrossRef
 
Arbyn M, Rebolj M, De Kok IM, Fender M, Becker N, O'Reilly M, et al. The challenges of organising cervical screening programmes in the 15 old member states of the European Union. Eur J Cancer. 2009; 45:2671-8.
PubMed
 
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; 103:368-83.
PubMed
 
Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, et al, Joint European Cohort Study. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008; 337:a1754.
PubMed
CrossRef
 
Sherman ME, Lorincz AT, Scott DR, Wacholder S, Castle PE, Glass AG, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003; 95:46-52.
PubMed
CrossRef
 
Kjaer S, Høgdall E, Frederiksen K, Munk C, van den Brule A, Svare E, et al. The absolute risk of cervical abnormalities in high-risk human papillomavirus-positive, cytologically normal women over a 10-year period. Cancer Res. 2006; 66:10630-6.
PubMed
CrossRef
 
Saraiya M, Berkowitz Z, Yabroff KR, Wideroff L, Kobrin S, Benard V. Cervical cancer screening with both human papillomavirus and Papanicolaou testing vs Papanicolaou testing alone: what screening intervals are physicians recommending? Arch Intern Med. 2010; 170:977-85.
PubMed
CrossRef
 
Kinney W, Stoler MH, Castle PE. Special commentary: patient safety and the next generation of HPV DNA tests. Am J Clin Pathol. 2010; 134:193-9.
PubMed
CrossRef
 
Stoler MH, Vichnin MD, Ferenczy A, Ferris DG, Perez G, Paavonen J, et al, FUTURE I, II and III Investigators. The accuracy of colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials. Int J Cancer. 2011; 128:1354-62.
PubMed
CrossRef
 

Letters

April 17, 2012
Guglielmo Ronco, MD; Chris J.L. Meijer, MD; Jack Cuzick, PhD; Paolo Giorgi-Rossi, PhD; Julian Peto, TSc; Nereo Segnan, MD; Joakim Dillner, MD
AIM. 2012;156(8):604-605  doi:10.7326/0003-4819-156-8-201204170-00014



April 17, 2012
Evelyn P. Whitlock, MD, MPH; Kimberly K. Vesco, MD, MPH; Jennifer S. Lin, MD, MCR; Michelle Eder, PhD; Brittany U. Burda, MPH
AIM. 2012;156(8):605-606  doi:10.7326/0003-4819-156-8-201204170-00015



NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Just to say thank you
Posted on October 28, 2011
Carlo A.Liverani, Chief of Preventive Gynecologic Oncology Unit
Policlinico Hospital, University of Milano (Italy)
Conflict of Interest: None Declared

An honest work, very useful to understand what is specultive and what is really needed

Conflict of Interest:

None declared

HUMAN PAPILLOMAVIRUS TESTING TO SCREEN FOR CERVICAL CANCER
Posted on November 11, 2011
GuglielmoRonco, Epidemiologist, Chris JL Meijer (VUMC University, Amsterdam, the Netherlands), Jack Cuzick (Queen Mary University, London, UK), Paolo Giorgi-Rossi (ASP Lazio, Rome, Italy), Julian Peto (London School of Hygiene, London, UK), Nereo Segnan (CPO, Turin, Italy ), Joakim Dill
Center for Cancer Prevention (CPO) , Turin, Italy
Conflict of Interest: None Declared

The USPSTF report(1) has evaluated the use of HPV testing and cytology in cervical cancer screening and concluded that more evidence is needed to determine the optimal approach. The report has considered the different possible strategies separately (HPV alone, HPV alone with cytology triage, co-testing, co-testing with cytology triage) in comparison to cytology only and considered solely results on prevention of invasive cancer.

It has been conclusively shown that HPV testing is able to detect about 50% more high-grade CIN, an established cancer precursor, than cytology(2) at an initial screening . Furthermore, all RCTs conducted in industrialized countries(3-6) have shown a similar reduction in CIN3+ after HPV testing (table 3 of the report) indicating that HPV testing is able to detect non-regressive lesions earlier than cytology, thereby reducing precancerous lesions in subsequent screening rounds. This lead- time gain was similar for all strategies studied. In addition, a pooled analysis of phase 1 (co-testing) and phase 2 (HPV alone) of the NTCC(6) trial also showed a major, clinically important and statistically significant reduction in invasive cancers. As different strategies using HPV testing have shown similar results, pooling data is not only reasonable but very much needed. As the protective effect is similar with all strategies, the least costly (HPV testing with cytology triage) should be chosen. As this strategy has the same need for colposcopy as cytology only(3,4), lack of data on colposcopies needed for other strategies is not relevant for costs (and obviously not for effectiveness).

