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P: Women between 18-69 years presenting for cervical cytology screening.
I: HPV DNA testing
C: Cytology Screening
O: Sensitivity for detecting cervical precancerous lesions.

Article 1:
Int J Cancer. 2014 Jul 1;135(1):166-77. doi: 10.1002/ijc.28640. Epub 2014 Jan 24. Is HPV DNA testing specificity comparable to that of cytological testing in primary cervical cancer screening? Results of a meta-analysis of randomized controlled trials. Pileggi C1, Flotta D, Bianco A, Nobile CG, Pavia M.

Author information
Abstract
Human-papillomavirus (HPV) DNA testing has been proposed as an alternative to primary cervical cancer screening using cytological testing. Review of the evidence shows that available data are conflicting for some aspects. The overall goal of the study is to update the performance of HPV DNA as stand-alone testing in primary cervical cancer screening, focusing particularly on the aspects related to the specificity profile of the HPV DNA testing in respect to cytology. We performed a meta-analysis of randomized controlled clinical trials. Eight articles were included in the meta-analysis. Three outcomes have been investigated: relative detection, relative specificity, and relative positive predictive value (PPV) of HPV DNA testing versus cytology. Overall evaluation of relative detection showed a significantly higher detection of CIN2+ and CIN3+ for HPV DNA testing versus cytology.

Meta-analyses that considered all age groups showed a relative specificity that favored the cytology in detecting both CIN2+ and CIN3+ lesions whereas, in the ≥30 years’ group, specificity of HPV DNA and cytology tests was similar in detecting both CIN2+ and CIN3+ lesions. Results of the pooled analysis on relative PPV showed a not significantly lower PPV of HPV DNA test over cytology. A main key finding of the study is that in women aged ≥30, has been found an almost overlapping specificity between the two screening tests in detecting CIN2 and above-grade lesions. Therefore, primary screening of cervical cancer by HPV DNA testing appears to offer the right balance between maximum detection of CIN2+ and adequate specificity, if performed in the age group ≥30 years. © 2013 UICC.

KEYWORDS:
HPV DNA test; cervical cancer screening; conventional cytology; specificity PMID:24302411
[PubMed – indexed for MEDLINE]

Article 2:
Cochrane Database Syst Rev. 2013 Mar 28;3:CD008054. doi: 10.1002/14651858.CD008054.pub2. Human papillomavirus testing versus repeat cytology for triage of minor cytological cervical lesions. Arbyn M1, Roelens J, Simoens C, Buntinx F, Paraskevaidis E, Martin-Hirsch PP, Prendiville WJ. Author information

Abstract
BACKGROUND:
Atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intra-epithelial lesions (LSIL) are minor lesions of the cervical epithelium, detectable by cytological examination of cells collected from the surface of the cervix of a woman.Usually, women with ASCUS and LSIL do not have cervical (pre-) cancer, however a substantial proportion of them do have underlying high-grade cervical intra-epithelial neoplasia (CIN, grade 2 or 3) and so are at increased risk for developing cervical cancer. Therefore, accurate triage of women with ASCUS or LSIL is required to identify those who need further management.This review evaluates two ways to triage women with ASCUS or LSIL: repeating the cytological test, and DNA testing for high-risk types of the human papillomavirus (hrHPV) – the main causal factor of cervical cancer. OBJECTIVES:

Main objective To compare the accuracy of hrHPV testing with the Hybrid Capture 2 (HC2) assay against that of repeat cytology for detection of underlying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+) in women with ASCUS or LSIL. For the HC2 assay, a positive result was defined as proposed by the manufacturer. For repeat cytology, different cut-offs were used to define positivity: Atypical squamous cells of undetermined significance or worse (ASCUS+), low-grade squamous intra-epithelial lesions or worse (LSIL+) or high-grade squamous intra-epithelial lesions or worse (HSIL+).Secondary objective To assess the accuracy of the HC2 assay to detect CIN2+ or CIN3+ in women with ASCUS or LSIL in a larger group of reports of studies that applied hrHPV testing and the reference standard (coloscopy and biopsy), irrespective whether or not repeat cytology was done. SEARCH METHODS:

