FROM GUIDELINES TO PRACTICE:
NEW INSIGHTS IN
CERVICAL CANCER SCREENING
CURRENT CERVICAL CANCER SCREENING GUIDELINES
The American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) recommend the following:1
- Women should begin cervical cancer screening at 21 years of age
- Women 21 to 29 years old should be screened with Pap testing alone every 3 years
- Women age 30 to 65 years should be screened with Pap testing plus human papillomavirus (HPV) testing (co-testing) every 5 years or Pap testing alone every 3 years
- Women with adequate negative prior screening should discontinue screening after age 65
While interim guidance suggesting intervals for use of screening with HPV alone has been published, primary HPV screening, also referred to as HPV alone* in this document, is not currently recommended by major societies, as 2015 guidelines from the American College of Physicians include only Pap testing and co-testing as recommended strategies2,3
Pap plus HPV testing is the preferred cervical cancer screening method for women 30 to 65 years old
*A positive HPV screening result may lead to further evaluation with cytology and/or colposcopy.
1. Saslow D, et al. CA Cancer J Clin.2012;62:147-72.
2. Huh WK, et al. GynecolOncol.2015;136:178-82.
3. SawayaGF, et al. Ann Intern Med.2015;162:851-9.
RECOMMENDATION: Screening with Pap Plus HPV Together (Co-testing) Should Remain the Preferred Method of Screening for Women 30 to 65 Years of Age
- Co-testing detects more precancerous lesions (cervical intraepithelialneoplasia and worse, CIN3+) than screening with HPV alone1,2
- In a study of more than a million women, the risk of developing CIN3+ within 3 years of screening was 29% lower in women who were co-test negative vs women who tested HPV negative (Figure A)1
- In 7 European studies, CIN3+ was later detected in 24% fewer women who were co-test negative compared with women who tested negative for HPV at baseline screening over a 6-year follow-up period2
Pap testing plus HPV testing together is more sensitive for detecting precancerous lesions than screening with HPV alone1
1. Graph adapted from: Gage JC, et al. J Natl Cancer Inst.2014;106(8). pii: dju153.
2. Dillner J, et al.BMJ.2008;337:a1754.
Screening with Pap plus HPV Together (Co-testing) Provides Greater Reassurance against Cervical Cancer than Screening with HPV alone
- Studies have consistently shown that screening with HPV alone misses more cases of cervical cancer than screening with co-testing1-7
- A study of over a million women in the Kaiser Permanente Health System found that, among 405 cases of cervical cancer detected during the study, 18.8% were HPV negative compared with 12.3% that were co-test negative1
- Investigation of screening results from over 250,000 women in the Quest Diagnostics Health Trends study found that, among 526 women with cancer, 18.6% tested negative for HPV less than 1 year prior to cancer detection, while only 5.5% were co-test negative less than 1 year before diagnosis (Figure A)2
- Several studies have reported similar results, with HPV testing alone failing to detect between 9% and 31% of cervical cancer cases (Figure B)1,3-7
1. Gage JC, et al. J Natl Cancer Inst. 2014;106. pii: dju153.
2. Graph adapted from: Blatt AJ, et al. Cancer Cytopathol. 2015;123:282-8.
3. Katki HA, et al. Lancet Oncol.2011;12:663-72.
4. Zhao Y, et al. J Med Virol.2012;84:1920-7.
5. Zhao C, et al. Am J ClinPathol.2013;140:47-54.
6. Zhao C, et al. Arch Pathol Lab Med.2014.
7. Hopenhayn C, et al. J Low Genit Tract Dis.2014;18:182-9.
Additional Benefits of Pap Testing
- In the Quest Diagnostics Health Trends study, among 169 adenocarcinomas detected, 26.6% were HPV negative less than one year prior to diagnosis compared with 8.3% that were co-test negative 1
- Levels of HPV L1 DNA decrease as cancer progresses, suggesting that advanced cervical diseases could be missed with an L1 DNA HPV (Figure A)2
Detecting adenocarcinoma and providing additional reassurance are among the additional benefits conferred by Pap plus HPV testing together1,2