The report also contains factual mistakes. For example, it is stated that "ARTISTIC had the opposite result: more cases of cancer were found after 2 screening rounds in the cotesting group (8 total) compared with cytology (4 total)". In this trial (5), there were proportionally more cancers with cytology because the cotesting: cytology randomization ratio was 3:1.

Further, the report considers quality issues used in pharmacological trials that are clearly irrelevant for large preventive trials. For example, masking patients is plausibly irrelevant when evaluating preventive programs where patient information is a vital part of the intervention itself and when the disease is asymptomatic and placebo effects unlikely. Observer bias is more plausible, but all trials had a blind assessment of the clinical endpoint.

Already in 2008, the EU guidelines(7) on cervical cancer screening concluded that existing evidence is sufficient at least for the launch of controlled pilot implementation projects using HPV screening. This could provide additional evidence on cancer-protective effect, but only after many years. In our view, requiring new RCTs with cancer incidence as the endpoint to compare with cytology every small variation (like triage methods) in HPV-based screening strategies is unreasonable, unsustainable and, given the time-frame of acquiring evidence, also unethical.

References

1. Whitlock EP, Vesco KK, Eder M, Lin JS, Senger CA, Burda BU. Liquid -Based Cytology and Human Papillomavirus Testing to Screen for Cervical Cancer: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med 2011 [PM:22006930].

2. Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand MH, Dillner J, Meijer CJL. Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries. Vaccine 2008; 26S:K29-41.

3. Naucler P, Ryd W, Tornberg S, et al. Human papillomavirus and Papanicolau tests to screen for cervical cancer. N Engl J Med 2007; 357: 1589-97.

4. Bulkmans N, Berkhof J, Rozendaal L, et al. Human papilllomavirus 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 24; 370: 1764-72.

5. Kitchener HC, Almonte M, Thomson C, 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.

6. 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 a randomised controlled trial. Lancet Oncol 2010; 11:249-57.

7. Arbyn M, Anttila A, Jordan J, .Ronco G, Schenck U, Segnan N, Wiener H, eds. European guidelines for quality assurance on cervical cancer screening. 2nd edition . Luxembourg: Office for Official Publications of the European Communities, 2008.

Conflict of Interest:

No conflict of interest for G Ronco, P Giorgi-Rossi, J Peto, N Segnan and J Dillner. Member scientific advisory board of Qiagen and occasional consultant for GSK, Merck, and Roche (CJL Meijer) His institution receives support from Abbott, Becton Dickinson, GenProbe, Qiagen and Roche to evaluate HPV tests and he isoccasional consultant for these companies (J Cuzick).

Author's response
Posted on November 17, 2011
EvelynWhitlock, MD, MPH, Kimberly K. Vesco, MD, MPH, Michelle Eder, PhD; Jennifer S. Lin, MD, MCR; Caitlyn A. Senger, MPH, Brittany U. Burda, MPH
Oregon Evidence-based Practice Center, Center for Health, Research, Kaiser Permanente Northwest, Por
Conflict of Interest: None Declared

To the Editor:

1. We have a revision of the first full paragraph on p. 693 (vol. 155:10) that accurately compares detection by cotesting against cytology alone with more detail about interpretation. Please include this paragraph as a correction to our published paragraph. Four large, fair-quality RCTs compared cotesting with cytology screening alone in European women aged30 to 64 years (Table 3). (46-49) These 4 studies included NTCC phase 1, POBASCAM, Swedescreen, and ARTISTIC, and comprised 82,390 participants. In contrast to HPV screening alone, cotesting did not detect more CIN3+ after 2 screening rounds than cytology alone (Table 3). Round-specific screening results were not completely consistent. Generally, cotesting detected relatively more CIN2+ (and sometimes CIN3+) after 1 screening round, compared with cytology alone. Cotesting identified lessCIN3+ (and, where reported, cancers) after the second round, tending toward fewer cancers cumulatively.

Interpreting these mixed results is complicated by: 1) uncertainty about the completeness of outcome ascertainment for cancers and high-grade precancers due to between-trial differences in duration and completeness of follow-up for the entire screened population and screening episode (Appendix Table,Vesco 2011 (15)); 2) lack of consensus on the appropriate surrogate outcome (Vesco 2011 (15) Table 17),with possible asymmetry bias due to limited long-term follow-up (1); and 3) screening protocol differences (Table 3, Appendix Table) between trials and with US practice.

