Screening

From National Cancer Control Policy
Cervical cancer > Screening


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Screening

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[1]. 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.

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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[2][3]. 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[2]. This is reflected in the renewed NCSP which recommends that screening start at the age of 25[4]. 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[4].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.

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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[5][6]. 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 (Gardasil 9) will be offered through the National Immunisation Program. It will protect against five additional HPV types, and in total against HPV types associated with approximately 90% of cervical cancers in Australia[7].

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[8]. In the longer term women vaccinated with second-generation vaccines may not need to be screened as frequently.

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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[9][10]. 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[11].

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[12][13][14]. Analysis of four European randomised controlled trials found that, compared with cytology, HPV-based screening provided 60–70% greater protection against invasive cervical cancers[12]. HPV DNA testing in cervical screening detects high-grade lesions more accurately, thus allowing them to be treated and preventing more invasive cervical cancers[15][16][17].

HPV DNA testing has greater sensitivity, but lower specificity for high-grade abnormalities, compared with cytology[4][18][19][15], and better reproducibility[20]. 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[21].

Other applications

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[22].

Liquid-based cytology

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 smears, but "not cost effective at the price requested"[23]. The evidence suggests that there is no substantial difference between manually read liquid-based cytology and conventional cytology in sensitivity for high-grade disease[18][24][25]. 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[23].

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[26]. This liquid-based cytology triage should increase specificity of primary HPV screening and minimise unnecessary follow-up procedures and .potential harms (overdiagnosis).

HPV self-collection

Studies show self-collected cervicovaginal samples show promising performance, with sensitivity that may approach that of physician-collected samples for HPV detection[27], supporting the potential use of self-sampling in primary cervical cancer screening[28].

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[4]. A subsequent meta-analysis has shown that the accuracy of HPV testing on self-collected sample is unaffected by the sample collection device. 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[29] with studies reporting most women found self-sampling devices easy to use[30][29], time saving, less embarrassing and more comfortable[31][32][29].

Self-sampling could increase participation by women who do not participate in current screening programs[4][33]. 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[34][35][36][37][38][39].

Self-sampling can supplement the organised screening program for under-screened and unscreened women[4]. 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[4]. 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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References

