Opinion
VIEWPOINT
Karen Smith-McCune, MD, PhD Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco.
Viewpoint page 1029
Author Audio Interview at jamainternalmedicine .com
Corresponding Author: Karen SmithMcCune, MD, PhD, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, 2340 Sutter St, Room S229, San Francisco, CA 941431702 (kmccune @obgyn.ucsf.edu).
Choosing a Screening Method for Cervical Cancer Papanicolaou Testing Alone or With Human Papillomavirus Testing Screening for cervical cancer with the Papanicolaou (Pap) test has been remarkably successful at reducing the morbidity and mortality rates associated with this disease. The discovery that human papillomavirus (HPV) has an essential role in cervical carcinogenesis led to the development of molecular tests to measure the presence of HPV types associated with cancer. In 2012, screening guidelines were updated to incorporate HPV testing.1,2 According to these guidelines, women 21 to 29 years old should undergo screening with a Pap test every 3 years; HPV testing is not recommended owing to the high prevalence of HPV infection in this age group. Women older than 65 years who have had adequate prior screening and are at low risk for cervical cancer should no longer undergo screening. There are 2 options for screening in women 30 to 65 years old. The US Preventive Services Task Force (USPSTF) recommends that women in this age group undergo screening with a Pap test every 3 years or Pap-plus-HPV testing (cotesting) every 5 years.1 The American Cancer Society, the American Society of Colposcopy and Cervical Pathology, and the American Society of Clinical Pathology (ACS/ ASCCP/ASCP) recommend the same options, except they classify Pap-plus-HPV testing every 5 years as “preferred” and screening with Pap testing alone every 3 years as “acceptable.”2 The updated guidelines leave physicians and other clinicians with a question: is cotesting with Pap-plusHPV testing truly preferred over Pap testing alone (the ACS/ASCCP/ASCP recommendation), or are the options equivalent (the USPSTF recommendation)? The current state of knowledge suggests that clinicians should not automatically adopt cotesting as the preferred screening strategy for cervical cancer and should consider the individual patient’s values and perspectives when choosing a screening method. A well-established benefit of cotesting with Papplus-HPV testing is the negative predictive value of this method: if both results are negative, the risk of precancer or cancer is low enough that the interval between screenings can be safely extended to 5 years.1,2 However, HPV infection is common in sexually active women, and most HPV infections clear spontaneously and are not associated with precancerous changes.3 Thus, HPV testing inherently has low specificity, results in increased rates of colposcopy,4 and can lead to anxiety and overtreatment in women who test positive.1 A recent study found that HPV testing helps further reduce a woman’s risk of invasive cervical cancer compared with Pap testing alone.5 Cervical cancer, however, is rare in wellscreened populations. Testing for HPV requires addi-
jamainternalmedicine.com
tional resources, and the economic and societal effects of seeking to further reduce the incidence of cervical cancer have not been rigorously studied. Although screening with the Pap test has led to uncertainty regarding the clinical management of mild cervical abnormalities (eg, atypia and low-grade abnormalities), cotesting has led to a new type of ambiguity: a normal Pap test result with a positive HPV test result. This outcome occurs in 3% to 8% of women screened with cotesting2 and is as high as 11% in US women 30 to 34 years old.6 The ACS/ASCCP/ASCP guidelines acknowledge that optimal management of women with normal Pap test and positive HPV test results requires further research.2 One proposed strategy is to repeat cotesting in 1 year, allowing time for HPV infections to clear,2 but this may cause anxiety and uncertainty during the year of waiting. Another strategy is to test for the 2 HPV types that confer the highest risk of cancer (HPV-16 and HPV-18) and toperformcolposcopyifeitherofthesetypesisdetected.2 However, the optimal management of women who persistently test positive for HPV-16 or HPV-18 but have negative colposcopic results is unknown. Some may undergo unnecessary colposcopic examinations, biopsies, and treatments. Women who choose screening with cotesting should therefore be aware that this method can lead to increased surveillance for cervical abnormalities and related anxiety, uncertainty, and costs. Given the complex considerations with cotesting, why did the ACS/ASCCP/ASCP recommend this method as the preferred screening strategy compared with Pap testing alone? Online material (CAAC_21139_sm_SuppInfo .pdf) provided with the guidelines indicates that this was a weak recommendation,2 meaning that “there is substantial uncertainty surrounding the balance of benefits and harms, and further research is needed to increase confidence in the results, or that benefits and harms are closely balanced, with decisions based largely on individual preferences and values.”2(p153) It is therefore puzzling that the guidelines did not state that the recommendation for cotesting as preferred was weak.2 For clinicians unaware of these caveats, the “preferred” designation could lead those offering Pap testing alone to be concerned that they are providing their patients with less-than-optimal care. Conflicts of interest on guideline committees are also important to consider. In the case of the ACS/ASCCP/ ASCP, approximately 25% of committee members reported financial associations with companies that make HPV tests, including the provision of research supplies and research funding, advisory and/or consulting roles, and speakers’ honoraria. To reduce the potential effect JAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
