Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial

Summary

Background

Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening.

Methods

In this randomised trial, women aged 29–56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131.

Findings

22 420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20 106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19 731 in the control group were eligible, of whom 16 750 and 16 743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19 731 in the control group; relative risk 0·73, 95% CI 0·55–0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19 731; 0·29, 0·10–0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20 106; 1·15, 0·92–1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19 286 vs 12 of 19 373; 2·85, 1·47–5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20 106; 1·25, 1·05–1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27–0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57–1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20 106; 0·96, 0·81–1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20 106; 1·08, 0·94–1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29–33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74–1·27; CIN grade 2 or worse in women aged 29–33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81–1·26; CIN grade 3 or worse in women aged 34–56 years: 157 of 16 860 vs 167 of 16 978; 0·95, 0·76–1·18; CIN grade 2 or worse in women aged 34–56 years: 274 of 16 860 vs 248 of 16 978; 1·11, 0·94–1·32).

Interpretation

Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older.

Funding

Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development).

Introduction

Infection with high-risk types of human papillomavirus (HPV) has a causal role in the development of cervical cancer.1, 2 This link has stimulated the development of HPV DNA testing, which might be useful in primary cervical screening.3, 4 Furthermore, prophylactic HPV16 and HPV18 vaccines have been developed and introduced in many countries as a primary prevention method.5, 6

Randomised controlled screening trials of HPV DNA testing7, 8, 9, 10, 11 have shown a decreased detection of high-grade cervical lesions at the second screening round compared with cytology alone. Although the screening protocols, study endpoints, and interval between screening rounds varied in these trials, the consistent results suggest that HPV DNA testing offers better protection against high-grade cervical lesions in second screening rounds than do cytology-based screening methods. Only one study¹⁰ was large enough to also show protection against cervical cancer in the second screening round.

We present the final results of the POpulation-BAsed SCreening study AMsterdam (POBASCAM) trial, a population-based, randomised controlled trial. Our main goal was to assess whether HPV DNA testing decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, of CIN grade 2 or worse, and of cervical cancer, in the second screening round. Additionally, to assess the most appropriate age at which HPV DNA testing should start, we analysed women invited for the first time (aged 29–33 years) and older women (34–56 years) separately. We also assessed how detection of high-grade lesions in two screening rounds was associated with particular HPV genotypes.