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

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Background

In women who have been treated for a high-grade squamous lesion (HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (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 LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. and testing for oncogenic HPV types (co-testHPV test and LBC both requested and performed on a cervical sample.) is used as a Test of Cure following treatment of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2/3), based on the high negative predictive value of the co-testHPV test and LBC both requested and performed on a cervical sample. 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 (NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears.) Safety Monitoring Committee[7] demonstrated that, in women aged 20–69 previously treated for a high-grade CINCervical Intraepithelial NeoplasiaRefers to abnormal changes in the cells on the surface of the cervix that are seen using a microscope (i.e. histologically-confirmed).CIN 1 – Mild dysplasiaCIN 2 – Moderate dysplasiaCIN 3 – Severe dysplasia to carcinoma in situ(The term CIN 2+ refers to CIN 2, 3, or invasive cervical cancer; CIN3+ refers to CIN 3 or invasive cervical cancer)CIN 2/3 refers to CIN 2 or CIN 3., 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 LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. was reported negative (negative co-testHPV test and LBC both requested and performed on a cervical sample.). 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 NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. 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 HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). based on a negative co-testHPV test and LBC both requested and performed on a cervical sample. 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 HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (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-testHPV test and LBC both requested and performed on a cervical sample. and following two negative co-tests. 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-testHPV test and LBC both requested and performed on a cervical sample. (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-testHPV test and LBC both requested and performed on a cervical sample. at 6 and 24 months post treatment, when compared with a negative co-testHPV test and LBC both requested and performed on a cervical sample. 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-testHPV test and LBC both requested and performed on a cervical sample. 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-testingHPV test and LBC both requested and performed on a cervical sample. performed at 12 months after treatment and annually thereafter. When a woman undergoing annual co-testingHPV test and LBC both requested and performed on a cervical sample. has had a negative co-testHPV test and LBC both requested and performed on a cervical sample. 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

ToC following tx for HGS abnormalities.PNG








Consensus-based recommendationQuestion mark transparent.png

REC10.7: Test of Cure after treatment for HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2/3)
A woman who has been treated for HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2/3) should have a co-testHPV test and LBC both requested and performed on a cervical sample. performed at 12 months after treatment, and annually thereafter, until she receives a negative co-testHPV test and LBC both requested and performed on a cervical sample. on two consecutive occasions, when she can return to routine 5 yearly screening.

Co-testingHPV test and LBC both requested and performed on a cervical sample. can be performed by the woman’s usual healthcare professional.

Consensus-based recommendationQuestion mark transparent.png

REC10.8: Abnormal Test of Cure results: positive oncogenic HPV (16/18)Women with a positive HPV test result of HPV types 16 and/or 18 detected using routine HPV testing in a pathology laboratory. test result
If, at any time post treatment, the woman has a positive oncogenic HPV (16/18)Women with a positive HPV test result of HPV types 16 and/or 18 detected using routine HPV testing in a pathology laboratory. test result, she should be referred for colposcopic assessment (regardless of the reflex LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. result).

Consensus-based recommendation*Question mark transparent.png

REC10.9: Abnormal Test of Cure results: LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. pHSILPossible HSIL in the Australian Modified Bethesda System is broadly equivalent to ASC-H in US Bethesda system./HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). or glandular abnormality
If, at any time during Test of Cure, the woman has a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of pHSILPossible HSIL in the Australian Modified Bethesda System is broadly equivalent to ASC-H in US Bethesda system./HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). or any glandular abnormality, irrespective of HPV status, she should be referred for colposcopic assessment.

Consensus-based recommendationQuestion mark transparent.png

REC10.10: Abnormal Test of Cure results: positive oncogenic HPV (not 16/18)Women with a positive HPV test result of other oncogenic HPV types other than types 16 and 18 detected using routine HPV testing in a pathology laboratory. test result
If, at any time post-treatment, the woman has a positive oncogenic HPV (not 16/18)Women with a positive HPV test result of other oncogenic HPV types other than types 16 and 18 detected using routine HPV testing in a pathology laboratory. test result and a LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. report of negative or prediction of pLSILPossible LSIL in the Australian Modified Bethesda System is broadly equivalent to ASCUS in US Bethesda system./LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category., she should continue to have annual co-testingHPV test and LBC both requested and performed on a cervical sample. until the she has a negative co-testHPV test and LBC both requested and performed on a cervical sample. on two consecutive occasions, when she can return to routine 5-yearly screening.

Practice pointQuestion mark transparent.png

REC10.11: Fluctuating Test of Cure results: positive oncogenic HPV (not 16/18)Women with a positive HPV test result of other oncogenic HPV types other than types 16 and 18 detected using routine HPV testing in a pathology laboratory. test result and/or pLSILPossible LSIL in the Australian Modified Bethesda System is broadly equivalent to ASCUS in US Bethesda system./LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category.
Some women may experience fluctuating results with a positive oncogenic HPV (not 16/18)Women with a positive HPV test result of other oncogenic HPV types other than types 16 and 18 detected using routine HPV testing in a pathology laboratory. test result and/or LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory. prediction of pLSILPossible LSIL in the Australian Modified Bethesda System is broadly equivalent to ASCUS in US Bethesda system./LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category.. These women do not need colposcopic review but, if the woman is anxious, a colposcopic assessment may be appropriate to provide reassurance.

Practice pointQuestion mark transparent.png

REC10.12: ColposcopyThe examination of the cervix and vagina with a magnifying instrument called a colposcope, to check for abnormalities. 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 NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears. 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 LBCLiquid based cytology(LBC) is a way of preparing cervical samples for examination in the laboratory..

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.

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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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23117059.
  2. 2.02.12.2 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 Abstract available at 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 Abstract available at 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 Abstract available at 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 Abstract available at 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17959735.
  7. 7.07.1 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: AIHWAustralian Institute of Health and Welfare; 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24981084.
  10. 10.010.1 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24769656.
  11. 11.011.1 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 Abstract available at 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18503572.
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Appendices

Jutta's magnifying glass icon.pngPICO question 16 View Systematic review report q 16View Systematic review report q 16 View General evidence summary table q 16View General evidence summary table q 16
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