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Risk-adapted primary HPV cervical cancer screening project in Wolfsburg, Germany – Experience over 3 years
Journal of Clinical Virology 46 (2009) S3, S5–S10
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Journal of Clinical Virology j o u r n a l h o m e p a g e : www.elsevier.com/locate/jcv
Risk-adapted primary HPV cervical cancer screening project in Wolfsburg, Germany – Experience over 3 years a Alexander Luytena , Sarah Scherbringa , Axel Reinecke-Luthge ¨ , Bernd Erich Brauna , Martina Pietrallab , b a, Klaus Theiler , K. Ulrich Petry * a Klinikum
der Stadt Wolfsburg, b Mecklenburger Str. 7, Wolfsburg, Germany
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Keywords: Primary cervical cancer screening Pap smear Cytology High-risk human papilloma virus HPV testing HC2 test
Background: Currently, the German cervical cancer screening program encompasses an annual cytological Papanicolaou (Pap) smear. However, primary screening for cervical cancer using human papillomavirus (HPV) DNA testing detects cervical pre-cancerous lesions with a significantly higher sensitivity than the Pap smear-based cytology. Objectives: In order to develop viable modalities for primary cervical screening incorporating DNA testing for high-risk (HR) types of HPV, we started a pilot project in the city of Wolfsburg, Germany, in February 2006. This program provided a risk-adapted HPV testing-based strategy with defined patient pathways and extended screening intervals for women of 30 years or older. We report here the data of a 3-year follow-up. Study design: In the context of the usual routine screening at their office-based gynecologists, women were offered conventional cytology plus the Hybrid Capture 2 (HC2) HPV DNA test. Women with inconspicuous cytological findings (Pap I/II) and negative HC2 test were re-tested after 5 years but continued their annual gynecological examinations. When cytology and HC2 were positive, women were immediately referred to colposcopy. In women with a negative cytology but positive HC2 test, Pap smear was repeated after 6 mo and HC2 testing after 12 mo, and women were called for colposcopy if the HC2 test was persistently positive. Results: From February 2006 to December 2008, 16,724 women agreed to participate in the project. Overall, 906 (5.41%) had positive HC2 results and 338 (2.02%) showed atypical Pap smears at recruitment. There were 417 (2.48%) women referred for colposcopy, 104 of whom were diagnosed with cervical intraepithelial neoplasia (CIN) 3 or worse, including 8 invasive cancers and 8 adenocarcinoma in situ (ACIS). No case of CIN 3 or worse occurred in HC2 negative women. Conclusions: The presented risk-adapted Wolfsburg Cervical Cancer Prevention Project (“Wolfsburg Model”) has been shown to be effective and feasible in identifying women at risk and for avoiding unnecessary procedures for those who are double negative, thus allowing longer screening intervals and cost savings. Acceptance rates for the program were high for both participating women and gynecologists. © 2009 Elsevier B.V. All rights reserved.
Abbreviations ACIS: AS-CUS: CIN: CIS: HC2 test: HPV: HR: HSIL: LSIL:
Adenocarcinoma in situ of the cervix Atypical squamous cells of undetermined significance Cervical intraepithelial neoplasia Carcinoma in situ Hybrid Capture 2 test Human papilloma virus High-risk High-grade squamous intraepithelial lesion Low-grade squamous intraepithelial lesion
* Corresponding author. Prof. Dr. K. Ulrich Petry, Frauenklinik im Klinikum Wolfsburg, Sauerbruchstr. 7, 38440 Wolfsburg, Germany. Tel.: +49 5361 801270; fax: +49 5361 801613. E-mail address: [email protected] (K.U. Petry). 1590-8658 /$ – see front matter © 2009 Elsevier B.V. All rights reserved.
Pap smear: Papanicolaou smear RLU: Relative light units 1. Background Cervical cancer remains the second most common tumor after breast cancer in women worldwide1 despite screening with the Papanicolaou (Pap) cervical cytologic test has been available for more than 50 years. Around two thirds of cervical cancers are squamous cell carcinoma (SCC), followed by adenocarcinoma. There are three systems used to classify several pre-malignant and benign cytological cervical abnormalities: • The World Health Organization (WHO) describes cervical dysplasia as mild, moderate, or severe as well as a separate category for carcinoma in situ (CIS).
