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The current and future role of screening in the era of HPV vaccination
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Gynecologic Oncology 109 (2008) S31 – S39 www.elsevier.com/locate/ygyno
The current and future role of screening in the era of HPV vaccination Evan Myers a,⁎, Warner K. Huh b , Jason D. Wright c , Jennifer S. Smith d a
c
Division of Clinical and Epidemiological Research, Department of Obstetrics and Gynecology, DUMC 3279, 244 Baker House, Duke University Medical Center, Durham, NC 27710, USA b Assistant Professor of Obstetrics and Gynecology, UAB Hospital, Birmingham, Alabama 35233, USA Columbia University, Division of Gynecologic Oncology, 161 Fort Washington Avenue, Suite 843, 8th Floor, New York, NY 10032, USA d University of North Carolina, Department of Epidemiology, 2103 McGavran-Greenberg Hall, CB# 7435, Chapel Hill, NC, USA Received 3 February 2008
Abstract With the introduction of cervical screening programs, the incidence and mortality of cervical cancer has been drastically reduced. Techniques such as the traditional Papanicolaou test and the newer liquid-based cytology allow for the early detection of cervical abnormalities prior to the development of invasive cervical cancer. As oncogenic human papillomavirus (HPV) infection is necessary for cervical cancer, HPV-DNA testing has also been proposed as a routine screening method for the general population. Screening limitations, such as adherence, test sensitivity and specificity, access, and cost-effectiveness are reflected in current screening guidelines. The development of prophylactic cervical cancer vaccines is a major milestone in cervical cancer prevention. These vaccines protect against the initial infection of certain oncogenic HPV types, and therefore prevent the development of cervical dysplasia, precancerous lesions, and cervical cancer. Considering routine cervical cancer vaccination in adolescent girls, screening guidelines must adapt in order to retain efficient and cost-effective prevention measures. Although the true epidemiological and economic impact of cervical cancer vaccines cannot be immediately realized, mathematical models predict various scenarios in which vaccination, in addition to cervical screening, will be cost-effective and further reduce cervical cancer disease. © 2008 Elsevier Inc. All rights reserved. Keywords: Screening; Cervical cancer; HPV; Vaccination
Introduction Invasive cervical cancer is the second most common cancer among women worldwide [1], with approximately 500,000 new cases diagnosed and more than 270,000 deaths annually [2]. With the implementation of cervical cancer screening programs during the past four decades, cervical cancer incidence and mortality have declined dramatically in developed countries [3]. Before 1950, invasive cervical cancer was the leading cause of cancerous death for women in the United States (US) [4]. Between 1955, when screening was introduced in the US, and 1992, the number of cervical cancer deaths dropped by 74%, and the death rate continues to decline [5]. Similar reductions have also been observed in other developed countries, including the United Kingdom (UK, Fig. 1) [5]. This decline in mortality due to cervical cancer is largely attributed to the increased use of ⁎ Corresponding author. Fax: +1 919 668 0295. E-mail address: [email protected] (E. Myers). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.02.001
the Papanicolaou (Pap) test to detect early stage cervical cancer and precancerous lesions [3]. The remarkable effectiveness of cervical cancer screening is in part due to the natural history of cervical cancer precursors, which makes it particularly amenable to secondary prevention [5]. However, challenges remain, including identifying optimal methods to improve both the sensitivity and the specificity of cervical cancer screening, determining ways to design screening guidelines that are both effective and affordable, and, most importantly, ascertaining how to ensure that all women are screened appropriately. Cervical cancer screening: screening tests Conventional cervical cytology — the Pap test Introducing a comprehensive Pap test screening program into a population has the potential to reduce the risk of developing cervical cancer by 60% to 90% within three years [6].
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Fig. 1. Incidence of cervical cancer in the US and UK, 1975−1995.
In countries where wide cervical cancer screening coverage has been achieved and quality assurance has been put in place, cervical cancer incidence and death rates have fallen by more than 50% (Fig. 1) [7]. In England, invasive cervical cancer rates were constant until the introduction of an organized screening program in 1988, after which incidence and mortality due to cervical cancer decreased by approximately 50% [7,8]. A similar trend was observed in Norway immediately after the introduction of a national cervical cancer cytology program in 1995 [7]. In countries where population-based screening is not available, cervical cancer rates have generally not declined to the same extent [9]. The Pap test, a cytologic evaluation of smears obtained from the cervix, has been the historic gold standard for cervical screening. The Pap test detects asymptomatic changes in the cervical epithelium, leading to a greater proportion of cancers diagnosed in earlier neoplasic stages [10]. With regular screening, early detection and treatment of precancerous lesions (cervical intraepithelial neoplasia [CIN]) is possible, which helps to reduce the incidence of cervical cancer [5,11]. Screening has also decreased cervical cancer mortality, as early stage cervical cancer has a high survival rate (approximately 90% for Stage I versus 75% for Stage II, 50% for Stage III, and 20% to 30% for Stage IV) [12]. In the US, the use of Pap testing has helped the death rate from cervical cancer to continually decline by nearly 4% a year [5]. Although the effectiveness of screening has never been proven in a randomized trial, the benefits of screening are demonstrated by the direct relationship between the percent of the population screened with Pap tests and the decline in cervical cancer incidence and mortality [4]. The reduction in cervical cancer incidence and mortality in the US and other developed countries has been accomplished despite the relatively low sensitivity of conventional cytology [13]. Metaanalyses suggest that the sensitivity of a single conventional Pap test for CIN 2/3 or higher is 50% to 60% [13,14]. Low Pap test sensitivity has been attributed to a combination of poor sample collection (5%–10% of all slides), incorrect slide preparation, and laboratory interpretation errors [14–16]. Liquid-based cytology Liquid-based cytology (LBC) was developed primarily to improve upon traditional Pap testing, and to improve the quality
of cervical samples [17,18]. LBC relies on a fluid medium to preserve collected cervical cells. The suspension is then processed to provide a more uniform, thin layer of cervical cells with less debris on a glass slide. This process aims to potentially reduce two of the main deficiencies observed with conventional cytology: the relatively small and potentially non-representative sample of cells (approximately 20% of harvested cells are actually transferred to the slide) [4], and the effect of other material, including mucous, blood, and other non-cervical cells, on the readability of the slide [15,19]. Nonrandomized studies show a reduction in unsatisfactory slides with LBC, and an improved or equivalent sensitivity in detecting cervical abnormalities compared with conventional cytology [20,21]. However, these gains have not been seen in the majority of randomized studies [20,22–24]. In the largest randomized trial to date, Italian investigators assigned 22,708 women (aged 25 to 60 years) to LBC and 22,466 women to conventional cytology [20]. Compared with conventional cytology, LBC detected more CIN 1 on histology, but not CIN 2 or higher, when both atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) were used as cutoff points for colposcopy. The overall positive predictive value of LBC for all CIN endpoints was significantly lower than that of conventional cytology, resulting in an increased number of colposcopies for an identical number of clinically significant lesions detected. However, one recent randomized trial (n = 13,484) found LBC to detect more high-grade lesions compared with the conventional Pap. Following histopathology, approximately 42% more high-grade lesions were identified as a result of LBC testing than with Pap testing (1.20% versus 0.85%, P = 0.05) [25]. In each of these randomized trials, LBC significantly reduced the number of unsatisfactory samples [20,25]. Although there are many potential reasons for these discrepancies, it is quite possible that liquid cytology is more “forgiving” of the variations in the techniques used to obtain specimens seen in typical practice. Reasons for changing to LBC include the high test repeat rates mostly generated by unsatisfactory samples with the conventional Pap, and an enhanced ability to automate the preparation and examination process in the setting of an over extended and limited laboratory workforce. Based primarily on the need for repeat smears seen in earlier nonrandomized studies with conventional cytology, both the Canadian and UK health systems have adapted LBC [8,26].
