ArticlesEfficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials
Introduction
Cervical screening aims to prevent invasive cervical carcinoma by detection and treatment of its precursors—cervical intraepithelial neoplasia grade 2 (CIN2) and, particularly, grade 3 (CIN3). In a cluster-randomised controlled trial from rural India,1 women who had received little or no previous cervical screening either underwent one round of human papillomavirus (HPV) testing or had no screening, cytological analysis, or visual inspection. Cumulative incidence of advanced cancer (stage ≥2), but not of stage 1 invasive cancer, was lower in women who had one HPV screening round compared with those who had no intervention.1 However, the effect of HPV testing—as an alternative to regular cytological screening—on incidence of invasive cancer has not been assessed adequately.
Four randomised controlled trials have been done—Swedescreen,2 POBASCAM,3, 4 ARTISTIC,5 and NTCC6—in which women from industrialised countries were followed up for at least two rounds of cervical screening. A lower CIN3 incidence was recorded after HPV testing compared with cytology. Despite different screening protocols, the relative incidence of CIN3 or worse histological findings after the first screening round was similar in all studies: rate ratios (HPV vs cytology) were 0·53 (95% CI 0·29–0·98) in Swedescreen, 0·52 (0·28–0·97) in ARTISTIC, 0·34 (0·15–0·75) in NTCC (in women aged 35 years or older), and 0·39 (0·27–0·53) in POBASCAM, with no evidence of heterogeneity (p=0·681).7 These results show that HPV-based screening detects persistent high-grade CIN before cytology, thus increasing the probability of treatment before invasion. Furthermore, the effect was similar with the different screening protocols applied, which suggests that efficacy in cancer prevention is dependent primarily on the screening test and not on the exact protocol used, providing a strong rationale for joint analysis of trials.
In the NTCC trial,6 the overall incidence of invasive cancers was reduced significantly with HPV screening compared with cytology, and in POBASCAM,4 incidence was diminished significantly at the second screening round. However, because none of the four randomised controlled trials was powered to show a reduction in cancer incidence, the numbers of cases in individual reports were small. Thus, precise direct estimates are absent for the relative efficacy of HPV-based versus cytology-based screening, of how efficacy changes according to age, cancer stage, and morphological features, and of the duration of protection against cancer. Such direct estimates are crucial to inform decisions about implementation of HPV-based screening as a routine activity and to define some important aspects of screening policies with HPV, such as the age at which to initiate screening and the optimum screening interval. Therefore, we pooled data from the four randomised trials and followed up the cohorts for analysis of invasive cervical carcinomas.
Section snippets
Study populations
Study populations and interventions used in the studies have been described elsewhere.3, 4, 5, 6, 8, 9, 10, 11, 12, 13 Women recruited to all four trials had not had a hysterectomy and were attending for routine screening within organised population-based programmes. Participants in Swedescreen were recruited from five Swedish regions between May, 1997, and November, 2000; those in NTCC were recruited from nine areas of Italy during two preplanned phases, between March, 2002, and December,
Results
Figure 1 shows the trial profiles for the four randomised controlled trials, and table 1 summarises the main features of every study. Overall, 176 464 women were enrolled. Median age at recruitment was identical in both arms within every study (41 years for NTCC and POBASCAM, 39 years for ARTISTIC, and 35 years for Swedescreen). The proportion of women with further screening beyond 2·5 years after recruitment was similar in both arms within every study, ranging from 71% in NTCC to 95% in
Discussion
Our pooled analysis of four randomised controlled trials of HPV-based cervical screening versus conventional cytology showed a significant reduction in invasive cervical cancers in women who had HPV-based screening. When all randomised women and all cancers diagnosed from enrolment—including cases already present (prevalent)—were considered, detection of invasive cervical carcinomas was significantly lower with HPV-based testing.
Data obtained at enrolment are essential to prove that HPV-based
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