Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials

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 10(5) (1.1-12.1) and 8.7 per 10(5) (3.3-18.6) at 3.5 and 5.5 years, respectively, in the experimental arm, and 15.4 per 10(5) (7.9-27.0) and 36.0 per 10(5) (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