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Cervical cancer screening

Test of Cure after treatment for HSIL (CIN2/3)

Clinical question

GUIDELINE UPDATES - This guideline was last updated 7/1/2022

Background

In women who have been treated for a high-grade squamous lesion (HSIL (CIN2/3)) the risk of recurrence and invasive cervical cancer remains elevated for 10–25 years[1][2][3][4][5][6] highlighting the importance of continued post-treatment surveillance to detect residual or recurrent disease. In Australia, the combination of LBC and testing for oncogenic HPV types (co-test) is used as a Test of Cure following treatment of HSIL (CIN2/3), based on the high negative predictive value of the co-test in detecting women at risk of recurrence. However, there has been some uncertainty regarding the length of time required for a women to be considered as cured and safe to return to the screening intervals recommended for the general population. 

Data published in the Report on monitoring activities of the National Cervical Screening Program (NCSP) Safety Monitoring Committee[7] demonstrated that, in women aged 20–69 previously treated for a high-grade CIN, the incidence of a subsequent high-grade lesion was very low, and there were no incidents of subsequent cervical cancer, following two consecutive occasions on which oncogenic HPV was not detected and LBC was reported negative (negative co-test). This holds true in more recent analyses of these data, which similarly show a low rate of subsequent high-grade lesions and no instances of cervical cancer following two consecutive negative co-tests.[8] These data support the effectiveness of two negative consecutive co-tests as Test of Cure,[7] as recommended in pre-renewal NCSP guidelines.

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Evidence

Systematic review evidence

A systematic review was performed to identify studies evaluating the safety and effectiveness of discharging women previously treated for HSIL based on a negative co-test at 12 months versus 12 and 24 months. No randomised or pseudorandomised studies were found.

General literature review evidence

In the absence of any direct evidence from the systematic review, a general review of the literature was performed on the use of HPV testing and cytology in the follow-up of women treated for HSIL (CIN2/3).

Five recent articles were found [9][10][11][2][12] of which three were directly relevant, reporting 5-year risks of recurrent high grade CIN following one negative co-test and following two negative cotests. Katki et al estimated a lower 5-year risk of recurrent CIN2+ for two negative co-tests (1.5%) when compared with one negative co-test (2.4%) (p=0.8). However, the authors stated that estimates were based on small numbers and therefore subject to considerable uncertainty.[11] These findings were in agreement with reports from a Dutch study[10][2] of lower 5- year cumulative risks of CIN2+ and CIN3+ disease for a negative co-test at 6 and 24 months post treatment, when compared with a negative co-test at 6 months post treatment. In this study, the 5-year cumulative risk of CIN2+ was 1.0 (0.2–4.6) and of CIN3+ was 0.0 (0.0–2.9) following a negative co-test at 6 and 24 months. 

Based on the evidence from these two studies, women who have been treated for high-grade squamous lesions should have co-testing performed at 12 months after treatment and annually thereafter. When a woman undergoing annual co-testing has had a negative co-test on two consecutive occasions, she can return to routine screening.

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Recommendations

Flowchart 10.1. Test of Cure following treatment for high-grade squamous abnormalities

Consensus-based recommendation
REC10.7: Test of Cure after treatment for HSIL (CIN2/3)
A woman who has been treated for HSIL (CIN2/3) should have a co-test† performed at 12 months after treatment, and annually thereafter, until she receives a negative co-test on two consecutive occasions, when she can return to routine 5 yearly screening.

†Co-testing can be performed by the woman’s usual healthcare professional.
Consensus-based recommendation
REC10.8: Abnormal Test of Cure results: positive oncogenic HPV (16/18) test result
If, at any time post treatment, the woman has a positive oncogenic HPV (16/18) test result, she should be referred for colposcopic assessment (regardless of the reflex LBC result).
Consensus-based recommendation*
REC10.9: Abnormal Test of Cure results: LBC pHSIL/HSIL or glandular abnormality
If, at any time during Test of Cure, the woman has a LBC prediction of pHSIL/HSIL or any glandular abnormality, irrespective of HPV status, she should be referred for colposcopic assessment.
Consensus-based recommendation
REC10.10: Abnormal Test of Cure results: positive oncogenic HPV (not 16/18) test result
If, at any time post-treatment, the woman has a positive oncogenic HPV (not 16/18) test result and a LBC report of negative or prediction of pLSIL/LSIL, she should continue to have annual co-testing until the she has a negative co-test on two consecutive occasions, when she can return to routine 5-yearly screening.
Practice point
REC10.11: Fluctuating Test of Cure results: positive oncogenic HPV (not 16/18) test result and/or pLSIL/LSIL
Some women may experience fluctuating results with a positive oncogenic HPV (not 16/18) test result and/or LBC prediction of pLSIL/LSIL. These women do not need colposcopic review but, if the woman is anxious, a colposcopic assessment may be appropriate to provide reassurance.
Practice point