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• The term cervical intraepithelial lesion (CIN) was developed to emphasize the spectrum of abnormality in these lesions, and to help standardize treatment. It classifies mild dysplasia as CIN 1, moderate dysplasia as CIN 2, and severe dysplasia and CIS as CIN 3. • The most recent Bethesda system divides all cervical epithelial precursor lesions into two groups: low-grade squamous intraepithelial lesion (LSIL) corresponds to CIN 1, and a high grade SIL (HSIL) encompasses both CIN 2 and CIN 3. The presence of high-risk human papillomavirus (HR-HPV) infection in virtually all cervical cancers2 has led to the suggestion that testing for HPV DNA should be included in existing cervical cancer-screening programs to further prevent the disease. Up to now, a number of large-scale randomized controlled trials and meta analyses have shown that HPV DNA testing as a primary screening parameter yields a higher sensitivity compared to the cytology Papanicolaou (Pap) smears.3–8 Cuzick et al. recently reported that primary cervical screening with the Hybrid Capture 2 (HC2) HPV DNA test (QIAGEN, Gaithersburg, USA) generally detects more than 90% of all CIN 2, CIN 3 or cancer cases, and is 25% relatively more sensitive than cytology at a cut-off of atypical squamous cells of undetermined significance (ASC-US) or LSIL if ASC-US is unavailable, but is 6% relatively less specific.9 The higher sensitivity offers several potential advantages, especially reduced cervical cancer rates and extended screening intervals for HR-HPV negative women due to the long interval of 8 to 50 years10 from initial HPV infection to the development of invasive disease. Given these facts, routine screening for cervical cancer based on Pap smears should ideally detect all high-grade neoplasia in a given population, while testing for HPV, as the causative agent of cervical cancer, should identify all individuals either having prevalent cervical neoplasia or of being at risk for developing incident cancer within the next decade. Combining both methods should enable a reliable risk stratification of the screened population and allow for the development of a risk-adapted screening program. In Germany, a yearly Pap smear based-routine cervical cancer screening program was established in 1971; it is available to all women 20 years of age or older and is covered by statutory health insurance. Although this screening has undoubtedly led to a large reduction of the disease, with 6200 annual new cervical cancer cases11 Germany still has one of the highest incidence rates in Western Europe, higher than in neighboring countries with similar socio-economic structures such as France, Italy and the Netherlands. Main disadvantages of the German screening concept based on annual Pap smears are the following: • low specificity of the routine cytology: as shown in the Hannover– Tuebingen prospective cohort study, more than 13% of healthy women attending for all annual screening rounds received at least one false positive result within five years12 • low sensitivity of the routine cytology: less than 50% will be detected by a single time Pap smear12 • poor colposcopy standards: cold knife conization without colposcopy is the standard of care in atypical Pap smears (HSIL and repeated LSIL/ASCUS) Therefore, a considerable effort was made to develop adequate screening protocols incorporating DNA testing for high-risk HPV types into existing cervical cancer screening programs to improve their quality and success.
