Cervical cancer is one of the few cancers where screening can detect precancerous cell growth. These abnormalities can be treated, preventing the development of cancer.
In Australia, the National Cervical Screening Program (NCSP) using the Pap test began in 1991. Since then, Australia’s cervical cancer incidence and death rates have halved. On 1 December 2017, the Pap test was replaced by HPV DNA testing with partial genotyping as part of the renewed NCSP.
The implementation of the HPV vaccination program has significantly reduced the average lifetime risk of cervical cancer of the vaccinated cohort. Despite the efficacy of the vaccine against the high-risk HPV types that cause most cervical cancers, cervical screening remains critical in cervical cancer prevention. The vaccine is not effective against existing HPV infections and does not protect against all high-risk HPV types, meaning a significant proportion of cervical cancers will not be prevented.
The NCSP has been renewed to reflect the latest evidence. The NCSP Renewal evaluation assessed the evidence for screening tests and pathways, the screening interval, age range and commencement for both vaccinated and non-vaccinated women, to determine an optimal screening pathway and program model.
Screening age range and intervals
A substantial body of evidence has found that screening in women younger than 25 years of age has little or no impact on the risk of developing invasive cancer. In 2005, the International Agency for Research on Cancer (IARC) recommended that regular cervical screening begin at age 25 as the benefits were outweighed by the potential harms for women aged under 25 years. This is reflected in the renewed NCSP which recommends that screening start at the age of 25. Cervical cancer in women under 25 years was very rare in Australia even prior to HPV vaccination. In the post-vaccination era it is expected that the risk of cancer in women aged under 25 years will be even lower.
The renewed NCSP recommends that screening takes place at an interval of five years, this is primarily due to recommendations to use HPV DNA testing at the primary screening tool, in place of Pap tests.The recommended screening age endpoint has been extended and it is recommended that women should have an exit test between 70 and 74 years of age.
Impact of HPV vaccination on screening
As successive cohorts of adolescents are vaccinated, and as vaccinated cohorts mature, the risk of cervical cancer decreases. Prophylactic HPV vaccination is expected to eliminate high-grade intraepithelial lesions and cancers attributable to HPV 16 and 18. Removing the most common and most dangerous (and more cytologically-apparent) cervical abnormalities – and leaving behind the more equivocal ones – will reduce the positive predictive value of cytology. In the era of HPV vaccination, as the population prevalence of HPV 16 and 18 falls, different screening tests and technologies have been shown to be better.
From 2018, a second-generation prophylactic HPV vaccine (Gardasil9) will be offered through the National HPV Vaccination Program. It will protect against five additional HPV types, and in total against HPV types associated with approximately 90% of cervical cancers in Australia.
Screening will remain necessary, even for vaccinated women. The vaccine does not protect against all HPV types that can lead to cervical cancer and may not be effective in women exposed to HPV prior to vaccination. It will take many years for the impact of the vaccine to reduce the incidence of invasive cervical cancer in women in middle age and beyond. In the longer term women vaccinated with second-generation vaccines may not need to be screened as frequently.
New screening technologies used in the renewed NCSP
In the past decade, a desire to improve the accuracy and reliability of cervical screening and an increased understanding about the role of HPV in cervical cancer has led to the development of new cervical screening technologies, outlined in this section.
HPV DNA testing
Due to the relationship between persistent infection with high-risk types of HPV and the development of cervical cancer, testing for the presence of (high-risk) HPV DNA in cervical cell specimens can identify women at increased risk of developing cervical cancer. Women who test HPV-negative are at very low risk for CIN3 and cancer for at least five years. For women who are cytology-negative but HPV-positive, HPV 16-positive or HPV 16/18-positive results are associated with medium-term risk of CIN3 or cancer.
Primary cervical screening
A large body of evidence, including data from randomised trials in developed countries, has shown HPV testing in primary screening is superior to cytology. Analysis of four European randomised controlled trials found that, compared with cytology, HPV-based screening provided 60–70% greater protection against invasive cervical cancers. HPV DNA testing in cervical screening detects high-grade lesions more accurately, thus allowing them to be treated and preventing more invasive cervical cancers.