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One clear advantage of LBC is the use of fluid for other tests, including oncogenic human papillomavirus (HPV) (see below), for either concurrent screening (both tests read simultaneously) or reflex testing (HPV testing performed only for specific cytology results). However, it should be noted that concurrent cytology and HPV testing may not translate into substantial clinical benefits, particularly for younger women [27]. The long-term impact of LBC on cancer incidence and mortality remains to be established, as does its cost-effectiveness. As LBC is more expensive than conventional cytology and requires additional instrumentation to prepare the smears, it may not be feasible to implement LBC in low-resource settings [19].
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testing has not been evaluated, however, type-specific testing is currently not commercially available. Patients, clinicians, and policy makers are in need of tools to help estimate the impact of introducing new technologies into population-based screening, due to the trade-offs in terms of health outcomes (such as missed or delayed diagnosis of cancer, and diagnosis and treatment of benign lesions), costs, and differences between test sensitivity, specificity, and associated screening intervals. In the case of cervical cancer prevention, this is most frequently done using mathematical modeling. Cervical cancer screening: using models to estimate cost-effectiveness
HPV-DNA testing Recent US data estimate that 24.9 million women between the ages of 14 and 59 are currently infected with the HPV [28]. Approximately 100 HPV types have been identified, of which 40 infect the genital mucosa [29]. It is estimated that over 80% of women will acquire a genital HPV infection by age 50 [30]. Of the 40 genital HPV types, 15 are considered oncogenic or high-risk [29]. It is now well established that infection with an oncogenic HPV type is a necessary cause for the development of cervical cancer [29,31], and the causal association between infection and invasive cervical disease is strongest with oncogenic virus types 16 and 18 [32,33]. Because infection with oncogenic HPV is the underlying cause of cervical cancer, the use of HPV testing as a primary screening test for cervical cancer is being considered [29]. Testing for the presence of carcinogenic HPV-DNA types associated with cervical cancer has been found to be significantly more sensitive than cytologic testing for the detection of CIN, is more reproducible, and provides an objective outcome [34–36]. Thus, with a higher sensitivity, HPV-DNA testing addresses a major disadvantage of both conventional and liquid cytology [37–39]. Randomized trials have demonstrated that HPV testing combined with conventional cytology is more sensitive, yet less specific than cytology alone for both the management of ASCUS [40] and in primary screening [41–43]. In the primary screening context, the lower specificity of HPV-DNA testing is a particularly important consideration. As a notable portion of HPVDNA positive women do not have cervical disease, a small decline in specificity could result in a large number of women with false-positive results. Without a change in screening intervals, this could increase both the time and costs needed for follow-up [14,19,34,44]. One limitation of cytology and currently available HPV tests is that most lesions and/or HPV infections detected will never progress to more serious high-grade lesions or invasive cervical cancer [45]. Identifying ways to ascertain which women with abnormal test results are truly at risk for developing high-grade neoplasia or invasive cancer, and those women who can safely be managed conservatively remains a high priority. There is evidence that certain specific HPV genotypes confer a substantially increased risk of incident CIN 2 or greater [40]. The sensitivity and specificity of individual high-risk HPV type
Mathematical models suggest that population-wide Pap test screening at three-year intervals reduces the rate of invasive cervical cancer by 91%, and at five-year intervals reduces the rate by 84% [6, 46]. In North America and Europe, the introduction of cervical screening programs has been associated with 20% to 60% reductions in cervical cancer mortality [6]. “Cost-effectiveness,” in economic terms, is relative; one screening strategy is only said to be “cost-effective” in comparison with another [47]. Most advances in healthcare result in both improved health outcomes and increased costs. This is certainly true for screening of cancers. Given that resources are finite, the issue is generally not whether a strategy with better outcomes costs more than an alternative — the main issue is whether the extra costs are “worth” the extra expense [47]. In the US, costs including follow-up care from abnormal cytology related to HPV and treatment for precancerous lesions approach $4 billion each year [48]. Thus, identifying more efficient strategies is clearly a priority. Most commonly, the measure of comparison in health economic analyses is the incremental cost-effectiveness ratio (ICER). This is calculated by dividing the difference in cost between two strategies by the difference in health outcomes. Typically, the measure of outcome is the difference in life expectancy or, ideally, quality adjusted life expectancy, expressed as life years saved or quality adjusted life years (QALY) saved. Typically, in the US, a strategy is considered cost-effective if the ICER is in the range of $50,000 to $80,000 per QALY saved [49,50]. In the case of cervical cancer prevention, direct comparison of different screening strategies is impossible due to practical and ethical limitations [47]. Estimates of the health and economic effects of different screening strategies are usually performed using computer simulation models. Despite variations in computer software, subtleties in modeling structure, changes in technology and costs, and changes in our understanding of the natural history of cervical cancer, results of modeling studies have been remarkably consistent in their findings over the past 30 years [47,51]. As the frequency of screening increases, the ICER increases — annual screening has an ICER of well over $100,000 or more compared with biennial screening. The relatively few cases of cervical cancer and the number of cancer deaths prevented by annual screening compared with biennial screening come at the cost of many additional tests, false-positives, and detection of lesions that are unlikely to progress to cancer [45]. At a fixed
