24 June 2009
Cervical screening is offered to all women in the UK between the ages of 20 and 60 years, to allow early identification and treatment of pre-cancerous changes. It involves the removal of a small sample of cells from the cervix and their examination by cytology for any abnormalities. Previously, samples for cytological exam were prepared by directly spreading cells onto a glass slide (known as a PAP smear); however, the current method of choice is liquid based cytology (LBC). This involves placing the sampled cells in a pot of liquid, allowing the cells to be better preserved and making the test results more reliable. Cytological results are reported based on the level of cell abnormality and cervical intraepithelial neoplasia (CIN) level.
The main risk factor for cervical cancer is infection with certain sub-types of human papilloma virus (HPV), and indeed high risk HPV sub-types have been found to be present in almost all cervical cancers. Several studies have shown that human papilloma virus (HPV) testing is more sensitive than cytology in detecting high grade CIN, and could improve the efficacy of screening (see previous news). In the USA, HPV testing is approved for primary screening when co-testing with cytology. However, in the UK a Health Technology Assessment review carried out in 1999 concluded that further research was needed prior to its inclusion in primary screening.
A Randomised Trial In Screening To Improve Cytology – ARTISTIC trial began in 2001 with the aim of investigating if HPV testing added to the effectiveness of the cervical screening programme. As part of this study, investigators compared the effectiveness of LBC alone or with a HPV co-test in primary screening, and found that co-testing did not identify significantly more cases than LBC alone [Kitchener et al (2009) Lancet Oncol Jun 17 Epub ahead of print]. The trial involved 24 510 eligible women aged between 20 and 64 years in Greater Manchester, three quarters of whom were randomly assigned to a “revealed” group and were told the result of their HPV test, the rest were assigned to a “concealed” group and not told their HPV result. HPV positive women with negative cytology in the “revealed” group were offered colposcopy (examination of the cervix for abnormal areas) at 12 months and 24 months if they were still HPV positive. All women were invited for a second screening round 3 years later and the pre-cancerous lesion detection rates in the “revealed” and “concealed” groups were compared.
The study found that when screening involved both LBC and the HPV co-test there was a small but significant reduction in the detection of high grade CIN in the second round of screening. However, when the results of both rounds were combined, the LBC and HPV co-test did not appear to detect significantly more of the high grade CIN than LBC alone. This was similar to results in previous randomised trials comparing conventional cytology along with a HPV co-test and cytology alone.
The ARTISTIC trial will continue through to a third round of screening six years after enrolment in order to see if HPV screening could extend screening intervals in those women who are cytology and HPV negative and may consequently be at lower risk. The authors cautioned against a stand-alone HPV test for screening as it has low specificity (women under 30 frequently test positive) and a colposcopy for all these women would be impractical. In addition, they state that identification of sub-types will be important in order to identify HPV type-specific persistence and the long-term effects of the HPV16 and HPV18 vaccines, if a stand-alone test is used.
Comment: Vaccination against infection with HPV 16 or 18, the most common papilloma viruses that can cause cervical cancer, was recently introduced in the UK for girls aged 12-18, and it is expected that this programme will dramatically reduce the future incidence of disease. Meanwhile, whilst the benefits of HPV testing as part of current screening approaches remain unproven, it seems prudent to continue investigation into the best applications of the test as screening programmes evolve.