1. Blatt AJ, et al. Cancer Cytopathol.2015;123:282-8.
2. Tjalma WA, et al. Eur J Obstet Gynecol Reprod Biol.2013;170:45-6.
3. “Ralf Hilfrich (2013). HPV L1 Detection as a Prognostic Marker for Management of HPV High Risk Positive Abnormal Pap Smears, Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective, Dr. Davy VandenBroeck (Ed.), InTech, DOI: 10.5772/55902. Available from: http://www.intechopen.com/books/humanpapillomavirus- and-related-diseases-from-bench-tobedside-a-diagnostic-and-preventive-perspective/hpv-l1-detection-as-a-prognostic-marker-for-management-of-hpv-high-risk-positive-abnormal-pap-smears”
RECOMMENDATION: Pap Testing every 3 Years Should Remain the Primary Screening Strategy for Women 21 to 29 Years of Age
- Cervical cancer is associated with persistent HPV infections. In young women who have recently become sexually active, the rate of HPV infection is high, but the large majority of those infections clear on their own (Figure A)1,2
- Women under age 30 are unlikely to develop cervical cancer (Figure B)3, and overtreatment of these women may represent a clinical concern because treatment of cervical lesions can be associated with pregnancy complications such as preterm birth4, 5
- Positive HPV results have been associated with increased anxiety shortly after testing6 and can result in women reporting worse feelings about their previous and future sexual relationships7
- The New Technologies for Cervical Cancer study found that screening with HPV alone resulted in overdiagnosis of cervical lesions in women 25 to 34 years old8
- In 2012, the ACS, ASCCP, and ASCP recommended that, “because of the high prevalence of HPV in women under the age of 30, HPV testing should not be used to screen women in this age group due to the potential harms” 9
1. Rodriguez AC, et al. J Natl Cancer Inst.2008;100:513-7.
2. Markowitz LE, et al. J Infect Dis.2013;208:385-93.
3. National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) Cancer Stats 2000-2006. Bethesda, MD: National Cancer Institute; 2015. 4. Kitson SJ, et al. Eur J ObstetGynecolReprod Biol.2014;180:51-5.
5. Miller ES, et al. AJOG. 2014;211(3):242 e1-4.
6. McCaffery KJ, et al. BMJ.2010;340:b4491.
7. McCaffery K, et al. BJOG.2004;111:1437-43.
8. Ronco G, et al. Lancet.2014;383:524-32.
9. Saslow D, et al. CA Cancer J Clin.2012;62:147-72.
10. National Cancer Institute. Cervix Uteri Cancer. http://seer.cancer.gov/statfacts/html/cervix.html. Accessed March30, 2016.
RECOMMENDATION: The Interval for Screening Women over 30 with Pap plus HPV Together (Co-testing) should be Changed from 5 Years to 3 Years
- A model of the outcomes associated with various cervical cancer screening strategies published by the United States Preventative Services Task Force in 2013 found that lengthened screening intervals may result in appreciable increases in cervical cancer cases1
- Lengthening screening intervals from 3 years to 5 years is estimated to double cervical cancer cases (Figure A), with an additional 1/369 women in the United States being diagnosed with cervical cancer using a 5-year interval1,2
Lengthening screening intervals from 3 to 5 years may substantially increase cervical cancer cases and deaths1-3
1. Kinney W, et al. ObstetGynecol.2015;125:311-5
2. KulasingamSL, et al. J Low Genit Tract Dis.2013;17:193-202.
“SCREENING WITH HPV ALONE IS EASIER”
- The screening algorithm put forth by the interim guidance document is complicated, confusing, and invites more risk of disease than screening with Pap plus HPV together(Figure A)1
Current interim guidance for screening with HPV alone is complex and adherence may be a challenge
1. Huh WK, et al. Gynecol Oncol. 2015;136(2):178-82.
“PATIENTS WILL BE UNAFFECTED BY ADDITIONAL CHANGES IN CERVICAL CANCER SCREENING”
Screening with HPV Alone and Extended Screening Intervals Cause Patient Anxiety
Women may be resistant to changes in screening intervals and methodology associated with changes in cervical screening technology
1. Cooper CP, et al. Am J Prev Med.2015;49:e99-e107.
2. Silver MI, et al.ObstetGynecol.2015;125:317-29.
3. Giorgi Rossi P, et al. Front Oncol.2014;4:20.
4. O’Connor M, et al. BJOG.2014;121(11):1421-30.
5. Kitchener HC, et al. Int J Gynecol Cancer.2008;18:743-8.
"SCREENING WITH HPV ALONE IS CHEAPER"
One Screening Test is not more Cost-Effective than Two
- Several factors affect the relative costs of screening with HPV alone vs with Pap plus HPV together (co-testing):
- Test performance (sensitivity/specificity)
- Test costs
- Treatment costs
- A cost-effectiveness model comparing different cervical screening strategies found that an HPV-alone screening strategy that included genotyping for 2 highrisk strains, HPV 16/18, reduced costs with similar effectiveness to a co-testing strategy that did not include genotyping for HPV 16/181
- Further investigation of the cost-effectiveness of co-testing with HPV 16/18 genotyping compared with screening with HPV with HPV 16/18 genotyping alone found that co-testing provided greater clinical benefit at similar costs (Figure A)2
- Co-testing at 3 years vs 5 years
- Screening with an mRNA-based HPV test and liquid-based cytology, compared to HPV alone screening with a DNA-based test
1. Huh WK, et al. Appl Health Econ Health Policy.2015;13:95-107.
2. Felix J, et al. Journal of Women's Health. 2016 [epub ahead of print]
CERVICAL CANCER SCREENING: THE FUTURE
Summary of Recommendations
- Maintain Pap plus HPV together (co-testing) as the preferred method for cervical cancer screening in women ≥30 years old
- Change the interval for co-testing women ≥30 years old from every 5 years to every 3 years
- Recommend that women 21 years of age begin cervical cancer screening with Pap testing every 3 years and not begin HPV screening until ≥30 years old
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