Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial

Guglielmo Ronco, Paolo Giorgi-Rossi, Francesca Carozzi, Massimo Confortini, Paolo Dalla Palma, Annarosa Del Mistro, Bruno Ghiringhello, Salvatore Girlando, Anna Gillio-Tos, Laura De Marco, Carlo Naldoni, Paola Pierotti, Raffaella Rizzolo, Patrizia Schincaglia, Manuel Zorzi, Marco Zappa, Nereo Segnan, Jack Cuzick

Research output: Contribution to journalArticle

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Abstract

Background: Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing. Methods: Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807. Findings: In total for both phases, 47 001 women were randomly assigned to the cytology group and 47 369 to HPV testing. 33 851 women from the cytology group and 32 998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0·62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0·004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0·028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2·00 (95% CI 1·44-2·77) for CIN2, 2·08 (1·47-2·95) for CIN3, and 2·03 (1·60-2·57) for CIN2 and 3 together. At round two the relative detection was 0·54 (0·23-1·28) for CIN2, 0·48 (0·21-1·11) for CIN3, and 0·51 (0·28-0·93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0·93 (0·52-1·64) in phase one and 3·91 (2·02-7·57) in phase two. At round two the relative detection was 1·34 (0·46-3·84) in phase one and 0·20 (0·04-0·93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4·09 (2·24-7·48) at round one and 0·64 (0·23-1·27) at round two. Interpretation: HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. Funding: European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.

Original languageEnglish
Pages (from-to)249-257
Number of pages9
JournalThe Lancet Oncology
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 2010

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Cervical Intraepithelial Neoplasia
Uterine Cervical Neoplasms
Randomized Controlled Trials
Cell Biology
Colposcopy
Health
European Union
Random Allocation
Early Detection of Cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia : a randomised controlled trial. / Ronco, Guglielmo; Giorgi-Rossi, Paolo; Carozzi, Francesca; Confortini, Massimo; Palma, Paolo Dalla; Del Mistro, Annarosa; Ghiringhello, Bruno; Girlando, Salvatore; Gillio-Tos, Anna; De Marco, Laura; Naldoni, Carlo; Pierotti, Paola; Rizzolo, Raffaella; Schincaglia, Patrizia; Zorzi, Manuel; Zappa, Marco; Segnan, Nereo; Cuzick, Jack.

In: The Lancet Oncology, Vol. 11, No. 3, 03.2010, p. 249-257.

Research output: Contribution to journalArticle

Ronco, G, Giorgi-Rossi, P, Carozzi, F, Confortini, M, Palma, PD, Del Mistro, A, Ghiringhello, B, Girlando, S, Gillio-Tos, A, De Marco, L, Naldoni, C, Pierotti, P, Rizzolo, R, Schincaglia, P, Zorzi, M, Zappa, M, Segnan, N & Cuzick, J 2010, 'Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial', The Lancet Oncology, vol. 11, no. 3, pp. 249-257. https://doi.org/10.1016/S1470-2045(09)70360-2
Ronco, Guglielmo ; Giorgi-Rossi, Paolo ; Carozzi, Francesca ; Confortini, Massimo ; Palma, Paolo Dalla ; Del Mistro, Annarosa ; Ghiringhello, Bruno ; Girlando, Salvatore ; Gillio-Tos, Anna ; De Marco, Laura ; Naldoni, Carlo ; Pierotti, Paola ; Rizzolo, Raffaella ; Schincaglia, Patrizia ; Zorzi, Manuel ; Zappa, Marco ; Segnan, Nereo ; Cuzick, Jack. / Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia : a randomised controlled trial. In: The Lancet Oncology. 2010 ; Vol. 11, No. 3. pp. 249-257.
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T1 - Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia

T2 - a randomised controlled trial

AU - Ronco, Guglielmo

AU - Giorgi-Rossi, Paolo

AU - Carozzi, Francesca

AU - Confortini, Massimo

AU - Palma, Paolo Dalla

AU - Del Mistro, Annarosa

AU - Ghiringhello, Bruno

AU - Girlando, Salvatore

AU - Gillio-Tos, Anna

AU - De Marco, Laura

AU - Naldoni, Carlo

AU - Pierotti, Paola

AU - Rizzolo, Raffaella

AU - Schincaglia, Patrizia

AU - Zorzi, Manuel

AU - Zappa, Marco

AU - Segnan, Nereo

AU - Cuzick, Jack

PY - 2010/3

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N2 - Background: Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing. Methods: Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807. Findings: In total for both phases, 47 001 women were randomly assigned to the cytology group and 47 369 to HPV testing. 33 851 women from the cytology group and 32 998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0·62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0·004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0·028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2·00 (95% CI 1·44-2·77) for CIN2, 2·08 (1·47-2·95) for CIN3, and 2·03 (1·60-2·57) for CIN2 and 3 together. At round two the relative detection was 0·54 (0·23-1·28) for CIN2, 0·48 (0·21-1·11) for CIN3, and 0·51 (0·28-0·93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0·93 (0·52-1·64) in phase one and 3·91 (2·02-7·57) in phase two. At round two the relative detection was 1·34 (0·46-3·84) in phase one and 0·20 (0·04-0·93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4·09 (2·24-7·48) at round one and 0·64 (0·23-1·27) at round two. Interpretation: HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. Funding: European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.

AB - Background: Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing. Methods: Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807. Findings: In total for both phases, 47 001 women were randomly assigned to the cytology group and 47 369 to HPV testing. 33 851 women from the cytology group and 32 998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0·62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0·004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0·028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2·00 (95% CI 1·44-2·77) for CIN2, 2·08 (1·47-2·95) for CIN3, and 2·03 (1·60-2·57) for CIN2 and 3 together. At round two the relative detection was 0·54 (0·23-1·28) for CIN2, 0·48 (0·21-1·11) for CIN3, and 0·51 (0·28-0·93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0·93 (0·52-1·64) in phase one and 3·91 (2·02-7·57) in phase two. At round two the relative detection was 1·34 (0·46-3·84) in phase one and 0·20 (0·04-0·93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4·09 (2·24-7·48) at round one and 0·64 (0·23-1·27) at round two. Interpretation: HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. Funding: European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.

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