1027
Opinion Viewpoint
of conflicts of interest, members of the Steering Committee and Writing Group and cochairs of the Working Group and Data Group could not have any financial ties to companies marketing or selling cervical cancer screening tests or devices used in screening. In contrast, members of the USPSTF have expertise in evidence-based preventive medicine and have no financial associations with industry related to cervical cancer screening. The USPSTF recommendations were based on a systematic review of the evidence, which was funded by the federal government, and on a decision analysis that the task force commissioned. Differences in the constitution and processes of the committees may help explain why the ACS/ASCCP/ ASCP designated cotesting as preferred and the USPSTF did not. CliniciansmayalsohaveopinionsaboutwhetherPaptestingalone or cotesting should be preferred for cervical cancer screening. Recent guidelines for the management of abnormal screening results are extremely complex.7 Substantial time may be required to discuss screening options, counsel patients with abnormal results, and determine appropriate management using the new algorithms. A woman may also have strong feelings about screening intervals. The USPSTF recommendations highlight the role of patients’ preferences by stating that cotesting is an option “for women who want to lengthen the screening interval.”1 If cotesting is adopted but screening intervals are not lengthened owing to the concerns of patients or clinicians about the every-5-year schedule, patients will be subjected to overscreening and thus more likely to incur its harms. To assess the role of women’s preferences and values in screening decisions, consider 2 hypothetical patients. ARTICLE INFORMATION Published Online: May 5, 2014. doi:10.1001/jamainternmed.2014.1368. Conflict of Interest Disclosures: Dr Smith-McCune is the Founding Chair of the Clinical and Scientific Advisory Board and holds stock options in OncoHealth Inc, which is developing diagnostic tests for cervical cancer and other cancers associated with HPV. She is a coinvestigator for a study of low-coherence interferometry in the cervical epithelium (grant R01 CA167421) and a study of cervical cancer screening options in the United States (grant R01CA169093) (both grants from the National Cancer Institute, US Department of Health and Human Services). REFERENCES 1. Moyer VA; U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive
1028
Patient A is a 56-year-old woman who has been undergoing annual screening with Pap tests for the past 30 years. She has never had an abnormal result. It is explained that the new recommendations advise Pap testing every 3 years or cotesting every 5 years. The patient would rather continue screening every year, but after it is explained that the longer intervals are safe and that overscreening is associated with potential harms, such as unnecessary colposcopic examinations and biopsies, she chooses the option with the shorter interval (Pap testing). Patient B is a 33-year-old woman who has been undergoing Pap testing every 1 to 2 years. She had a mildly abnormal Pap test result at age 24 that led to colposcopy and biopsies but never required treatment, and her test results have since been normal. Although she initially thinks that screening with cotesting every 5 years would simplify her life, it is explained that for someone her age there is an 11% risk of detecting an asymptomatic HPV infection that would require annual cotesting and might lead to colposcopy. She remembers colposcopy as painful and unpleasant and does not want to choose an option that might increase her risk of undergoing the procedure. She chooses screening with Pap testing every 3 years. Once a straightforward process, screening for cervical cancer is now increasingly complex. Absent better data about the advantages and disadvantages of Pap testing and cotesting in various settings, clinicians should help their patients make individual decisions about cervical cancer screening that incorporate their values and preferences. The designation of cotesting as the preferred approach in one set of screening guidelines may be premature.
Services Task Force recommendation statement [published correction appears in Ann Intern Med. 2013;158(11):852]. Ann Intern Med. 2012;156(12):880-891, W312. 2. Saslow D, Solomon D, Lawson HW, et al; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62(3):147-172. 3. Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003;348(6):489-490. 4. Ogilvie GS, Krajden M, van Niekerk DJ, 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;107(12):1917-1924.
5. Ronco G, Dillner J, Elfström KM, et al; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383 (9916):524-532. 6. Datta SD, Koutsky LA, Ratelle S, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003-2005. Ann Intern Med. 2008;148(7): 493-500. 7. Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5) (suppl 1):S1-S27.
JAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
jamainternalmedicine.com
VIEWPOINT
Karen Smith-McCune, MD, PhD Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco.