  1. Australian Institute of Health and Welfare. Cervical screening in Australia 2011–2012. Canberra: AIHW; 2014. Report No.: Cancer series no.82. Cat. no. CAN 79. Available from: http://aihw.gov.au/publication-detail/?id=60129546865.
  2. 2.0 2.1 International Agency for Research on Cancer. IARC handbooks of cancer prevention: volume 10 - cervix cancer screening. Lyon: IARC Press; 2005 Available from: http://www.iarc.fr/en/publications/pdfs-online/prev/handbook10/HANDBOOK10.pdf.
  3. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data. BMJ 2009 Jul 28;339:b2968 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19638651.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Medical Service Advisory Committee. National Cervical Screening Program Renewal: Executive summary. Commonwealth of Australia; 2013 Nov. Report No.: MSAC application no. 1276. Available from: http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/754127911763F571CA257B8A001ADDC5/$File/WebAccessiblility_Combined_Executive_summary__Final_27Nov2013_SentToDoHA.pdf.
  5. Schiffman M. Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing. Cancer 2007 Jun 25;111(3):145-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17487850.
  6. Franco EL, Mahmud SM, Tota J, Ferenczy A, Coutlée F. The expected impact of HPV vaccination on the accuracy of cervical cancer screening: the need for a paradigm change. Arch Med Res 2009 Aug;40(6):478-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19853188.
  7. Brotherton JML, Tabrizi SN, Phillips S, Pyman J, Cornall AM, Lambie N, et al. Looking beyond human papillomavirus (HPV) genotype 16 and 18: Defining HPV genotype distribution in cervical cancers in Australia prior to vaccination. Int J Cancer 2017 Oct 15;141(8):1576-1584 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28677147.
  8. Bosch FX, Castellsagué X, de Sanjosé S. HPV and cervical cancer: screening or vaccination? Br J Cancer 2008 Jan 15;98(1):15-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18182975.
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  10. Joint European Cohort Study, Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ 2008 Oct 13;337:a1754 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18852164.
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  12. 12.0 12.1 Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014 Feb 8;383(9916):524-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24192252.
  13. Franceschi S, Denny L, Irwin KL, Jeronimo J, Lopalco PL, Monsonego J, et al. Eurogin 2010 roadmap on cervical cancer prevention. Int J Cancer 2011 Jun 15;128(12):2765-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21207409.
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  15. 15.0 15.1 New Technologies for Cervical Cancer screening (NTCC) Working Group, Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 2010 Mar;11(3):249-57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20089449.
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  17. Gage JC, Schiffman M, Katki HA, Castle PE, Fetterman B, Wentzensen N, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst 2014 Aug;106(8) Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25038467.
  18. 18.0 18.1 Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006 Sep 1;119(5):1095-101 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16586444.
  19. Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007 Nov 24;370(9601):1764-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17919718.
  20. Carozzi FM, Del Mistro A, Confortini M, Sani C, Puliti D, Trevisan R, et al. Reproducibility of HPV DNA Testing by Hybrid Capture 2 in a Screening Setting. Am J Clin Pathol 2005 Nov;124(5):716-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16203283.
  21. Lew JB, Simms KT, Smith MA, Hall M, Kang YJ, Xu XM, Caruana M, Velentzis LS, Bessell T, Saville M, Hammond I. ary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program. The Lancet Public Health 2017 Feb Abstract available at http://www.sciencedirect.com/science/article/pii/S2468266717300075.
  22. Department of Health and Ageing. New technologies for cervical screening. [homepage on the internet] Canberra: DoHA; 2008 May [cited 2013 Oct 8; updated 2011 May 17]. Available from: http://www.health.gov.au/internet/screening/publishing.nsf/Content/new-technology-policy.
  23. 23.0 23.1 Medical Services Advisory Committee. Automation-assisted and liquid-based cytology for cervical cancer screening. Canberra: Commonwealth of Australia; 2009 Mar. Report No.: MSAC application 1122. Available from: http://www.health.gov.au/internet/msac/publishing.nsf/Content/BAE45713D7D0FDEBCA257817001CB46D/$File/1122_MSAC_Assessment_Report.pdf.
  24. Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ 2007 Jul 7;335(7609):28 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17517761.
  25. Siebers AG, Klinkhamer PJ, Grefte JM, Massuger LF, Vedder JE, Beijers-Broos A, et al. Comparison of liquid-based cytology with conventional cytology for detection of cervical cancer precursors: a randomized controlled trial. JAMA 2009 Oct 28;302(16):1757-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19861667.
  26. Ogilvie GS, Krajden M, van Niekerk DJ, Martin RE, Ehlen TG, Ceballos K, et al. Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial -- the HPV FOCAL Study. Br J Cancer 2012 Dec 4;107(12):1917-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23169286.
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  28. Schmeink CE, Bekkers RL, Massuger LF, Melchers WJ. The potential role of self-sampling for high-risk human papillomavirus detection in cervical cancer screening. Rev Med Virol 2011 May;21(3):139-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21538664.
  29. 29.0 29.1 29.2 Sultana F, Mullins R, English DR, Simpson JA, Drennan KT, Heley S, et al. Women's experience with home-based self-sampling for human papillomavirus testing. BMC Cancer 2015 Nov 4;15:849 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26536865.
  30. Jones HE, Wiegerinck MA, Nieboer TE, Mol BW, Westhoff CL. Women in the Netherlands prefer self-sampling with a novel lavaging device to clinician collection of specimens for cervical cancer screening. Sex Transm Dis 2008 Nov;35(11):916-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18665020.
  31. Dzuba IG, Díaz EY, Allen B, Leonard YF, Lazcano Ponce EC, Shah KV, et al. The acceptability of self-collected samples for HPV testing vs. the pap test as alternatives in cervical cancer screening. J Womens Health Gend Based Med 2002 Apr;11(3):265-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11988136.
  32. Waller J, McCaffery K, Forrest S, Szarewski A, Cadman L, Austin J, et al. Acceptability of unsupervised HPV self-sampling using written instructions. J Med Screen 2006;13(4):208-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17217611.
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  34. Bais AG, van Kemenade FJ, Berkhof J, Verheijen RH, Snijders PJ, Voorhorst F, et al. Human papillomavirus testing on self-sampled cervicovaginal brushes: an effective alternative to protect nonresponders in cervical screening programs. Int J Cancer 2007;120(7): 1505-1510. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17205514.
  35. Gök M, Heideman DA, van Kemenade FJ, Berkhof J, Rozendaal L, Spruyt JW, et al. HPV testing on self collected cervicovaginal lavage specimens as screening method for women who do not attend cervical screening: cohort study. BMJ 2010 Mar 11;340:c1040 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20223872.
  36. Self-Sampling Study Working Group, Giorgi Rossi P, Marsili LM, Camilloni L, Iossa A, Lattanzi A, et al. The effect of self-sampled HPV testing on participation to cervical cancer screening in Italy: a randomised controlled trial (ISRCTN96071600). Br J Cancer 2011 Jan 18;104(2):248-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21179038.
  37. Szarewski A, Cadman L, Mesher D, Austin J, Ashdown-Barr L, Edwards R, et al. HPV self-sampling as an alternative strategy in non-attenders for cervical screening - a randomised controlled trial. Br J Cancer 2011 Mar 15;104(6):915-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21343937.
  38. Virtanen A, Anttila A, Luostarinen T, Nieminen P. Self-sampling versus reminder letter: effects on cervical cancer screening attendance and coverage in Finland. Int J Cancer 2011 Jun 1;128(11):2681-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20669228.
  39. Wikström I, Lindell M, Sanner K, Wilander E. Self-sampling and HPV testing or ordinary Pap-smear in women not regularly attending screening: a randomised study. Br J Cancer 2011 Jul 26;105(3):337-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21730977.

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