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screening interval, ICERs increase as test specificity decreases, because the cost of diagnosis and evaluation of false-positive tests comes with no gain in health outcomes (and, potentially worse quality of life, given the anxiety frequently experienced as the result of abnormal tests) [45]. ICERs also increase as test sensitivity increases, since many of the additional cervical abnormalities detected represent lesions that would not progress to cancer. These effects of sensitivity and specificity on the ICER become more predominant as test frequency increases [52]. In addition to screening intervals, the age at which women begin screening is an important factor in determining the efficiency of a screening program. After their first sexual intercourse, younger women have a high incidence of HPV and HPV-related benign cervical changes. Thus, there is a very high probability of detecting, diagnosing, and treating cervical changes that will never develop into cancer [45]. In addition, there is evidence that many CIN 2 lesions in this age group do not truly represent precancerous lesions with a clear potential to progress to invasive cervical cancer [37]. Aggressive treatment of these lesions also increases the risk of subsequent adverse obstetric outcomes [53]. In women older than 65 years, screening is also inefficient, especially if they have recently documented normal screening tests [45], since the incidence of cervical cancer in this age group is low [54]. Cervical cancer screening: considering access and adherence Insights gained from modeling have been extremely helpful in identifying the main trade-offs involved in balancing screening frequency, test characteristics, and ages of screening. However, much of the historical reluctance to embrace less frequent screening intervals in the US has been due to the issues of access and adherence. The risk for developing cervical cancer is 2 to 10 times higher among those women who have never been screened, and increases with the length of time since a woman's last cervical screen [15]. In the US, more than 50% of women with cervical cancer have never been screened for the disease,
and 60% of women have not undergone screening in the past five years [3,55,56]. Significant disparities in cervical cancer incidence and mortality exist in certain ethnic populations, and between education and income levels. These disparities are largely related to screening access and utilization [57,58]. Screening: current guidelines Current cervical screening guidelines are provided in Table 1, which include consideration of the issues previously discussed, including costs and cost-effectiveness. Although different groups may have some variation in specific recommendations, all recognize that there is no perfect balance between test sensitivity and specificity, age to begin screening, frequency and access of screening, adherence to guidelines, and cost-effectiveness. Screening: issues prior to the introduction of HPV vaccines Without considering the potential impact of prophylactic HPV vaccines, screening as a method for the prevention of cervical cancer faces several challenges. Of these, the most important appears to be identifying ways to increase coverage and adherence. It is also important to determine whether it is possible to incorporate more sensitive but less specific tests, particularly by considering lengthening screening intervals. Another challenge is the development of affordable methods to identify women truly at risk for cervical cancer. The introduction of effective HPV prophylactic vaccines will impact all three of these major areas. Vaccines against cervical cancer and modeling of the impact of HPV vaccines on screening Two prophylactic vaccines protecting against precancerous lesions and invasive cervical cancer have been developed; one currently licensed in the US (Gardasil®; Merck & Co., Whitehouse Station, NJ), and another (Cervarix®; GlaxoSmithKline, Rixensart, Belgium) that expects to gain US approval
Table 1 Screening guidelines for detection of precancerous lesions and cervical cancer
Initiation of Screening
American Cancer Society (ACS) 1, 2
US Preventive Services Task Force (USPSTF) 3
Screening initiated at age 21 or 3 years after sexual debut, whichever occurs first
Screening initiated at age 21 or 3 years after Screening initiated at age 21 or 3 years after sexual debut, whichever occurs first sexual debut, whichever occurs first
Screening Interval Annually Women b30 years Not applicable Every 2 to 3 Years Women ≥30 years: Not applicable • Conventional Pap test after 3 negative screens • LBC after 3 negative screens Every 3 Years Women ≥30 years: Either conventional Pap test or LBC 3 years after first sexual activity or age 21 • LBC plus HPV testing if both HPV-DNA and cytology are negative 1 2 3 4
Saslow D et al. CA: A Cancer J Clin. 2002; 52:342–62. U.S. Preventive Services Task Force. Available at: http://www.ahrq.gov/clinic/uspstf/uspscerv.htm. ACOG. Practice Bulletin 45: Cervical Cytology Screening. 2003. American Cancer Society Guidelines for the Early Detection of Cancer. 2007.
American College of Obstetricians and Gynecologists (ACOG) 4
Women b30 years Women ≥30 years: • Conventional Pap test after 3 negative screens • LBC after 3 negative screens Women ≥30 years: • LBC plus HPV testing if both HPV-DNA and cytology are negative
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Table 2 Modeling of the impact of vaccination on screening⁎ [61] Sanders and Taira [74]
Kulasingam and Myers [63]
Goldie, et al [64]
Taira, et al [75]
Main Characteristics Model
State-transition Markov model
State-transition Markov model
State-transition Markov model
Perspective
Direct medical costs (QOL)
Benefits
QALY
Direct medical costs (time costs and QOL in sensitivity) LYS
Societal (direct medical costs, time costs, and QOL) QALY
Hybrid (dynamic/Markov model) Direct medical costs (QOL)
90% against 70% of HR HPV types 100% of 12-year-old girls
90% against HPV 16/HPV18 (65% of cervical cancers) 100% of 12-year-old girls
63.0%
58.5%
100%
100% (5.2% never screened, 70.5% b1 year ago, 12.6% b 2 years, 4.3% b3years, 3.0% b 5 years. 9.6% b5 years Lifelong
Base-case Assumptions Efficacy 75% against 13 HR types (90% of cervical cancers) Vaccine Coverage in 70% of 12-year-old girls Target Groups Estimated Effective 47.3% Coverage Screening Compliance 71% every 2 years (same) (estimate used for comparison with current practice) Duration of Protection 10 years (boosters every 10 years) Results The Most Effective Strategy Compared with Next Best Strategy†
ICER Compared with Current Practice Main Shortcomings Factors not Accounted for
10 years
..
Vaccination of girls at 12 years, plus biennial screening at 24 years. ICER of US $44,889/LYS vs. triennial screening only starting at age 18 (US $50,000 threshold)
US $22,755 per QALY gained
..
QALY
90% against HPV 16/HPV 18 70% of 12-year-old girls only, or girls and boys 40.1% 71% every 2 years (same)
10 years (boosters every 10 years)
Vaccination of girls at 12 years .. plus triennial screening at 25 years. ICER of US $58,500/QALY gained vs. vaccination and screening every 5 years at age 21 (US $60,000 threshold) US $24,300 per QALY gained US $14,583 per QALY gained (girls only)
Herd immunity; vaccinating males; Herd immunity; vaccinating Herd immunity; vaccinating reactivation of latent infections; males; genital warts males; reactivation of latent infections; genital warts; changes genital warts in screening initiation stage
Genital warts; reactivation of latent infections; changes in screening initiation age
⁎From Newall, AT. Lancet Inf Dis. 2007. ICER = incremental cost-effectiveness ration. HR = high risk. LYS = life year saved. QALY = quality adjusted life year. QOL = quality of life. ..= not applicable. Defined here as (vaccine coverage) × (vaccine efficacy against targeted types) × (proportion of cancer caused by these types). †The next best alternative to options including vaccination is not always current practice (e.g., currently screening is not applied in the best way in many settings).
