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Screening for cervical cancer l.jpg

Screening for cervical cancer

Human Papillomavirus DNA versus Papanicolaou Screening Tests for Cervical Cancer

Marie-Helene Mayrand, M.D., Eliane Duarte-Franco, M.D., Isabel Rodrigues, M.D., Stephen D. Walter, Ph.D., James Hanley, Ph.D., Alex Ferenczy, M.D. Sam Ratnam, Ph.D., Francois Coutlee, M.D., and Eduardo L. Franco, Dr.P.H., for Canadian Cervical Cancer Screening Trial Study Group NEJM. October 18, 2007.

Ivania Rizo

February 19, 2008


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Cervical Cancer

  • Second most common cause of cancer-related morbidity and mortality among women in developing countries

    - 371,200 new cases annually with a 50 percent mortality rate

  • Past 50 years: 75% decrease in incidence and mortality in developed countries due to Pap tests and the detection of precursor lesions and earlier-stage cancers

  • However in the US, invasive cervical cancer remains the cause of death for almost 4000 women each year, approximately 1.3% of cancer deaths in women.

  • Squamous cell carcinomas account for

    approximately 80 percent of cervical

    cancers and adenocarcinomas

    15 percent.


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Background

  • Risk factors include early onset of sexual activity, multiple sexual partners, smoking, and immunosuppression

  • Mean age of diagnosis of invasive cervical cancer is 47 in the US, and the incidence increases with age

  • Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in almost all cervical cancers


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Current Screening guidelines

  • Annual Pap testing approximately 3 years after

    onset of sexual activity or at age 21 ( ACS and USPSTF)

  • Cease screening after hysterectomy for benign conditions or after age 65 (USPSTF) or 70 ( ACS) in women with adequate recent screening, who are not otherwise at high risk of cervical cancer

  • Max screening interval should be 3 years, with more frequent screening at onset and in high-risk situations (HIV, prior dysplasia, chronic immunosuppression)


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Current Screening Guidelines

  • HPV testing as an adjunct to cervical cytology for screening is an acceptable strategy when used in women aged 30 years or older. Combined screening should only be done once every 3 years since combined tests have a high NPV (99-100%) for high grade lesions.

  • Preferred management of ASCUS in most situations is reflex HPV testing ( high risk types) on the original LBC specimen collected for Pap test

  • Women with positive ASC-H and LSIL tests should undergo colposcopy

  • Minimal follow up for high grade squamous intraepithelial lesion, atypical glandular cells, and AIS interpretations includes colposcopy and endocervical curettage


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Objective

  • To determine whether testing for DNA of oncogenic HPV is superior to the Pap test for cervical-cancer screening


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Participants

  • Women ages 30 – 69 years. Per Mayrand et al., the study was limited to women older than 30, since in sexually active women younger than 30 years, transient HPV infections are common, which gives HPV DNA testing an unacceptably low specificity in identifying cervical cancer precursors.

  • Women who sought screening tests for cervical cancer in any of 30 clinics in Montreal and St. John’s, Canada


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Currently being followed for a cervical lesion

Lack of cervix

Pregnant

Hx of cervical cancer

Undergone Pap testing in the previous year

Unable to provide consent

Exclusion Criteria


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Study design

  • Randomized, controlled trial

  • Participants were randomized 1:1 to 1 of 2 arms: the Pap screening arm or the HPV screening arm. Participants were blinded to arm allocation.

  • There was insufficient evidence regarding the efficacy of HPV DNA testing as a stand-alone screening test to withhold Pap cytology from women in the trial. Therefore, each arm included both tests and the authors randomized the order in which the test samples were collected.

  • A random sub sample of 10% of the women in St. John’s and 20% of the women in Montreal with negative index tests were invited to undergo colposcopy. Per Mayrant et al. this allows for correction of verification bias.

  • Cytotechnologists and cytopathologists were not aware of the patient’s status as participants in the study or HPV test results. Colposcopists and pathologists were not aware of the screening- test results.

  • Supported by a grant from the Canadian Institute of Health Research and partially by unrestricted grant from Merck Frosst Canada


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Outline of Study Design

Mayrand MH et al. Randomized controlled trial of human papillomavirus testing versus Pap cytology in the primary screening for cervical cancer precursors: design, methods, and preliminary accrual results of the Canadian Cervical Cancer Screening Trial. International Journal of Cancer 2006; 119:615-23


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Screening Tests

  • Conventional ( slide smear) Pap test- results reported according to the Bethesda System terminology

  • Results of ASCUS, AGC (atypical glandular cells), or worse were considered positive

  • Hybrid Capture 2 test ( HC2 probe B, Digene) was used for HPV testing and tested for the 13 high-risk HPV types most commonly associated with high-grade dysplasia and cancer

  • Positive HPV test if specimen had at least 1 pg of HPV DNA per milliliter


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Terminology Used in Reporting Cervical cytology

Bundrick et al. Screening for cervical cancer and initial treatment of patients with abnormal results from papanicolaou testing. Mayo clinic proceedings.2005; 80(8): 1063-1068.


