Journal of the National Cancer Institute Advance Access published online on March 25, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn065
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Results at Recruitment From a Randomized Controlled Trial Comparing Human Papillomavirus Testing Alone With Conventional Cytology as the Primary Cervical Cancer Screening Test
Affiliations of authors: Unit of Cancer Epidemiology, Centro per la Prevenzione Oncologica (CPO), Turin, Italy (GR, RR, NS); Agency for Public Health, Lazio Region, Rome, Italy (PGR); Centro per lo Studio e la Prevenzione Oncologica, Florence, Italy (FC, MC, MZ); Unit of Pathology, Ospedale di Trento, Italy (PDP); Istituto Oncologico Veneto Istituto di Ricerca e Cura a Carattere Speciale, Padua, Italy (ADM, MZ); Unit of Cancer Epidemiology, CPO, Center for Experimental Research and Medical Studies, University of Turin, Italy (AGT); Azienda Ospedaliera di Padova, Padua, Italy (DM); Regione Emilia-Romagna, Bologna, Italy (CN); Centro Prevenzione Oncologica, Azienda Unità Sanitaria Locale Ravenna, Italy (PS); Ospedale S. Anna, Turin, Italy (RV); Queen Mary’s School of Medicine and Dentistry and Cancer Research UK, London, UK (JC)
Correspondence to: Guglielmo Ronco, MD, PhD, Unit of Cancer Epidemiology, CPO Piemonte, Via San Francesco da Paola 31, 10123 Torino, Italy (e-mail: guglielmo.ronco{at}cpo.it).
Background: In the first recruitment phase of a randomized trial of cervical cancer screening methods (New Technologies for Cervical Cancer Screening [NTCC] study), we compared screening with conventional cytology with screening by human papillomavirus (HPV) testing in combination with liquid-based cytology. HPV-positive women were directly referred to colposcopy if aged 35 or older; if younger, they were retested after 1 year.
Methods: In the second recruitment phase of NTCC, we randomly assigned women to conventional cytology (n = 24661) with referral to colposcopy if cytology indicated atypical squamous cells of undetermined significance or more severe abnormality or to testing for high-risk HPV DNA alone by Hybrid Capture 2 (n = 24535) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater. For the main endpoint of the study, histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+), we calculated and compared sensitivity and positive predictive value (PPV) of the two screening methods using HPV DNA cutoffs of 1 pg/mL and 2 pg/mL. All statistical tests were two-sided.
Results: For women aged 35–60 years, the relative sensitivity of HPV testing for detection of CIN2+ at a cutoff of 1 pg/mL vs conventional cytology was 1.92 (95% CI = 1.28 to 2.87) and the relative PPV was 0.80 (95% CI = 0.55 to 1.18). At a cutoff of 2 pg/mL HPV DNA, the relative sensitivity was 1.81 (95% CI = 1.20 to 2.72) and the relative PPV was 0.99 (95% CI = 0.67 to 1.46). In this age group, there was no evidence of heterogeneity between study phases. Among women aged 25–34 years, the relative sensitivity for detection of CIN2+ of HPV testing at a cutoff of 1 pg/mL vs cytology was 3.50 (95% CI = 2.11 to 5.82), statistically significantly larger (P = .019) than that observed in phase 1 at this age (1.58; 95% CI = 1.03 to 2.44).
Conclusions: For women aged 35–60 years, HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity over cytology with only a small reduction in PPV. Among women aged 25–34 years, the large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1 and 2 suggests that there is frequent regression of CIN2+ that are detected by direct referral of younger HPV-positive women to colposcopy. Thus, triage test or repeat testing is needed if HPV is to be used for primary testing in this context.
| CONTEXT AND CAVEATS Prior knowledge The optimal strategy for screening women for cervical cancer precursors to ensure high sensitivity without overtreatment was not known. Study design Randomized trial of screening methods (conventional cytology vs human papillomavirus [HPV] testing) for which the main endpoint was histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+). Contribution Screening by HPV testing alone achieved a substantial gain in sensitivity compared with conventional cytology with limited loss of positive predictive value. Among younger women there was frequent regression of CIN2+ lesions. Implications HPV testing with a somewhat higher cutoff value than the one conventionally used can be applied as a sole primary screening test. HPV-positive women aged 25–34 should be referred to colposcopy only if either cytology is also abnormal or HPV infection persists for 1 year. Limitations The percentage of women whose lesions were destined to regress could not be directly estimated in this study.
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Manuscript received August 28, 2007; revised January 14, 2008; accepted February 20, 2008.
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J Natl Cancer Inst 2008 100: 447.
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