in 2008 (Table 2). Both vaccines protect against infection from oncogenic HPV types 16 and 18 [59], which cause the majority (~ 77%) of all cervical cancer cases and over 50% of high-grade intraepithelial lesions in North America [58]. Gardasil® also protects against infection from HPV types 6 and 11, which are primarily associated with genital warts. As these vaccines are introduced into settings where screening is already available, estimates are needed for the short- and long-term impact on health and economic outcomes [60]. Modeling studies Similar to the cervical screening models, published studies modeling the impact of HPV vaccines on cervical cancer screening are consistent in their qualitative findings [61]. Under assumptions of lifetime immunity and vaccine costs similar to current prices, vaccination is cost-effective (ICERs of $75,000 per QALY or less for US resources) [62] in screening settings, especially if screening intervals are lengthened [47]. Vaccination
may also help address two of the key inefficiencies with current screening: age to begin screening and screening frequency. Models have predicted that a vaccinated cohort can begin screening later and at less frequent intervals, with equivalent or better health outcomes and lower costs than an unvaccinated cohort [63,64]. Vaccines also have the potential to address the issues related to screening access and adherence. In theory, widespread vaccine coverage, particularly in targeted age groups, should be easier to ensure than ongoing coverage and adherence to screening recommendations over a lifetime. However, if vaccinated women are less likely to adhere to screening recommendations because of a belief of complete cervical cancer protection, outcomes could actually worsen [63–65]. The cost-effectiveness of cervical cancer vaccination is dependent on many currently unknown parameters, most importantly the duration of protection, and the cost and need for booster doses. One study, which compared screening practices with or without vaccination (assumed 90% vaccine efficacy) at different ages, found vaccination at age 12 with triennial screening beginning
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at age 25 years was the most cost-effective strategy, with an ICER of less than $60,000 per QALY, and a 94% reduction in the lifetime risk of cervical cancer compared with no intervention [64]. An additional model compared vaccination or cytology alone with vaccination followed by screening at varying intervals. Results showed vaccination at 12 years of age with biennial screening beginning at age 24 was the most appealing costeffective strategy ($44,889 ICER per QALY) compared with vaccination plus biennial screening beginning at age 18, or biennial screening alone at age 18 [63]. In this analysis, the ability to implement effective screening policies was dependent on adequate vaccine protection during the ages of peak oncogenic incidence [63].
One key factor should be considered in designing screening strategies for vaccinated women. Although the vaccines do not protect against oncogenic HPV types, the incidence and therefore the prevalence of precancerous lesions will decrease significantly. This means that the negative predictive value of any screening test will improve, and the positive predictive value will worsen [60]. If screening intervals are not lengthened, or test specificity not improved, then the absolute number of false-positive results will increase, with a subsequent adverse impact on both health outcomes and costs [60,65]. Especially in screening tests with high sensitivity, the increase in false-positives resulting from reduced prevalence is substantially greater than the reduction in false-negatives (Fig. 2).
Fig. 2. Effect of reduction in prevalence of CIN 2/3+ due to vaccines on absolute number of false-negatives (A) and false-positives (B) per million women screened at different levels of sensitivity and specificity.
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HPV vaccines: unanswered questions Discussion of HPV vaccines is found in other sections of this supplement In addition to questions regarding the duration of protection, there are a number of other factors that will impact both the effectiveness and cost-effectiveness of vaccination and screening. Concerns whether other oncogenic HPV types will emerge as leading factors in cervical cancer once HPV 16 and 18 are largely eliminated with vaccination have been raised [66]. Occult lesions that would previously have been removed during treatment of more aggressive lesions caused by HPV 16 or 18 could now have the chance to develop [67]. However, data indicate that both vaccines provide partial cross-protection against oncogenic virus types genetically related to HPV types 16 and 18 [59,68], which could potentially increase their overall effectiveness and cost-effectiveness. The vaccination of males is currently not indicated in the US, as HPV vaccine efficacy data in this cohort are not yet available. However, studies show high seroconversion rates in young boys following vaccination against HPV types 6, 11, 16, and 18, and immunogenicity results are not statistically different from those observed in similarly aged girls [69,70]. Ongoing studies of the safety and efficacy of vaccines in young male adolescents may lead to approval for this population, as modeling studies suggest that vaccination of boys and men may introduce additional efficiencies [71]. Based on available trial data, vaccination is currently indicated for young female adolescents aged 9 to 26 years [72]. Ongoing studies in older women (up to age 55) may lead to changes in the upper age for catch-up vaccination, or may change the threshold for boosters if efficacy is not life-long and if vaccination of older women is proven to be cost-effective on a population level. In addition, current mathematical models do not comprehensively address the impact of vaccines on other diseases caused by HPV 16/18 (such as anal and oropharyngeal cancer) or HPV 6/11 (such as genital warts and recurrent respiratory papillomatosis) — diseases which also have notable health and economic burdens [73]. Conclusions Vaccination is highly effective against infection with HPV types 16 and 18, which cause the majority of all cervical cancer cases. Cervical cancer screening guidelines will need revisions; as new technologies become available, the optimal screening policies should aim to retain a balance between maximizing efficiency using more sensitive and specific tests at less frequent intervals, starting at later ages, and minimizing cancer risk on the population level. Models for vaccination suggest that the integration of vaccines into these secondary prevention measures may be cost-effective, especially if screening ages and intervals can be safely changed and successfully implemented. Although the true epidemiological and cost impact may not be seen for at least a decade, a dramatic decline in the detection of precancerous cervical
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lesions should be expected, as well as a substantial decrease in the incidence and mortality due to cervical cancer in the longer term. Conflict of interest statement EM has received research funding and done consulting for Merck & Co. WKH has done consulting for GSK, Merck, MGI Biologics, Takeda, Roche Pharmaceuticals, and Roche Molecular Systems, been a speaker for Merck, Digene, and Cytyc, served on the Advisory Board for Nventa Pharmaceuticals, and conducted research for GSK, Merck, Roche, MGI, Takeda, and Hologic. JDW has served on the Speakers’ Bureau for Merck. JSS has received research grants, honoraria, or consulting fees during the last three years from GSK, Digene and GenProbe.
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E. Myers et al. / Gynecologic Oncology 109 (2008) S31–S39 [64] Goldie SJ, Kohli M, Grima D, Weinstein MC, Wright TC, Bosch FX, et al. Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J Natl Cancer Inst Apr 21 2004;96(8):604–15. [65] Kulasingam SL, Pagliusi S, Myers E. Potential effects of decreased cervical cancer screening participation after HPV vaccination: an example from the U.S. Vaccine Nov 23 2007;25(48):8110–3. [66] Sawaya GF, Smith-McCune K. HPV vaccination—more answers, more questions. New Engl J Med May 10 2007;356(19):1991–3. [67] Koutsky LA, Harper DM. Chapter 13: current findings from prophylactic HPV vaccine trials. Vaccine Aug 21 2006;24(Suppl 3):S114–21. [68] Brown D. For the Future Study Group. HPV type 6/11/16/18 vaccine: first analysis of cross-protection against persistent infection, cervical intraepithelial neoplasia, and adenocarcinoma in situ caused by oncogenic HPV types in addition to 16/18. Presentation: G-1720b. Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, Il 2007. [69] Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD, et al. Comparison of the immunogenicity and reactogenicity of a prophylactic
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quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics Nov 2006;118(5):2135–45. Reisinger KS, Block SL, Lazcano-Ponce E, Samakoses R, Esser MT, Erick J, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J Mar 2007;26(3):201–9. Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis Jan 2007;13(1):28–41. CDC. CDC. ACIP recommendations for the use of quadrivalent HPV vaccine. Morbidity and mortality weekly report; 2006. Insinga RP, Glass AG, Rush BB. The health care costs of cervical human papillomavirus-related disease. Am J Obstet Gynecol Jul 2004;191(1):114–20. Sanders GD, Taira AV. Cost-effectiveness of a potential vaccine for human papillomavirus. Emerg Infect Dis Jan 2003;9(1):37–48. Taira AV, Neukermans CP, Sanders GD. Evaluating human papillomavirus vaccination programs. Emerg Infect Dis Nov 2004;10(11):1915–23.