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Screening Tests

  • Colposcopists followed standard protocol:

    - endocervical curettage

    - ectocervical biopsies of all abnormal-appearing cervical regions

    - at least one biopsy of normal-appearing ectocervical epithelium aiming at an aceto-white transformation zone

  • Biopsy first and then treatment afterwards if warranted


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Study Endpoint

Primary endpoint: Histological CIN2, CIN3, and cervical cancer

2 Case definitions:

  • Liberal definition: all cases of grade 2 or 3 CIN, adenocarcinoma in situ, or cervical cancers that were histologically confirmed on the basis of any of the histologic specimens

  • Conservative definition: met liberal criteria and in addition were confirmed in the LEEP specimen or confirmed on biopsy when ablation was done


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Statistical analysis

  • Differences in categorical data were assessed by Fisher’s test and the chi-square test

  • Differences in continuous data was assessed by Kruskal-Wallis test

  • Mayrand et. al. obtained verification in a random sample of participants with negative screening

  • Verification bias: caused by verification of the lesion only in participants with a positive result, can lead to overestimates of sensitivity


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Enrollment and Outcomes

Mayrand M et al. N Engl J Med 2007;357:1579-1588


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Characteristics of Participants According to Study Group and Center

Mayrand M et al. N Engl J Med 2007;357:1579-1588


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Results Center

  • According to the conservative definition: sensitivity of the Pap test (55.4%) was significantly lower than the sensitivity of the HPV test ( 94.6%, P=0.01)

  • Specificity of the Pap test after the correction for verification bias was 96.8% versus 94.1% in the HPV test ( P<0.001) using the conservative definition

  • Difference in corrected sensitivity between the liberal and the conservative definitions

  • There were 4 cases of high-grade intraepithelial neoplasia among participants in whom both screening tests were negative according to the liberal definition. According to conservative definition there were no cases. These 4 cases influenced how the authors extrapolated the occurrence of high-grade cervical intraepithelial neoplasia lesions among all women with negative tests. The authors state that this explains the difference in corrected sensitivity between the liberal and conservative definitions.

  • The results of the tests were not influenced by the order in which they were collected; therefore, the authors pooled the two groups to access different screening algorithms.


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Group-Specific Comparison of Pap and HPV Testing to Identify High-Grade Cervical Intraepithelial Neoplasia and Cancer

Mayrand M et al. N Engl J Med 2007;357:1579-1588


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Comparison of Pap Testing and HPV DNA Testing Using Combined Study Groups According to Different Positivity Thresholds and Test Combinations

Mayrand M et al. N Engl J Med 2007;357:1579-1588


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Discussion Study Groups According to Different Positivity Thresholds and Test Combinations

  • According to the CONSERVATIVE definition the HPV test was more sensitive (39.2 % difference) and only 2.7% less specific than Pap testing

  • Corrections for verification bias provided absolute rather than relative estimates

  • Per Mayrand et al. the protocol mandated endocervical curettage and biopsies in all participants who underwent colposcopy, therefore reducing the possibility of missing CIN. But the protocol reveals more indolent lesions that would probably be missed in routine colposcopy.

  • Per authors, the liberal definition detected lesions not routinely found in community screening and the conservative definition reduced overdiagnosis.

  • The authors believed that some of the specimens classified as CIN negative per LEEP but positive per cytology or colposcopy were false positives, due to misclassification of squamous metaplasia as cervical intraepithelial neoplasia.


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Weaknesses Study Groups According to Different Positivity Thresholds and Test Combinations

  • Outcome measure (conservative versus liberal outcome definitions) perhaps chosen after the fact

  • Alternative outcome measure such as “histologically verified, high-grade cervical intraepithelial neoplasia in either the colposcopically targeted biopsy specimen or the final excision.”

  • Negative HPV tests that were consequently positive on biopsy and negative on excision were interpreted as false positive results versus false negative results

  • Selection bias and inability to generalize results to the screening population

    - Exclusion of young women and pregnant women perhaps causes a bias against Pap tests and for HPV testing

    - Authors did state they excluded women under 30 because HPV DNA testing would result in low specificity


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Weaknesses Study Groups According to Different Positivity Thresholds and Test Combinations

  • Per Berkhof and Meijer, in order to reliably state the sensitivity of HPV tests, the sample size of women with two negative tests and histological verification needs to be larger.

  • They state that a very small number of positive CIN 2 or worse makes a big impact on the sensitivity of the HPV test.


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So what can we conclude? Study Groups According to Different Positivity Thresholds and Test Combinations

  • We are not ready to use HPV tests for primary screening.

  • Need rapid, simple, accurate , and affordable HPV tests

  • At this time, we may choose to use HPV DNA test as adjunct to cytology for screening women over 30 years of age and no more frequently than every 3 years.


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References Study Groups According to Different Positivity Thresholds and Test Combinations

  • Bundrick J, Cook D, Gostout B. Screening for Cervical Cancer and Initial Treatment of Patients With Abnormal Results From Papanicolaou Testing. Mayo Clinic Proceedings. 2005;80:1063-1068.

  • Lytwyn et al. Correspondence to Human Papillomavirus DNA versus Papancolaou Screening Tests for Cervical Cancer. 2008;358 (2): 641- 644.

  • Mayrand MH, Duarte-Franco E, Coutlee F, et al. Randomized controlled trial of human papillomavirus testing versus Pap cytology in the primary screening for cervical cancer precursors: design, methods and preliminary accrual results of the Canadian Cervical Cancer Screening Trial (CCCaST). Int J Cancer 2006;119:615-623.


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