ABSTRACT: Human papillomavirus (HPV)–based screening is more effective than cytology-based screening for detecting the precursors of invasive cervical carcinoma, cervical intraepithelial neoplasia grade 2 (CIN2), and, particularly, grade 3 (CIN3). Four randomized controlled trials (Swedescreen, POBASCAM, ARTISTIC, and NTCC) compared HPV-based screening for cervical cancer with cytology-based cervical screening. Precursors of this cancer were the end point in each of these trials. In all 4 trials, HPV-based screening detected persistent CIN3 before cytology, increasing the likelihood of treatment before invasion. However, direct estimates are absent in the 4 trials on the relative efficacy of HPV-based versus cytology-based screening for prevention of invasive cancer in women who undergo regular screening and of how efficacy changes according to modifiers of this relative efficacy (age, cancer stage, and morphology) and of the duration of protection against cancer.
This extended follow-up study was designed to investigate these outcomes. Data were pooled from the 4 trials. The primary study end point was detected invasive cervical carcinomas in women who have regular screening. A total of 176,464 women with a mean age of 35 to 41 years (range, 20–64 years) were randomly assigned to either HPV-based (experimental arm [HPV group]) or cytology-based (control arm [control group]) screening in the 4 trials. The trials were conducted in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). Participants were followed for a median of 6.5 years (1,214,415 person-years). A total of 107 invasive cervical carcinomas were detected by linkage with screening, pathology, and cancer registries and by masked review of histological specimens or from reports. The incidence of invasive cervical carcinoma in the 2 groups was determined by calculating cumulative and study-adjusted rate ratios.
The overall rate ratio for detection of invasive cervical carcinoma among all women from recruitment to end of follow-up was 0.60, with a 95% confidence interval (CI) of 0.40 to 0.89; there was no heterogeneity between studies (P = 0.52).
During the first 2.5 years of follow-up, the rate ratio for invasive cervical carcinoma was similar between screening methods (0.79; 95% CI, 0.46–1.36) but thereafter was significantly lower in the HIV group (0.45; 95% CI, 0.25–0.81).
The rate ratio among women with a negative screening test at entry was 0.30 (95% CI, 0.15–0.60). The cumulative incidence of invasive cervical carcinoma in women with negative entry tests was as follows: HIV group at 3.5 and 5.5 years (4.6 per 105 [95% CI, 1.1–12.1] and 8.7 per 105 [95% CI, 3.3–18.6], respectively) versus control group at 3.5 and 5.5 years (15.4 per 105 [95% CI, 7.9–27.0] and 36.0 per 105 [95% CI, 23.2–53.5], respectively). Rate ratios were lower for adenocarcinoma (0.31; 95% CI, 0.14–0.69) than for squamous cell carcinoma (0.78; 95% CI, 0.49–1.25), but did not differ by cancer stage. The lowest rate ratio (0.36; 95% CI, 0.14–0.94) was found among women aged 30 to 34 years.
These data show that HPV-based screening provides 60% to 70% greater protection against invasive cervical cancers compared with cytology. The lower cumulative incidence of cervical cancer 5.5 years after a negative HPV test than 3.5 years after a negative cytology test indicates that 5-year intervals for HPV screening are safer than 3-year intervals for cytology.
Center for Cancer Epidemiology and Prevention, AO City of Health and Science, Turin, Italy (G.R., S.T., N.S.); International Agency for Research on Cancer (IARC), Lyon, France (N.S.); Karolinska Institutet, Stockholm, Sweden (J.D., K.M.E.); VU University Medical Centre, Amsterdam, the Netherlands (P.J.F.S., J.B., C.J.L.M.M.); Scientific Institute of Public Health, Brussels, Belgium (M.A.); Institute of Cancer Sciences, University of Manchester, Manchester, UK (H.K.); Azienda Sanitaria Locale, Reggio Emilia, Italy (P.G.-R.); and London School of Hygiene and Tropical Medicine, London, UK (C.G., J.P.)