Gynecologic Oncology 109 (2008) S31 – S39 www.elsevier.com/locate/ygyno
The current and future role of screening in the era of HPV vaccination Evan Myers a,⁎, Warner K. Huh b , Jason D. Wright c , Jennifer S. Smith d a
c
Division of Clinical and Epidemiological Research, Department of Obstetrics and Gynecology, DUMC 3279, 244 Baker House, Duke University Medical Center, Durham, NC 27710, USA b Assistant Professor of Obstetrics and Gynecology, UAB Hospital, Birmingham, Alabama 35233, USA Columbia University, Division of Gynecologic Oncology, 161 Fort Washington Avenue, Suite 843, 8th Floor, New York, NY 10032, USA d University of North Carolina, Department of Epidemiology, 2103 McGavran-Greenberg Hall, CB# 7435, Chapel Hill, NC, USA Received 3 February 2008
Abstract With the introduction of cervical screening programs, the incidence and mortality of cervical cancer has been drastically reduced. Techniques such as the traditional Papanicolaou test and the newer liquid-based cytology allow for the early detection of cervical abnormalities prior to the development of invasive cervical cancer. As oncogenic human papillomavirus (HPV) infection is necessary for cervical cancer, HPV-DNA testing has also been proposed as a routine screening method for the general population. Screening limitations, such as adherence, test sensitivity and specificity, access, and cost-effectiveness are reflected in current screening guidelines. The development of prophylactic cervical cancer vaccines is a major milestone in cervical cancer prevention. These vaccines protect against the initial infection of certain oncogenic HPV types, and therefore prevent the development of cervical dysplasia, precancerous lesions, and cervical cancer. Considering routine cervical cancer vaccination in adolescent girls, screening guidelines must adapt in order to retain efficient and cost-effective prevention measures. Although the true epidemiological and economic impact of cervical cancer vaccines cannot be immediately realized, mathematical models predict various scenarios in which vaccination, in addition to cervical screening, will be cost-effective and further reduce cervical cancer disease. © 2008 Elsevier Inc. All rights reserved. Keywords: Screening; Cervical cancer; HPV; Vaccination
Introduction Invasive cervical cancer is the second most common cancer among women worldwide [1], with approximately 500,000 new cases diagnosed and more than 270,000 deaths annually [2]. With the implementation of cervical cancer screening programs during the past four decades, cervical cancer incidence and mortality have declined dramatically in developed countries [3]. Before 1950, invasive cervical cancer was the leading cause of cancerous death for women in the United States (US) [4]. Between 1955, when screening was introduced in the US, and 1992, the number of cervical cancer deaths dropped by 74%, and the death rate continues to decline [5]. Similar reductions have also been observed in other developed countries, including the United Kingdom (UK, Fig. 1) [5]. This decline in mortality due to cervical cancer is largely attributed to the increased use of ⁎ Corresponding author. Fax: +1 919 668 0295. E-mail address: [email protected] (E. Myers). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.02.001
the Papanicolaou (Pap) test to detect early stage cervical cancer and precancerous lesions [3]. The remarkable effectiveness of cervical cancer screening is in part due to the natural history of cervical cancer precursors, which makes it particularly amenable to secondary prevention [5]. However, challenges remain, including identifying optimal methods to improve both the sensitivity and the specificity of cervical cancer screening, determining ways to design screening guidelines that are both effective and affordable, and, most importantly, ascertaining how to ensure that all women are screened appropriately. Cervical cancer screening: screening tests Conventional cervical cytology — the Pap test Introducing a comprehensive Pap test screening program into a population has the potential to reduce the risk of developing cervical cancer by 60% to 90% within three years [6].
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Fig. 1. Incidence of cervical cancer in the US and UK, 1975−1995.
In countries where wide cervical cancer screening coverage has been achieved and quality assurance has been put in place, cervical cancer incidence and death rates have fallen by more than 50% (Fig. 1) [7]. In England, invasive cervical cancer rates were constant until the introduction of an organized screening program in 1988, after which incidence and mortality due to cervical cancer decreased by approximately 50% [7,8]. A similar trend was observed in Norway immediately after the introduction of a national cervical cancer cytology program in 1995 [7]. In countries where population-based screening is not available, cervical cancer rates have generally not declined to the same extent [9]. The Pap test, a cytologic evaluation of smears obtained from the cervix, has been the historic gold standard for cervical screening. The Pap test detects asymptomatic changes in the cervical epithelium, leading to a greater proportion of cancers diagnosed in earlier neoplasic stages [10]. With regular screening, early detection and treatment of precancerous lesions (cervical intraepithelial neoplasia [CIN]) is possible, which helps to reduce the incidence of cervical cancer [5,11]. Screening has also decreased cervical cancer mortality, as early stage cervical cancer has a high survival rate (approximately 90% for Stage I versus 75% for Stage II, 50% for Stage III, and 20% to 30% for Stage IV) [12]. In the US, the use of Pap testing has helped the death rate from cervical cancer to continually decline by nearly 4% a year [5]. Although the effectiveness of screening has never been proven in a randomized trial, the benefits of screening are demonstrated by the direct relationship between the percent of the population screened with Pap tests and the decline in cervical cancer incidence and mortality [4]. The reduction in cervical cancer incidence and mortality in the US and other developed countries has been accomplished despite the relatively low sensitivity of conventional cytology [13]. Metaanalyses suggest that the sensitivity of a single conventional Pap test for CIN 2/3 or higher is 50% to 60% [13,14]. Low Pap test sensitivity has been attributed to a combination of poor sample collection (5%–10% of all slides), incorrect slide preparation, and laboratory interpretation errors [14–16]. Liquid-based cytology Liquid-based cytology (LBC) was developed primarily to improve upon traditional Pap testing, and to improve the quality
of cervical samples [17,18]. LBC relies on a fluid medium to preserve collected cervical cells. The suspension is then processed to provide a more uniform, thin layer of cervical cells with less debris on a glass slide. This process aims to potentially reduce two of the main deficiencies observed with conventional cytology: the relatively small and potentially non-representative sample of cells (approximately 20% of harvested cells are actually transferred to the slide) [4], and the effect of other material, including mucous, blood, and other non-cervical cells, on the readability of the slide [15,19]. Nonrandomized studies show a reduction in unsatisfactory slides with LBC, and an improved or equivalent sensitivity in detecting cervical abnormalities compared with conventional cytology [20,21]. However, these gains have not been seen in the majority of randomized studies [20,22–24]. In the largest randomized trial to date, Italian investigators assigned 22,708 women (aged 25 to 60 years) to LBC and 22,466 women to conventional cytology [20]. Compared with conventional cytology, LBC detected more CIN 1 on histology, but not CIN 2 or higher, when both atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) were used as cutoff points for colposcopy. The overall positive predictive value of LBC for all CIN endpoints was significantly lower than that of conventional cytology, resulting in an increased number of colposcopies for an identical number of clinically significant lesions detected. However, one recent randomized trial (n = 13,484) found LBC to detect more high-grade lesions compared with the conventional Pap. Following histopathology, approximately 42% more high-grade lesions were identified as a result of LBC testing than with Pap testing (1.20% versus 0.85%, P = 0.05) [25]. In each of these randomized trials, LBC significantly reduced the number of unsatisfactory samples [20,25]. Although there are many potential reasons for these discrepancies, it is quite possible that liquid cytology is more “forgiving” of the variations in the techniques used to obtain specimens seen in typical practice. Reasons for changing to LBC include the high test repeat rates mostly generated by unsatisfactory samples with the conventional Pap, and an enhanced ability to automate the preparation and examination process in the setting of an over extended and limited laboratory workforce. Based primarily on the need for repeat smears seen in earlier nonrandomized studies with conventional cytology, both the Canadian and UK health systems have adapted LBC [8,26].
