POBASCAM, a population‐based randomized controlled trial for implementation of high‐risk HPV testing in cervical screening: Design, methods and baseline data of 44,102 women

Abstract

Cytological cervical screening is rather inefficient because of relatively high proportions of false negative and false positive smears. To evaluate the efficiency of high-risk human papillomavirus (hrHPV) testing, by GP5؉/6؉ PCR-enzyme immunoassay (EIA), in conjunction with cytology (Intervention Group) to that of the classical cytology (Control Group), we initiated the Population Based Screening Study Amsterdam (POBASCAM). POBASCAM is a population-based randomized controlled trial for implementation of hrHPV testing in cervical screening. The outcome measure is the proportion of histologically confirmed >CIN3 lesions in each study arm up to and including the next screening round after 5 years. We present the design, methods and baseline data of POBASCAM. When, in the next 5 years, the follow-up will be completed, the data obtained will be used in model studies, including a cost-effectiveness study, to advise the Dutch Ministry of Public Health in deciding whether cervical screening should be based on combined hrHPV and cytology testing instead of cytology alone. Between January 1999 and September 2002, 44,102 women (mean age ‫؍‬ 42.8 years; range ‫؍‬ 29 -61) that participated in the regular Dutch screening program were included in our study. In the Intervention Group the distribution of cytology and hrHPV by cytology class was as follows: normal cytology 96.6% (3.6% hrHPV positive); borderline and mild dyskaryosis (BMD) 2.5% (34.6% hrHPV positive); and moderate dyskaryosis or worse (>BMD) 0.8% (88.3% hrHPV positive), i.e., 0.4% moderate dyskaryosis (82.9% hrHPV positive), 0.3% severe dyskaryosis (92.5% hrHPV positive), 0.1% carcinoma in situ (95.2% hrHPV positive), <0.1% suspected for invasive cancer (hrHPV positive 100.0%). In the Control Group 96.5% of the women had normal cytology, 2.4% BMD and 0.8% >BMD, i.e., 0.4% moderate dyskaryosis, 0.3% severe dyskaryosis, 0.1% carcinoma in situ, <0.1% suspected for invasive cancer. The presence of hrHPV was age-dependent, decreasing from 12.0% at 29 -33 years to 2.4% at 59 -61 years. Among women with a positive hrHPV test, the prevalence of BMD was age-dependent ranging from 20.2% at 29 -33 years to 7.8% at 54 -58 years. In contrast, the risk of >BMD of 13.7% among women with a positive hrHPV test was not age-dependent. Our study indicates that large-scale hrHPV testing by GP5؉/6؉ PCR-EIA in the setting of population-based cervical screening is practically feasible, is accepted by both participating women and general practitioners and yields highly reproducible results.

Routine cervical screening with primary HPV testing and cytology triage protocol in a randomised setting

“…In the Guanacaste trial, sensitivity and specificity of the HC 2 r testing were compared to Pap testing using ASC-US cut point for colposcopy (Schiffman et al, 2000); however, the women tested for hrHPVs had multiple tests (a pelvic examination, conventional cytological test and LBC test, cervigrams) performed, which makes evaluating the outcome effectiveness of these tests impossible (The working group of IARC, 2005). Like in our study, in the ALTS and POBASCAM trial women were randomised to intervention and control groups, but in these trials hrHPV test (by HC 2 r in ALTS and by GP5 þ /6 þ PCR immunoassay in POBASCAM) was used as a confirmatory test for cytological test, which is just the opposite to our study (Schiffman and Solomon, 2003;Bulkmans et al, 2004). The Indian trial, being most comparable to our study, resulted in specificity of HC 2 r test in detecting CIN2 þ lesions ranging from 91.7 to 94.6%, and PPV from 9.1 to 16.7% -for the same cutoff in the current study, specificity estimate was 91.7% and PPV 4.0% (Sankaranarayanan et al, 2004).…”

Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up

“…The study design of the POBASCAM trial (Trial registration ID: NTR218; ISRCTN20781131), a population‐based randomized controlled trial for implementation of high‐risk HPV testing in cervical screening, has been published before 3, 29, 30. In brief, women aged 29–61 were included from January 1999 to September 2002.…”

High-risk HPV type-specific clearance rates in cervical screening

“…From January 1999 to September 2002, 44 102 women between 30 and 60 years of age invited for the regular Dutch cervical screening programme participated in the Population-Based Screening Amsterdam (POBASCAM) trial (Bulkmans et al, 2004). In this prospective randomised controlled trial, the efficacy of hrHPV testing in conjunction with cytology (intervention group) is compared with that of classical cytology alone (control group, hrHPV results blinded) in the setting of population-based cervical screening.…”