Viewpoint page 1029
Author Audio Interview at jamainternalmedicine .com
Corresponding Author: Karen SmithMcCune, MD, PhD, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, 2340 Sutter St, Room S229, San Francisco, CA 941431702 (kmccune @obgyn.ucsf.edu).
Choosing a Screening Method for Cervical Cancer Papanicolaou Testing Alone or With Human Papillomavirus Testing Screening for cervical cancer with the Papanicolaou (Pap) test has been remarkably successful at reducing the morbidity and mortality rates associated with this disease. The discovery that human papillomavirus (HPV) has an essential role in cervical carcinogenesis led to the development of molecular tests to measure the presence of HPV types associated with cancer. In 2012, screening guidelines were updated to incorporate HPV testing.1,2 According to these guidelines, women 21 to 29 years old should undergo screening with a Pap test every 3 years; HPV testing is not recommended owing to the high prevalence of HPV infection in this age group. Women older than 65 years who have had adequate prior screening and are at low risk for cervical cancer should no longer undergo screening. There are 2 options for screening in women 30 to 65 years old. The US Preventive Services Task Force (USPSTF) recommends that women in this age group undergo screening with a Pap test every 3 years or Pap-plus-HPV testing (cotesting) every 5 years.1 The American Cancer Society, the American Society of Colposcopy and Cervical Pathology, and the American Society of Clinical Pathology (ACS/ ASCCP/ASCP) recommend the same options, except they classify Pap-plus-HPV testing every 5 years as “preferred” and screening with Pap testing alone every 3 years as “acceptable.”2 The updated guidelines leave physicians and other clinicians with a question: is cotesting with Pap-plusHPV testing truly preferred over Pap testing alone (the ACS/ASCCP/ASCP recommendation), or are the options equivalent (the USPSTF recommendation)? The current state of knowledge suggests that clinicians should not automatically adopt cotesting as the preferred screening strategy for cervical cancer and should consider the individual patient’s values and perspectives when choosing a screening method. A well-established benefit of cotesting with Papplus-HPV testing is the negative predictive value of this method: if both results are negative, the risk of precancer or cancer is low enough that the interval between screenings can be safely extended to 5 years.1,2 However, HPV infection is common in sexually active women, and most HPV infections clear spontaneously and are not associated with precancerous changes.3 Thus, HPV testing inherently has low specificity, results in increased rates of colposcopy,4 and can lead to anxiety and overtreatment in women who test positive.1 A recent study found that HPV testing helps further reduce a woman’s risk of invasive cervical cancer compared with Pap testing alone.5 Cervical cancer, however, is rare in wellscreened populations. Testing for HPV requires addi-
jamainternalmedicine.com
tional resources, and the economic and societal effects of seeking to further reduce the incidence of cervical cancer have not been rigorously studied. Although screening with the Pap test has led to uncertainty regarding the clinical management of mild cervical abnormalities (eg, atypia and low-grade abnormalities), cotesting has led to a new type of ambiguity: a normal Pap test result with a positive HPV test result. This outcome occurs in 3% to 8% of women screened with cotesting2 and is as high as 11% in US women 30 to 34 years old.6 The ACS/ASCCP/ASCP guidelines acknowledge that optimal management of women with normal Pap test and positive HPV test results requires further research.2 One proposed strategy is to repeat cotesting in 1 year, allowing time for HPV infections to clear,2 but this may cause anxiety and uncertainty during the year of waiting. Another strategy is to test for the 2 HPV types that confer the highest risk of cancer (HPV-16 and HPV-18) and toperformcolposcopyifeitherofthesetypesisdetected.2 However, the optimal management of women who persistently test positive for HPV-16 or HPV-18 but have negative colposcopic results is unknown. Some may undergo unnecessary colposcopic examinations, biopsies, and treatments. Women who choose screening with cotesting should therefore be aware that this method can lead to increased surveillance for cervical abnormalities and related anxiety, uncertainty, and costs. Given the complex considerations with cotesting, why did the ACS/ASCCP/ASCP recommend this method as the preferred screening strategy compared with Pap testing alone? Online material (CAAC_21139_sm_SuppInfo .pdf) provided with the guidelines indicates that this was a weak recommendation,2 meaning that “there is substantial uncertainty surrounding the balance of benefits and harms, and further research is needed to increase confidence in the results, or that benefits and harms are closely balanced, with decisions based largely on individual preferences and values.”2(p153) It is therefore puzzling that the guidelines did not state that the recommendation for cotesting as preferred was weak.2 For clinicians unaware of these caveats, the “preferred” designation could lead those offering Pap testing alone to be concerned that they are providing their patients with less-than-optimal care. Conflicts of interest on guideline committees are also important to consider. In the case of the ACS/ASCCP/ ASCP, approximately 25% of committee members reported financial associations with companies that make HPV tests, including the provision of research supplies and research funding, advisory and/or consulting roles, and speakers’ honoraria. To reduce the potential effect JAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