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One clear advantage of LBC is the use of fluid for other tests, including oncogenic human papillomavirus (HPV) (see below), for either concurrent screening (both tests read simultaneously) or reflex testing (HPV testing performed only for specific cytology results). However, it should be noted that concurrent cytology and HPV testing may not translate into substantial clinical benefits, particularly for younger women [27]. The long-term impact of LBC on cancer incidence and mortality remains to be established, as does its cost-effectiveness. As LBC is more expensive than conventional cytology and requires additional instrumentation to prepare the smears, it may not be feasible to implement LBC in low-resource settings [19].
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testing has not been evaluated, however, type-specific testing is currently not commercially available. Patients, clinicians, and policy makers are in need of tools to help estimate the impact of introducing new technologies into population-based screening, due to the trade-offs in terms of health outcomes (such as missed or delayed diagnosis of cancer, and diagnosis and treatment of benign lesions), costs, and differences between test sensitivity, specificity, and associated screening intervals. In the case of cervical cancer prevention, this is most frequently done using mathematical modeling. Cervical cancer screening: using models to estimate cost-effectiveness
HPV-DNA testing Recent US data estimate that 24.9 million women between the ages of 14 and 59 are currently infected with the HPV [28]. Approximately 100 HPV types have been identified, of which 40 infect the genital mucosa [29]. It is estimated that over 80% of women will acquire a genital HPV infection by age 50 [30]. Of the 40 genital HPV types, 15 are considered oncogenic or high-risk [29]. It is now well established that infection with an oncogenic HPV type is a necessary cause for the development of cervical cancer [29,31], and the causal association between infection and invasive cervical disease is strongest with oncogenic virus types 16 and 18 [32,33]. Because infection with oncogenic HPV is the underlying cause of cervical cancer, the use of HPV testing as a primary screening test for cervical cancer is being considered [29]. Testing for the presence of carcinogenic HPV-DNA types associated with cervical cancer has been found to be significantly more sensitive than cytologic testing for the detection of CIN, is more reproducible, and provides an objective outcome [34–36]. Thus, with a higher sensitivity, HPV-DNA testing addresses a major disadvantage of both conventional and liquid cytology [37–39]. Randomized trials have demonstrated that HPV testing combined with conventional cytology is more sensitive, yet less specific than cytology alone for both the management of ASCUS [40] and in primary screening [41–43]. In the primary screening context, the lower specificity of HPV-DNA testing is a particularly important consideration. As a notable portion of HPVDNA positive women do not have cervical disease, a small decline in specificity could result in a large number of women with false-positive results. Without a change in screening intervals, this could increase both the time and costs needed for follow-up [14,19,34,44]. One limitation of cytology and currently available HPV tests is that most lesions and/or HPV infections detected will never progress to more serious high-grade lesions or invasive cervical cancer [45]. Identifying ways to ascertain which women with abnormal test results are truly at risk for developing high-grade neoplasia or invasive cancer, and those women who can safely be managed conservatively remains a high priority. There is evidence that certain specific HPV genotypes confer a substantially increased risk of incident CIN 2 or greater [40]. The sensitivity and specificity of individual high-risk HPV type
Mathematical models suggest that population-wide Pap test screening at three-year intervals reduces the rate of invasive cervical cancer by 91%, and at five-year intervals reduces the rate by 84% [6, 46]. In North America and Europe, the introduction of cervical screening programs has been associated with 20% to 60% reductions in cervical cancer mortality [6]. “Cost-effectiveness,” in economic terms, is relative; one screening strategy is only said to be “cost-effective” in comparison with another [47]. Most advances in healthcare result in both improved health outcomes and increased costs. This is certainly true for screening of cancers. Given that resources are finite, the issue is generally not whether a strategy with better outcomes costs more than an alternative — the main issue is whether the extra costs are “worth” the extra expense [47]. In the US, costs including follow-up care from abnormal cytology related to HPV and treatment for precancerous lesions approach $4 billion each year [48]. Thus, identifying more efficient strategies is clearly a priority. Most commonly, the measure of comparison in health economic analyses is the incremental cost-effectiveness ratio (ICER). This is calculated by dividing the difference in cost between two strategies by the difference in health outcomes. Typically, the measure of outcome is the difference in life expectancy or, ideally, quality adjusted life expectancy, expressed as life years saved or quality adjusted life years (QALY) saved. Typically, in the US, a strategy is considered cost-effective if the ICER is in the range of $50,000 to $80,000 per QALY saved [49,50]. In the case of cervical cancer prevention, direct comparison of different screening strategies is impossible due to practical and ethical limitations [47]. Estimates of the health and economic effects of different screening strategies are usually performed using computer simulation models. Despite variations in computer software, subtleties in modeling structure, changes in technology and costs, and changes in our understanding of the natural history of cervical cancer, results of modeling studies have been remarkably consistent in their findings over the past 30 years [47,51]. As the frequency of screening increases, the ICER increases — annual screening has an ICER of well over $100,000 or more compared with biennial screening. The relatively few cases of cervical cancer and the number of cancer deaths prevented by annual screening compared with biennial screening come at the cost of many additional tests, false-positives, and detection of lesions that are unlikely to progress to cancer [45]. At a fixed