HPV DNA testing has greater sensitivity, but lower specificity for high-grade abnormalities, compared with cytology, and better reproducibility. Because of its high sensitivity and objectivity, HPV DNA testing has replaced the Pap test as the primary screening test in the renewed NCSP.
Concerns about overdiagnosis with HPV testing have been raised because of its lower cross-sectional specificity for high-grade disease, when compared to cytology. However, this is being managed through triage of HPV-positive women with partial genotyping and reflex liquid-based cytology, so that women are managed on the basis of whether HPV types 16/18 or other HPV types are present. Overdiagnosis is further reduced by starting screening at 25 years of age.
The modelled evaluation that informed the renewal of the NCSP predicted that the updated screening program and clinical management guidelines to use HPV testing would decrease cervical cancer incidence by 24–31% and cervical cancer mortality by 29–36% over the longer term, compared with screening with the Pap test and that it would avert approximately 2000 cancer cases and 587 cancer deaths over the period 2018– 2035.
Since July 2006, HPV DNA testing has been recommended in Australia for use in women following treatment of a high-grade abnormality. The test is used to determine whether the virus has been cleared and whether women can thus be discharged back to routine screening.
Liquid-based cytology is a technique where the cervical cells collected on the sampling instruments are suspended in liquid. At the laboratory the liquid sample is filtered to remove unnecessary material such as blood, bacteria and other matter. The cells are then deposited as a single layer onto a slide, stained and examined under a microscope.
In 2009 MSAC reviewed liquid-based cytology as a primary test – both automated and with manual reading – and concluded that both were safe and at least as effective as conventional Pap tests, but "not cost effective at the price requested." The evidence suggests that there is no substantial difference between manually read liquid-based cytology and conventional cytology in sensitivity for high-grade disease. However, MSAC reported that two medium-quality Australian studies have found image read liquid-based cytology (using the ThinPrep Imager system) identified more histologically confirmed CIN2+ lesions than conventional cytology.
Liquid-based cytology is used in the renewed NCSP to triage HPV-positive women. Using liquid-based cytology to triage women reduced referrals to colposcopy in comparison to HPV DNA testing alone. This liquid-based cytology triage should increase specificity of primary HPV screening and minimise unnecessary follow-up procedures and potential harms (overdiagnosis).
Studies show self-collected cervicovaginal samples show promising performance, with sensitivity that may approach that of physician-collected samples for HPV detection, supporting the potential use of self-collection in primary cervical cancer screening.
The NCSP Renewal evaluation found that HPV self-collection has a moderate-high sensitivity and comparably high specificity for detecting CIN2+, compared to clinic HPV testing. A subsequent meta-analysis has shown that the accuracy of HPV testing on self-collected sample is unaffected by the sample collection device, but does vary depending on the HPV test technology used. HPV DNA tests performed using validated PCR-based assays were found to be “as accurate on self-collected samples as on clinician-collected samples”, whereas signal-based HPV tests were less accurate. Consequently, only validated PCR-based assays are to be used in Australian for HPV DNA testing on self-collected samples.
Self-sampling is highly accepted by women, including women in Australia with studies reporting most women found self-collection devices easy to use, time saving, less embarrassing and more comfortable.
Self-sampling could increase participation by women who do not participate in current screening programs. Randomised controlled trials and cohort studies in other developed countries have shown that offering self-sampling to women who did not attend regular screening increases participation significantly.
Self-sampling can supplement the organised screening program for under-screened and unscreened women and, by enabling screening, could substantially reduce cervical cancer risk in these women. To ensure that the safety and efficacy of self-sampling, the test should only be provided in conjunction with patient counselling and clinical interpretation of results, patient follow-up for positive results when required and testing in a safe environment with infection control procedures. In the renewed NCSP, HPV testing on a self-collected sample may be offered to women aged 30 or older who have never been screened or are two or more years overdue.
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