2. We would also like to correct two citation errors in the first paragraph in the right column of p. 695.

We would like to add citation #67 to the end of the sentence "...100% sensitive for detecting preinvasive disease."(67) A couple sentences later, we would like to replace citation #67 with citation #1 so it reads

"...gives a truer picture of the relative effect of different screening strategies on disease."(1)

Author's Response
Posted on February 3, 2012
Evelyn P.Whitlock, MD, MPH, Kimberly K. Vesco, MD, MPH, Jennifer S. Lin, MD, MCR, Michelle Eder, PhD, Brittany U. Burda, MPH
Conflict of Interest: None Declared

We thank Dr. Ronco and colleagues for pointing out our error in contrasting a higher cumulative cancer detection after co-testing in ARTISTIC with the opposite pattern in other co-testing trials. Fortunately, this error was only in the manuscript and not in our draft report the USPSTF used for its deliberations. The error was introduced when we omitted proportional cancer results from tables as we were editing to fit within space constraints for dissemination products, including the manuscript. This error has now been corrected to indicate that co-testing trials tended to find fewer cancers cumulatively than cytology and, where reported, after the second screening round (1).

In response to Dr. Ronco and colleagues' other points: We separated the different types of HPV-based primary screening due to their heterogeneity in approaches to screening and abnormal test management protocols (2;3). This is especially important since compliance with recommended followup procedures was incompletely reported, but available data indicate variability (4). Particularly without longer term follow-up, different screening strategies that result in differential opportunities for confirmatory testing with colposcopy, or that differ in compliance with recommended followup, may distort comparisons of screening sensitivity through asymmetry bias (5;6). Considering HPV-based primary screening strategies separately also facilitated indirect comparisons between different programmatic strategies; co-testing and primary HPV screening strategies differed little in benefit, with more potential harms with co-testing, which may be mitigated by adding a triage step (such as cytology) to primary HPV. However, we disagree with the assertion by Dr. Ronco and colleagues that colposcopy requirements for HPV with cytology triage will necessarily be similar to cytology alone. Recent reports from the FOCAL trial suggest they are 1.7-fold higher when the entire first screening round is considered (7). These increases may be offset by relative decreases in colposcopy requirements in the second round (not yet reported). Thus, we still believe that determining the net impact of HPV with cytology triage will not be possible until we have more complete results from important ongoing trials (8;9).

While we considered a hierarchy of potential outcomes, not just invasive cancers, no consensus exists on which outcomes are minimally sufficient to demonstrate a benefit over cytology screening in the absence of a clear impact on cervical cancer mortality or invasive cancer incidence. Demonstrated impacts on surrogates alone (e.g., reduced CIN3+ incidence) may require modeling to inform health policy changes (6). As such, while most co-testing evaluations within national screening programs in Europe found reduced incidence of CIN3+ in the second screening round (compared with cytology alone), relative CIN2+ detection was generally increased during the first round, and in some cases, cumulatively. An increased detection of CIN2+ cumulatively indicates a possible tradeoff between early disease detection and overdiagnosis (10), a serious concern in a disease with very low prevalence of progressive cancers (6).

Estimating both effectiveness and over-diagnosis requires longitudinal data from at least two screening rounds within a randomized trial (10). At the time of our report, complete data from two screening rounds was available from only two of four co-testing trials (NTCC Phase I, ARTISTIC) and one primary HPV screening trial (NTCC Phase II). Incident cervical cancer cases after co-testing were sparsely reported and represented complete follow-up for the entire study population in one study only (11). Since the publication of our report, complete second- round results from another trial (POBASCAM) suggest a similar pattern of reduced cancer incidence (12), although data on cancer stages were not reported. The benefit of earlier detection might be considered more robust with a demonstrated reduction in cancer 1B+ incidence (6).

Based on these new POBASCAM results, others have calculated that 3.2 additional CIN2/CIN3 would be treated to prevent 1 case of incident cancer as a means of estimating the potential over-treatment associated with cancer prevention (13). To address the programmatic impact, however, one might consider the incremental difference in cumulative cancers due to higher cross-sectional sensitivity with HPV-based screening compare to cytology alone. Under these considerations, 8 CIN2/CIN3 would be treated to prevent 1 cancer diagnosis. Neither of these calculations, however, considers potential increased harms other than those stemming from overtreatment (i.e. not harms related to unnecessary retesting, colposcopy, biopsies).

By design, our systematic review was limited to reporting available empirical data to directly quantify benefits and harms. The tradeoffs between earlier disease detection and overdiagnosis still cannot be well- quantified without more complete reporting from trials, unless supplemented by the addition of modeling exercises. To help further illuminate this issue, we highlighted the need for more complete reporting from available trials for all participants (complete second round screening and followup, perhaps with linkage to registries) and for a larger array of process measures and health outcomes (recommendations for and compliance with retesting for abnormal results, colposcopies, biopsies, and treatment, ideally with related harms). In doing so, we did not intend to suggest that randomized controlled trials are needed to evaluate every potential advance or nuance in cervical cancer screening, as we agree this would be inappropriate. Instead, comparative effectiveness evaluations to improve established cancer screening must rely on other evidence-based standards wherever appropriate (14).