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screening interval, ICERs increase as test specificity decreases, because the cost of diagnosis and evaluation of false-positive tests comes with no gain in health outcomes (and, potentially worse quality of life, given the anxiety frequently experienced as the result of abnormal tests) [45]. ICERs also increase as test sensitivity increases, since many of the additional cervical abnormalities detected represent lesions that would not progress to cancer. These effects of sensitivity and specificity on the ICER become more predominant as test frequency increases [52]. In addition to screening intervals, the age at which women begin screening is an important factor in determining the efficiency of a screening program. After their first sexual intercourse, younger women have a high incidence of HPV and HPV-related benign cervical changes. Thus, there is a very high probability of detecting, diagnosing, and treating cervical changes that will never develop into cancer [45]. In addition, there is evidence that many CIN 2 lesions in this age group do not truly represent precancerous lesions with a clear potential to progress to invasive cervical cancer [37]. Aggressive treatment of these lesions also increases the risk of subsequent adverse obstetric outcomes [53]. In women older than 65 years, screening is also inefficient, especially if they have recently documented normal screening tests [45], since the incidence of cervical cancer in this age group is low [54]. Cervical cancer screening: considering access and adherence Insights gained from modeling have been extremely helpful in identifying the main trade-offs involved in balancing screening frequency, test characteristics, and ages of screening. However, much of the historical reluctance to embrace less frequent screening intervals in the US has been due to the issues of access and adherence. The risk for developing cervical cancer is 2 to 10 times higher among those women who have never been screened, and increases with the length of time since a woman's last cervical screen [15]. In the US, more than 50% of women with cervical cancer have never been screened for the disease,
and 60% of women have not undergone screening in the past five years [3,55,56]. Significant disparities in cervical cancer incidence and mortality exist in certain ethnic populations, and between education and income levels. These disparities are largely related to screening access and utilization [57,58]. Screening: current guidelines Current cervical screening guidelines are provided in Table 1, which include consideration of the issues previously discussed, including costs and cost-effectiveness. Although different groups may have some variation in specific recommendations, all recognize that there is no perfect balance between test sensitivity and specificity, age to begin screening, frequency and access of screening, adherence to guidelines, and cost-effectiveness. Screening: issues prior to the introduction of HPV vaccines Without considering the potential impact of prophylactic HPV vaccines, screening as a method for the prevention of cervical cancer faces several challenges. Of these, the most important appears to be identifying ways to increase coverage and adherence. It is also important to determine whether it is possible to incorporate more sensitive but less specific tests, particularly by considering lengthening screening intervals. Another challenge is the development of affordable methods to identify women truly at risk for cervical cancer. The introduction of effective HPV prophylactic vaccines will impact all three of these major areas. Vaccines against cervical cancer and modeling of the impact of HPV vaccines on screening Two prophylactic vaccines protecting against precancerous lesions and invasive cervical cancer have been developed; one currently licensed in the US (Gardasil®; Merck & Co., Whitehouse Station, NJ), and another (Cervarix®; GlaxoSmithKline, Rixensart, Belgium) that expects to gain US approval
Table 1 Screening guidelines for detection of precancerous lesions and cervical cancer
Initiation of Screening
American Cancer Society (ACS) 1, 2
US Preventive Services Task Force (USPSTF) 3
Screening initiated at age 21 or 3 years after sexual debut, whichever occurs first
Screening initiated at age 21 or 3 years after Screening initiated at age 21 or 3 years after sexual debut, whichever occurs first sexual debut, whichever occurs first
Screening Interval Annually Women b30 years Not applicable Every 2 to 3 Years Women ≥30 years: Not applicable • Conventional Pap test after 3 negative screens • LBC after 3 negative screens Every 3 Years Women ≥30 years: Either conventional Pap test or LBC 3 years after first sexual activity or age 21 • LBC plus HPV testing if both HPV-DNA and cytology are negative 1 2 3 4
Saslow D et al. CA: A Cancer J Clin. 2002; 52:342–62. U.S. Preventive Services Task Force. Available at: http://www.ahrq.gov/clinic/uspstf/uspscerv.htm. ACOG. Practice Bulletin 45: Cervical Cytology Screening. 2003. American Cancer Society Guidelines for the Early Detection of Cancer. 2007.
American College of Obstetricians and Gynecologists (ACOG) 4
Women b30 years Women ≥30 years: • Conventional Pap test after 3 negative screens • LBC after 3 negative screens Women ≥30 years: • LBC plus HPV testing if both HPV-DNA and cytology are negative
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Table 2 Modeling of the impact of vaccination on screening⁎ [61] Sanders and Taira [74]
Kulasingam and Myers [63]
Goldie, et al [64]
Taira, et al [75]
Main Characteristics Model
State-transition Markov model
State-transition Markov model
State-transition Markov model
Perspective
Direct medical costs (QOL)
Benefits
QALY
Direct medical costs (time costs and QOL in sensitivity) LYS
Societal (direct medical costs, time costs, and QOL) QALY
Hybrid (dynamic/Markov model) Direct medical costs (QOL)
90% against 70% of HR HPV types 100% of 12-year-old girls
90% against HPV 16/HPV18 (65% of cervical cancers) 100% of 12-year-old girls
63.0%
58.5%
100%
100% (5.2% never screened, 70.5% b1 year ago, 12.6% b 2 years, 4.3% b3years, 3.0% b 5 years. 9.6% b5 years Lifelong
Base-case Assumptions Efficacy 75% against 13 HR types (90% of cervical cancers) Vaccine Coverage in 70% of 12-year-old girls Target Groups Estimated Effective 47.3% Coverage Screening Compliance 71% every 2 years (same) (estimate used for comparison with current practice) Duration of Protection 10 years (boosters every 10 years) Results The Most Effective Strategy Compared with Next Best Strategy†
ICER Compared with Current Practice Main Shortcomings Factors not Accounted for
10 years
..
Vaccination of girls at 12 years, plus biennial screening at 24 years. ICER of US $44,889/LYS vs. triennial screening only starting at age 18 (US $50,000 threshold)
US $22,755 per QALY gained
..