We made a comprehensive literature search that included the Cochrane Register of Diagnostic Test Accuracy Studies; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (through PubMed), and EMBASE (last search 6 January 2011). Selected journals likely to contain relevant papers were handsearched from 1992 to 2010 (December). We also searched CERVIX, the bibliographic database of the Unit of Cancer Epidemiology at the Scientific Institute of Public Health (Brussels, Belgium) which contains more than 20,000 references on cervical cancer.More recent searches, up to December 2012, targeted reports on the accuracy of triage of ASCUS or LSIL with other HPV DNA assays, or HPV RNA assays and other molecular markers. These searches will be used for new Cochrane reviews as well as for updates of the current review. SELECTION CRITERIA:

Studies eligible for inclusion in the review had to include: women presenting with a cervical cytology result of ASCUS or LSIL, who had undergone both HC2 testing and repeat cytology, or HC2 testing alone, and were subsequently subjected to reference standard verification with colposcopy and colposcopy-directed biopsies for histologic verification. DATA COLLECTION AND ANALYSIS:

The review authors independently extracted data from the selected studies, and obtained additional data from report authors.Two groups of meta-analyses were performed: group I concerned triage of women with ASCUS, group II concerned women with LSIL. The bivariate model (METADAS-macro in SAS) was used to assess the absolute accuracy of the triage tests in both groups as well as the differences in accuracy between the triage tests. MAIN RESULTS:

The pooled sensitivity of HC2 was significantly higher than that of repeat cytology at cut-off ASCUS+ to detect CIN2+ in both triage of ASCUS and LSIL (relative sensitivity of 1.27 (95% CI 1.16 to 1.39; P value < 0.0001) and 1.23 (95% CI 1.06 to 1.4; P value 0.007), respectively. In ASCUS triage, the pooled specificity of the triage methods did not differ significantly from each other (relative specificity: 0.99 (95% CI 0.97 to 1.03; P value 0.98)). However, the specificity of HC2 was substantially, and significantly, lower than that of repeat cytology in the triage of LSIL (relative specificity: 0.66 (95% CI 0.58 to 0.75) P value < 0.0001). AUTHORS’ CONCLUSIONS:

HPV-triage with HC2 can be recommended to triage women with ASCUS because it has higher accuracy (significantly higher sensitivity, and similar specificity) than repeat cytology. When triaging women with LSIL, an HC2 test yields a significantly higher sensitivity, but a significantly lower specificity, compared to a repeat cytology. Therefore, practice recommendations for management of women with LSIL should be balanced, taking local circumstances into account. PMID:

Article 3:
J Natl Cancer Inst. 2009 Jan 21;101(2):88-99. doi: 10.1093/jnci/djn444. Epub 2009 Jan 13. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. Naucler P1, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, Rådberg T, Strander B, Forslund O, Hansson BG, Hagmar B, Johansson B, Rylander E, Dillner J. Author information

Abstract
BACKGROUND:
Primary cervical screening with both human papillomavirus (HPV) DNA testing and cytological examination of cervical cells with a Pap test (cytology) has been evaluated in randomized clinical trials. Because the vast majority of women with positive cytology are also HPV DNA positive, screening strategies that use HPV DNA testing as the primary screening test may be more effective. METHODS:

We used the database from the intervention arm (n = 6,257 women) of a population-based randomized trial of double screening with cytology and HPV DNA testing to evaluate the efficacy of 11 possible cervical screening strategies that are based on HPV DNA testing alone, cytology alone, and HPV DNA testing combined with cytology among women aged 32-38 years. The main outcome measures were sensitivity for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) within 6 months of enrollment or at colposcopy for women with a persistent type-specific HPV infection and the number of screening tests and positive predictive value (PPV) for each screening strategy. All statistical tests were two-sided. RESULTS:

Compared with screening by cytology alone, double testing with cytology and for type-specific HPV persistence resulted in a 35% (95% confidence interval [CI] = 15% to 60%) increase in sensitivity to detect CIN3+, without a statistically significant reduction in the PPV (relative PPV = 0.76, 95% CI = 0.52 to 1.10), but with more than twice as many screening tests needed. Several strategies that incorporated screening for high-risk HPV subtypes were explored, but they resulted in reduced PPV compared with cytology. Compared with cytology, primary screening with HPV DNA testing followed by cytological triage and repeat HPV DNA testing of HPV DNA-positive women with normal cytology increased the CIN3+ sensitivity by 30% (95% CI = 9% to 54%), maintained a high PPV (relative PPV = 0.87, 95% CI = 0.60 to 1.26), and resulted in a mere 12% increase in the number of screening tests (from 6,257 to 7,019 tests). CONCLUSIONS:

Primary HPV DNA-based screening with cytology triage and repeat HPV DNA testing of cytology-negative women appears to be the most feasible cervical screening strategy.

Article 4:
The Lancet, Volume 383, Issue 9916, Pages 524 – 532, 8 February 2014
doi:10.1016/S0140-6736(13)62218-7Cite or Link Using DOI
This article can be found in the following collections: Obstetrics & Gynaecology (Gynaecological cancer); Oncology (Gynaecological cancer) Published Online: 03 November 2013
Copyright © 2014 Elsevier Ltd All rights reserved.

Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials Dr Guglielmo Ronco MD a , Prof Joakim Dillner MD c, K Miriam Elfström MPH c, Sara Tunesi PhD a, Prof Peter J F Snijders PhDd, Marc Arbyn MD e, Prof Henry Kitchener MD f, Nereo Segnan MD a b, Clare Gilham MSc h, Paolo Giorgi-Rossi PhD g, Johannes Berkhof PhD d, Prof Julian Peto DSc h, Prof Chris J L M Meijer MD d, the International HPV screening working group† Summary

Background
In four randomised trials, human papillomavirus (HPV)-based screening for cervical cancer was compared with cytology-based cervical screening, and precursors of cancer were the endpoint in every trial. However, direct estimates are missing of the relative efficacy of HPV-based versus cytology-based screening for prevention of invasive cancer in women who undergo regular screening, of modifiers (eg, age) of this relative efficacy, and of the duration of protection. We did a follow-up study of the four randomised trials to investigate these outcomes. Methods

176 464 women aged 20—64 years were randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). We followed up these women for a median of 6·5 years (1 214 415 person-years) and identified 107 invasive cervical carcinomas by linkage with screening, pathology, and cancer registries, by masked review of histological specimens, or from reports. Cumulative and study-adjusted rate ratios (experimental vs control) were calculated for incidence of invasive cervical carcinoma. Findings

The rate ratio for invasive cervical carcinoma among all women from recruitment to end of follow-up was 0·60 (95% CI 0·40—0·89), with no heterogeneity between studies (p=0·52). Detection of invasive cervical carcinoma was similar between screening methods during the first 2·5 years of follow-up (0·79, 0·46—1·36) but was significantly lower in the experimental arm thereafter (0·45, 0·25—0·81). In women with a negative screening test at entry, the rate ratio was 0·30 (0·15—0·60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was 4·6 per 105 (1·1—12·1) and 8·7 per 105 (3·3—18·6) at 3·5 and 5·5 years, respectively, in the experimental arm, and 15·4 per 105 (7·9—27·0) and 36·0 per 105 (23·2—53·5), respectively, in the control arm. Rate ratios did not differ by cancer stage, but were lower for adenocarcinoma (0·31, 0·14—0·69) than for squamous-cell carcinoma (0·78, 0·49—1·25). The rate ratio was lowest in women aged 30—34 years (0·36, 0·14—0·94). Interpretation

HPV-based screening provides 60—70% greater protection against invasive cervical carcinomas compared with cytology. Data of large-scale randomised trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years. Funding

European Union, Belgian Foundation Against Cancer, KCE-Centre d’Expertise, IARC, The Netherlands Organisation for Health Research and Development, the Italian Ministry of Health.

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