1027
Opinion Viewpoint
of conflicts of interest, members of the Steering Committee and Writing Group and cochairs of the Working Group and Data Group could not have any financial ties to companies marketing or selling cervical cancer screening tests or devices used in screening. In contrast, members of the USPSTF have expertise in evidence-based preventive medicine and have no financial associations with industry related to cervical cancer screening. The USPSTF recommendations were based on a systematic review of the evidence, which was funded by the federal government, and on a decision analysis that the task force commissioned. Differences in the constitution and processes of the committees may help explain why the ACS/ASCCP/ ASCP designated cotesting as preferred and the USPSTF did not. CliniciansmayalsohaveopinionsaboutwhetherPaptestingalone or cotesting should be preferred for cervical cancer screening. Recent guidelines for the management of abnormal screening results are extremely complex.7 Substantial time may be required to discuss screening options, counsel patients with abnormal results, and determine appropriate management using the new algorithms. A woman may also have strong feelings about screening intervals. The USPSTF recommendations highlight the role of patients’ preferences by stating that cotesting is an option “for women who want to lengthen the screening interval.”1 If cotesting is adopted but screening intervals are not lengthened owing to the concerns of patients or clinicians about the every-5-year schedule, patients will be subjected to overscreening and thus more likely to incur its harms. To assess the role of women’s preferences and values in screening decisions, consider 2 hypothetical patients. ARTICLE INFORMATION Published Online: May 5, 2014. doi:10.1001/jamainternmed.2014.1368. Conflict of Interest Disclosures: Dr Smith-McCune is the Founding Chair of the Clinical and Scientific Advisory Board and holds stock options in OncoHealth Inc, which is developing diagnostic tests for cervical cancer and other cancers associated with HPV. She is a coinvestigator for a study of low-coherence interferometry in the cervical epithelium (grant R01 CA167421) and a study of cervical cancer screening options in the United States (grant R01CA169093) (both grants from the National Cancer Institute, US Department of Health and Human Services). REFERENCES 1. Moyer VA; U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive
1028
Patient A is a 56-year-old woman who has been undergoing annual screening with Pap tests for the past 30 years. She has never had an abnormal result. It is explained that the new recommendations advise Pap testing every 3 years or cotesting every 5 years. The patient would rather continue screening every year, but after it is explained that the longer intervals are safe and that overscreening is associated with potential harms, such as unnecessary colposcopic examinations and biopsies, she chooses the option with the shorter interval (Pap testing). Patient B is a 33-year-old woman who has been undergoing Pap testing every 1 to 2 years. She had a mildly abnormal Pap test result at age 24 that led to colposcopy and biopsies but never required treatment, and her test results have since been normal. Although she initially thinks that screening with cotesting every 5 years would simplify her life, it is explained that for someone her age there is an 11% risk of detecting an asymptomatic HPV infection that would require annual cotesting and might lead to colposcopy. She remembers colposcopy as painful and unpleasant and does not want to choose an option that might increase her risk of undergoing the procedure. She chooses screening with Pap testing every 3 years. Once a straightforward process, screening for cervical cancer is now increasingly complex. Absent better data about the advantages and disadvantages of Pap testing and cotesting in various settings, clinicians should help their patients make individual decisions about cervical cancer screening that incorporate their values and preferences. The designation of cotesting as the preferred approach in one set of screening guidelines may be premature.
Services Task Force recommendation statement [published correction appears in Ann Intern Med. 2013;158(11):852]. Ann Intern Med. 2012;156(12):880-891, W312. 2. Saslow D, Solomon D, Lawson HW, et al; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62(3):147-172. 3. Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003;348(6):489-490. 4. Ogilvie GS, Krajden M, van Niekerk DJ, 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;107(12):1917-1924.
5. Ronco G, Dillner J, Elfström KM, et al; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383 (9916):524-532. 6. Datta SD, Koutsky LA, Ratelle S, et al. Human papillomavirus infection and cervical cytology in women screened for cervical cancer in the United States, 2003-2005. Ann Intern Med. 2008;148(7): 493-500. 7. Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5) (suppl 1):S1-S27.
JAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
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