QALY
90% against HPV 16/HPV 18 70% of 12-year-old girls only, or girls and boys 40.1% 71% every 2 years (same)
10 years (boosters every 10 years)
Vaccination of girls at 12 years .. plus triennial screening at 25 years. ICER of US $58,500/QALY gained vs. vaccination and screening every 5 years at age 21 (US $60,000 threshold) US $24,300 per QALY gained US $14,583 per QALY gained (girls only)
Herd immunity; vaccinating males; Herd immunity; vaccinating Herd immunity; vaccinating reactivation of latent infections; males; genital warts males; reactivation of latent infections; genital warts; changes genital warts in screening initiation stage
Genital warts; reactivation of latent infections; changes in screening initiation age
⁎From Newall, AT. Lancet Inf Dis. 2007. ICER = incremental cost-effectiveness ration. HR = high risk. LYS = life year saved. QALY = quality adjusted life year. QOL = quality of life. ..= not applicable. Defined here as (vaccine coverage) × (vaccine efficacy against targeted types) × (proportion of cancer caused by these types). †The next best alternative to options including vaccination is not always current practice (e.g., currently screening is not applied in the best way in many settings).
in 2008 (Table 2). Both vaccines protect against infection from oncogenic HPV types 16 and 18 [59], which cause the majority (~ 77%) of all cervical cancer cases and over 50% of high-grade intraepithelial lesions in North America [58]. Gardasil® also protects against infection from HPV types 6 and 11, which are primarily associated with genital warts. As these vaccines are introduced into settings where screening is already available, estimates are needed for the short- and long-term impact on health and economic outcomes [60]. Modeling studies Similar to the cervical screening models, published studies modeling the impact of HPV vaccines on cervical cancer screening are consistent in their qualitative findings [61]. Under assumptions of lifetime immunity and vaccine costs similar to current prices, vaccination is cost-effective (ICERs of $75,000 per QALY or less for US resources) [62] in screening settings, especially if screening intervals are lengthened [47]. Vaccination
may also help address two of the key inefficiencies with current screening: age to begin screening and screening frequency. Models have predicted that a vaccinated cohort can begin screening later and at less frequent intervals, with equivalent or better health outcomes and lower costs than an unvaccinated cohort [63,64]. Vaccines also have the potential to address the issues related to screening access and adherence. In theory, widespread vaccine coverage, particularly in targeted age groups, should be easier to ensure than ongoing coverage and adherence to screening recommendations over a lifetime. However, if vaccinated women are less likely to adhere to screening recommendations because of a belief of complete cervical cancer protection, outcomes could actually worsen [63–65]. The cost-effectiveness of cervical cancer vaccination is dependent on many currently unknown parameters, most importantly the duration of protection, and the cost and need for booster doses. One study, which compared screening practices with or without vaccination (assumed 90% vaccine efficacy) at different ages, found vaccination at age 12 with triennial screening beginning
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at age 25 years was the most cost-effective strategy, with an ICER of less than $60,000 per QALY, and a 94% reduction in the lifetime risk of cervical cancer compared with no intervention [64]. An additional model compared vaccination or cytology alone with vaccination followed by screening at varying intervals. Results showed vaccination at 12 years of age with biennial screening beginning at age 24 was the most appealing costeffective strategy ($44,889 ICER per QALY) compared with vaccination plus biennial screening beginning at age 18, or biennial screening alone at age 18 [63]. In this analysis, the ability to implement effective screening policies was dependent on adequate vaccine protection during the ages of peak oncogenic incidence [63].
One key factor should be considered in designing screening strategies for vaccinated women. Although the vaccines do not protect against oncogenic HPV types, the incidence and therefore the prevalence of precancerous lesions will decrease significantly. This means that the negative predictive value of any screening test will improve, and the positive predictive value will worsen [60]. If screening intervals are not lengthened, or test specificity not improved, then the absolute number of false-positive results will increase, with a subsequent adverse impact on both health outcomes and costs [60,65]. Especially in screening tests with high sensitivity, the increase in false-positives resulting from reduced prevalence is substantially greater than the reduction in false-negatives (Fig. 2).
Fig. 2. Effect of reduction in prevalence of CIN 2/3+ due to vaccines on absolute number of false-negatives (A) and false-positives (B) per million women screened at different levels of sensitivity and specificity.
E. Myers et al. / Gynecologic Oncology 109 (2008) S31–S39
HPV vaccines: unanswered questions Discussion of HPV vaccines is found in other sections of this supplement In addition to questions regarding the duration of protection, there are a number of other factors that will impact both the effectiveness and cost-effectiveness of vaccination and screening. Concerns whether other oncogenic HPV types will emerge as leading factors in cervical cancer once HPV 16 and 18 are largely eliminated with vaccination have been raised [66]. Occult lesions that would previously have been removed during treatment of more aggressive lesions caused by HPV 16 or 18 could now have the chance to develop [67]. However, data indicate that both vaccines provide partial cross-protection against oncogenic virus types genetically related to HPV types 16 and 18 [59,68], which could potentially increase their overall effectiveness and cost-effectiveness. The vaccination of males is currently not indicated in the US, as HPV vaccine efficacy data in this cohort are not yet available. However, studies show high seroconversion rates in young boys following vaccination against HPV types 6, 11, 16, and 18, and immunogenicity results are not statistically different from those observed in similarly aged girls [69,70]. Ongoing studies of the safety and efficacy of vaccines in young male adolescents may lead to approval for this population, as modeling studies suggest that vaccination of boys and men may introduce additional efficiencies [71]. Based on available trial data, vaccination is currently indicated for young female adolescents aged 9 to 26 years [72]. Ongoing studies in older women (up to age 55) may lead to changes in the upper age for catch-up vaccination, or may change the threshold for boosters if efficacy is not life-long and if vaccination of older women is proven to be cost-effective on a population level. In addition, current mathematical models do not comprehensively address the impact of vaccines on other diseases caused by HPV 16/18 (such as anal and oropharyngeal cancer) or HPV 6/11 (such as genital warts and recurrent respiratory papillomatosis) — diseases which also have notable health and economic burdens [73]. Conclusions Vaccination is highly effective against infection with HPV types 16 and 18, which cause the majority of all cervical cancer cases. Cervical cancer screening guidelines will need revisions; as new technologies become available, the optimal screening policies should aim to retain a balance between maximizing efficiency using more sensitive and specific tests at less frequent intervals, starting at later ages, and minimizing cancer risk on the population level. Models for vaccination suggest that the integration of vaccines into these secondary prevention measures may be cost-effective, especially if screening ages and intervals can be safely changed and successfully implemented. Although the true epidemiological and cost impact may not be seen for at least a decade, a dramatic decline in the detection of precancerous cervical
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lesions should be expected, as well as a substantial decrease in the incidence and mortality due to cervical cancer in the longer term. Conflict of interest statement EM has received research funding and done consulting for Merck & Co. WKH has done consulting for GSK, Merck, MGI Biologics, Takeda, Roche Pharmaceuticals, and Roche Molecular Systems, been a speaker for Merck, Digene, and Cytyc, served on the Advisory Board for Nventa Pharmaceuticals, and conducted research for GSK, Merck, Roche, MGI, Takeda, and Hologic. JDW has served on the Speakers’ Bureau for Merck. JSS has received research grants, honoraria, or consulting fees during the last three years from GSK, Digene and GenProbe.
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