Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test.
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 = 24,661) 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 = 24,535) 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.
Ronco
Guglielmo
G
Unit of Cancer Epidemiology, Centro per la Prevenzione Oncologica, Turin, Italy. guglielmo.ronco@cpo.it
Giorgi-Rossi
Paolo
P
Carozzi
Francesca
F
Confortini
Massimo
M
Dalla Palma
Paolo
P
Del Mistro
Annarosa
A
Gillio-Tos
Anna
A
Minucci
Daria
D
Naldoni
Carlo
C
Rizzolo
Raffaella
R
Schincaglia
Patrizia
P
Volante
Renza
R
Zappa
Marco
M
Zorzi
Manuel
M
Cuzick
Jack
J
Segnan
Nereo
N
D000328:Adult; D000367:Age Factors; D052685:Alphapapillomavirus / Q000235:genetics / Q000302:isolation & purification*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000821:virology; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D003127:Colposcopy; D003588:Cytopathogenic Effect, Viral; D004279:DNA, Viral / Q000302:isolation & purification; D005260:Female; D006801:Humans; D007558:Italy; D008403:Mass Screening / Q000379:methods*; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications / Q000175:diagnosis* / Q000821:virology; D018579:Patient Selection; D012680:Sensitivity and Specificity; D014412:Tumor Virus Infections / Q000150:complications / Q000175:diagnosis* / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000821:virology; D014626:Vaginal Smears; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000821:virology
D004279:DNA, Viral