In this paper, the interim findings of Round 1 for over 18
000 women of a primary HPV screening trial based within an organised cervical screening programme in Canada are presented. At baseline screening, the CIN2+ detection rates were similar in the cytology and HPV arms. However, after subsequent screening with the recommended reflex testing for women who were either persistently hrHPV positive or persistently ASC-US positive, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm. In contrast, the CIN2+ detection rate remained unchanged after subsequent testing of persistently ASC-US-positive women in the cytology arm.
The potential benefits of using the detection of hrHPV DNA for primary cervical cancer screening are increasingly apparent. However, the high rate of insignificant HPV infections, especially in women under the age of 35 years, has been an impediment to its potential use, so exploring the ability to improve the specificity of hrHPV testing is a crucial step for successful implementation of HPV-based cervical cancer screening (Ronco et al, 2006
). In this study, preliminary results indicate that use of cytology triage reduces the number of women who would potentially be referred to colposcopy on the basis of a single hrHPV test. The rates of referral to colposcopy at baseline testing were similar in the HPV and control arms and, as both arms have abnormal cytology, this suggests that similar women are being referred in each arm. Results from the baseline screen of the first round demonstrate that is what happens, with disease detection rates being similar in both arms. However, re-testing of hrHPV-positive women at up to 12 months after baseline screening restores sensitivity, while still managing to control specificity by providing an opportunity for insignificant hrHPV infections to regress. There is the possibility to further increase specificity by extending the re-testing interval for hrHPV-positive/cytology-negative women to 24 months with little potential for disease progression. This may offer a similar disease detection rate to subsequent testing at 12 months, but could decrease unnecessary colposcopies in women by providing more time for transient hrHPV infections to resolve.
In British Columbia, screening participation is not delivered through a population-based invitation framework but relies on physician guidelines and communication between the laboratory and practitioner. Over the past decade, family physician availability and practices have altered and episode-based care has become more common. In addition, women may seek care from multiple sources. Ethical guidelines in Canada require that all women actively consent to participate in the trial, and privacy laws limit direct contact to potential participants for research purposes, that is, invitation letters must come from family physicians willing to participate in the trial. Thus, although 44
000 invitations were sent out by CFPs, the study centre is unable to directly confirm what proportion of women actually received, reviewed and understood their invitation letter. Consequently, this could impact on the representativeness and overall disease risk of women who participate in the trial compared with women who participate in cervical cancer screening in British Columbia. It is certainly accepted that the complex nature of consent required for randomised trials impacts on the general representativeness of participants compared with the overall population, which could impact on overall risk for disease equally in both arms. However, the fundamental question for this study remains the relative effectiveness of the two screening tools, and given the quality of the trial design, we believe the validity of our findings are maintained.
One of the significant concerns with the use of hrHPV testing for primary cervical screening is the increased use of colposcopy services for women who are hrHPV positive. This is a particular concern, both from a systems perspective, with increased cost and unnecessary use of colposcopy, and from an individual perspective, because of the unintended negative consequences of ablative treatment on future fertility and reproductive outcomes (Kyrgiou et al, 2006
). Thus, the careful monitoring of colposcopy referral patterns in each arm is essential. In British Columbia, because there is a highly standardised colposcopy programme, this facilitates standardised measurement, with reasonable confidence, the impact of the actual screening tool (hrHPV vs
cytology) on referral patterns to colposcopy. Colposcopy referral rates were similar in both the HPV and control arm at baseline screening, but as a result of the follow-up of hrHPV-positive/cytology-negative women, the colposcopy referral rate increased substantially overall.
Although LBC was initially promoted as offering improved sensitivity and disease detection compared with conventional cytology, this has not been consistently supported by the published literature (Ronco et al, 2007
; Siebers et al, 2009
). Nonetheless, LBC collection is widely used, and offers an important advantage as it supports both hrHPV DNA testing and cytology from a single sample. Authors have noted that one reason for reluctance to switch to hrHPV screening may be that the previous clinical trials comparing hrHPV testing and cytology used conventional Pap smears, as opposed to LBC, and thus the benefits of HPV testing may have been over-estimated (Castle, 2010
). The HPV FOCAL study offers an important opportunity to compare hrHPV testing against LBC, and will help to inform this important discussion. Liquid-based cytology also offers other benefits compared with conventional smears for HPV-based primary cervical cancer screening. Women can simply have one specimen taken, and reflex testing can be done on the specimens, avoiding the need for either a repeat visit or dual specimen collection. In addition, liquid-based specimens could provide opportunities for other testing, such as cervical cancer biomarkers and sexually transmitted infections.
The HPV FOCAL study has particular methodological strengths that warrant consideration and position the study to offer key guidance for cervical cancer screening recommendations. This study is based in British Columbia, where cervical cancer screening, follow-up and care are all organised through one centralised provincial agency, the BC Cancer Agency. All Pap smears are read at one centralised laboratory, with high-quality assurance and standardised cytology interpretation and recommendations for care. The HPV FOCAL participants are drawn from a broad base of family practices. For HPV FOCAL, all colposcopies are conducted at BC Cancer Agency referral centres, and colposcopy care is founded in well-established care protocols, offering even further standardisation and minimising heterogeneity in colposcopy interpretation, recommendations and management for all participants in the HPV FOCAL trial. Finally, all histological specimens are analysed at two pathology sites, both of which are experienced cancer referral centres in the province. Pathologists are blinded to the screening results at the time of interpretation of histology specimens. The highly organised nature of screening and post-screening disease diagnosis and management in British Columbia are a particular strength of HPV FOCAL. Recommendations were made for future cervical cancer screening trials to ensure similar delivery of colposcopy, and the HPV FOCAL trial has achieved this owing to the organisational structure of cervical cancer screening in British Columbia (Whitlock et al, 2011
The protocol of HPV FOCAL is closely aligned with proposed EUROGIN screening algorithm, which outlines the future of cervical cancer screening for developed countries (Franco and Cuzick, 2008
; Franceschi et al, 2009
). The HPV FOCAL study is well positioned to determine the utility of this proposed approach and to provide evidence for cervical cancer screening guidelines internationally, and further data from completed Round 1 and Round 2 of screening will validate the potential impact of hrhPV on cervical cancer prevention in organised screening programs.