REC10.12: Colposcopy is not necessary at the initial post-treatment visit
A post-treatment colposcopic assessment at 4–6 months has been the usual practice under pre-renewal NCSP guidelines. This practice is not evidence-based, but may provide reassurance to both the patient and clinician regarding the visual appearance of the cervix and allows for the discussion of any other relevant issues (bleeding, fertility, related symptoms etc.) following treatment.

The post-treatment review should:

  • include speculum examination of the vagina and cervix (but colposcopy is not considered necessary)
  • not involve HPV testing or LBC.

Subsequent post-treatment Test of Cure surveillance should be performed by the woman’s GP or health professional, who should follow the recommendations for the management of any abnormal test results.

Author(s):

References

  1. Rebolj M, Helmerhorst T, Habbema D, Looman C, Boer R, van Rosmalen J, et al. Risk of cervical cancer after completed post-treatment follow-up of cervical intraepithelial neoplasia: population based cohort study. BMJ 2012 Oct 31;345:e6855 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23117059.
  2. Kocken M, Helmerhorst TJ, Berkhof J, Louwers JA, Nobbenhuis MA, Bais AG, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol 2011 May;12(5):441-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21530398.
  3. Melnikow J, McGahan C, Sawaya GF, Ehlen T, Coldman A. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the British Columbia Cohort Study. J Natl Cancer Inst 2009 May 20;101(10):721-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19436026.
  4. Soutter WP, Sasieni P, Panoskaltsis T. Long-term risk of invasive cervical cancer after treatment of squamous cervical intraepithelial neoplasia. Int J Cancer 2006 Apr 15;118(8):2048-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16284947.
  5. Kalliala I, Anttila A, Pukkala E, Nieminen P. Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia: retrospective cohort study. BMJ 2005 Nov 19;331(7526):1183-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16293840.
  6. Strander B, Andersson-Ellström A, Milsom I, Sparén P. Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study. BMJ 2007 Nov 24;335(7629):1077 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17959735.
  7. Australian Institute of Health and Welfare. Report on monitoring activities of the National Cervical Screening Program Safety Monitoring Committee. Cancer series 80. Cat. no. CAN 77. Canberra: AIHW; 2013 Available from: http://www.aihw.gov.au/publication-detail/?id=60129545158).
  8. Australian Institute of Health and Welfare. AIHW analysis of state and territory cervical screening register data. Unpublished; 2014.
  9. Morrell S, Qian L. A whole-population profile of HPV testing as a test of cure for high-grade cervical dysplasia in NSW, Australia. J Med Screen 2014 Sep;21(3):151-62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24981084.
  10. Uijterwaal MH, Kocken M, Berkhof J, Bekkers RL, Verheijen RH, Helmerhorst TJ, et al. Posttreatment assessment of women at risk of developing high-grade cervical disease: proposal for new guidelines based on data from the Netherlands. J Low Genit Tract Dis 2014 Oct;18(4):338-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24769656.
  11. Katki HA, Schiffman M, Castle PE, Fetterman B, Poitras NE, Lorey T, et al. Five-year risks of CIN 3+ and cervical cancer among women with HPV-positive and HPV-negative high-grade Pap results. J Low Genit Tract Dis 2013 Apr;17(5 Suppl 1):S50-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23519305.
  12. Kitchener HC, Walker PG, Nelson L, Hadwin R, Patnick J, Anthony GB, et al. HPV testing as an adjunct to cytology in the follow up of women treated for cervical intraepithelial neoplasia. BJOG 2008 Jul;115(8):1001-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18503572.

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