Modeling allows comparisons of different rescreening intervals for different tests, different starting and stopping ages, and other approaches not tested in trials. Modeled results from the US suggest that a longer rescreening interval after co-testing (every five years) is required to achieve comparability with cytology in programmatic benefits and harms (15). These programmatic benefits, however, require adherence with prolonged intervals after co-testing to avoid expected harms from detecting transient HPV infections, among other issues (16). There is no national screening program in the US and evidence suggests prolonged screening intervals up to three years (or longer) are not standard after co-testing in individual or small-group practices (17). Thus, judgment is required as to how trial and modeling results for co-testing apply in the US outside of contexts such as the Veterans Administration, health maintenance organizations, or others managing stable populations over time. These judgments about applicability and other inferential activities are clearly the role of the USPSTF (18). Finally, we did not down-grade the quality of trials for issues such as participant blinding. Instead, we noted factors that could affect interpretation of results for these pragmatic trials, through mechanisms such as likelihood of seeking screening outside the program.

Yours sincerely, Evelyn P. Whitlock, MD, MPH Kimberly K. Vesco, MD, MPH Jennifer S. Lin, MD, MCR Michelle Eder, PhD Brittany U. Burda, MPH

Reference List

(1) Whitlock EP, Vesco KK, Eder M, Lin JL, Senger CA, Burda BU. Correction: Liquid-based cytology and human papillomavirus screening for cervical cancer. Ann Intern Med 2012; 156(1):71-72.

(2) Whitlock EP, Vesco KK, Eder M, Lin JS, Senger CA, Burda BU. Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2011; 155(10):687-5.

(3) Vesco KK, Whitlock EP, Eder M, Lin J, Burda BU, Senger CA et al. Screening for cervical cancer: a systematic evidence review for the US Preventive Services Task Force. Evidence Report No. 86. AHRQ Publication No. 11-05156-EF-1. 2011. Rockville, MD, Agency for Healthcare Research and Quality.

(4) Rebolj M, Lynge E. Incomplete follow-up of positive HPV tests: overview of randomised controlled trials on primary cervical screening. Br J Cancer 2010; 103(3):310-314.

(5) International Agency for Research on Cancer. IARC Handbooks of Cancer Prevention: Cervix Cancer Screening. Lyon, France: IARC Press; 2005.

(6) Arbyn M, Ronco G, Cuzick J, Wentzensen N, Castle PE. How to evaluate emerging technologies in cervical cancer screening? Int J Cancer 2009; 125:2489-2496.

(7) Ogilvie GS, van Niekerk D, Krajden M, Ceballos K, Ehlen TG, Martine RE, et al. HPV FOCAL: Round one results of a cervical cancer screening trial. 11 Sep 21; Berlin, Germany: International Papillomavirus; 2011.

(8) 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(23):1612-1623.

(9) Ogilvie GS, van Niekerk DJ, Krajden M, Martin RE, Ehlen TG, Ceballos K et al. A randomized controlled trial of Human Papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL Trial). BMC Cancer 2010; 10(1):111.

(10) Ronco G, Miejer C. HPV screening: available data and recommendations for clinical practice. Curr Cancer Ther Rev 2010; 6(2):104 -109.

(11) Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla PP, Del MA et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncology 2010; 11(3):249-257.

(12) Rijkaart DC, Berkhof J, Rozendaal L, van Kemenade FJ, Bulkmans NW, Heideman DA et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol 2012; 13(1):78-88.

(13) Katki HA, Wentzensen N. How might HPV testing be integrated into cervical screening? Lancet Oncol 2012; 13(1):8-10.

(14) Lord SJ, Irwig L, Simes RJ. When is measuring sensitivity and specificity sufficient to evaluate a diagnostic test, and when do we need randomized trials? Ann Intern Med 2006; 144(11):850-855.

(15) Kulasingam S, Havrilesky L, Ghebre R, Myers ER. Screening for Cervical Cancer: A Decision Analysis for the United States Preventive Services Task Force. AHRQ Publication No. 11-05157-EF-1. 2011. Rockville, MD, Agency for Heatlhcare Research and Quality.

(16) 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(5):368-383.

(17) Saraiya M, Berkowitz Z, Yabroff KR, Wideroff L, Kobrin S, Benard V. Cervical cancer screening with both human papillomavirus and Papanicolaou testing vs Papanicolaou testing alone: what screening intervals are physicians recommending? Arch Intern Med 2010; 170(11):977- 985.

(18) U.S.Preventive Services Task Force. USPSTF procedure manual. AHRQ Publication No. 08-05118-EF. 2008. Rockville, MD, Agency for Healthcare Research and Quality.

Conflict of Interest:

None declared

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