Wolfsburg Cervical Cancer Prevention Project (“Wolfsburg Model”) were: • reduction in the incidence of cervical cancer • risk-adapted, preferably minimal-invasive diagnostics – the introduction of HPV DNA testing as a cervical cancer screening test for women 30 years and older provides an important tool for risk stratification – colposcopical assessment of women with an assumed high risk of having high-grade cervical neoplasia • establishment of defined and guideline-structured patient pathways with quality control • improvement in cervical cancer screening adherence In an earlier publication with 18 months of follow-up, we demonstrated that the acceptance of the screening concept was high with less than 1% of the screening population refusing to participate.10 In addition, there was a good selection of women at risk for cervical disease, the study demonstrated a better and earlier detection of CIN 3+, and there was a low transferral rate.10 Here we report the data based on the 3 years of follow-up since the initiation of the study. 3. Study design 3.1. Project partner The Deutsche BKK as well as the clinic of Wolfsburg/Germany and the health organizations in the German cities of Wolfsburg, Gifhorn and Braunschweig were partners for the project. Officebased gynecologists could only take part in the project if they were clients of one of these organizations. 3.2. Participants Women were eligible for the project if they were 30 years or older, a client of the Deutsche BKK and gave their written informed consent. In addition, data concerning pariety, contraception, smoking, and gynecological history of all participating women were collected. Exclusion criteria were a history of atypical Pap smear in the preceding year, previous cervical cancer or conization, hysterectomy and pregnancy. All participating women were intensively informed by their gynecologists about the screening project and the causal relation between HPV and cervical cancer. ¨ The ethics committee of the Arztekammer Niedersachsen was informed, but did not see a need for a formal opinion since the project did not involve a trial but an evidence-based pivotal project in the routine screening process. Associated scientific studies concerning new diagnostic procedures received opinions of the ethics committee without any objections. 3.3. Cytology As usual, all cervical smears were taken at each gynecological practice. All smears were analyzed at one of the cytology laboratories normally used by each participating gynecological office, and reported in accordance with the Second Munich Cytological Classification (Table 1). The “PapIIw” (w = wiederholen = repeat) is a widely used category although it is not an official cytological classification. It is employed by cytologists to describe inadequate specimens, minimal changes, koilocytes in the absence of further abnormalities or AS-CUS.
2. Objectives In February 2006, a pilot project was started in the city of Wolfsburg, Germany, offering regular routine screening for cervical cancer to women who are clients of the Deutsche BKK, a large German health insurance company. The primary aims of the
3.4. HPV DNA testing All primary HPV DNA testing was done using the HC2 test at the clinical diagnostic laboratory of the clinic of Wolfsburg. Digene cervical samplers (cervical brushes and small tubes with STM for
A. Luyten et al. / Journal of Clinical Virology 46 (2009) S5–S10 Table 1 Correlation between second Munich classification and the Bethesda system a Munich classification
Bethesda correlate
PapI/II
Normal/inflammatory
PapIII
ASC-H and AGUS – cannot exclude high-grade disease or cancer
PapIIId
CIN 1–2
PapIVa
CIN 3 – carcinoma in situ
PapIVb
Carcinoma in situ – microinvasive carcinoma
PapV
Microinvasive carcinoma – invasive carcinoma
Unofficial classification PapIIw a
Includes inadequate and ASC-US
Modified from Petry KU et al.,12 Br J Cancer 2003;88:1570–77).
transportation) were used. The HC2 test is the first FDA-approved in vitro diagnostic test for primary HPV testing in the screening setting (specific for women 30 and older). In the Wolfsburg project, only the HR-HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, included in the HC2 test, were evaluated. Samples were considered positive if they attained or exceeded the FDA-approved threshold of 1.0 pg HPV DNA ml−1 , which corresponds to 1.0 relative light units (RLU). 3.5. Patient pathways Women with negative results on both cytology (Pap I/II) and HC2 test were asked to continue their annual gynecological examination but without a Pap smear (Fig. 1). Cytology and the HPV testing would be repeated after 5 years. In women with a positive Pap smear (PapIIw, III, IIID) but a negative HC2 test, cytology was repeated after 6 months. In the case of persistent atypical Pap smears, women were referred to colposcopy. In the case of negative cytology (Pap I/II), annual Pap smears were recommended and cytology in combination with HPV testing after 5 years. In women with Pap I/II but positive HC2 test, cytology was repeated after 6 months and 12 months, and HC2 test after 12 months. In the event of positive findings, women were immediately referred to colposcopy. In unsuspicious results, there was an annual cytology testing and afterwards cytology and HC2 after 5 years. All women with PapIIw, III, IIID and positive HC2 test as well as women with Pap IV/V cytology regardless of the HC2 result were referred immediately to colposcopy.
generated request by the project headquarter followed. In the case of any discrepancy, the gynecologist was informed. The colposcopy clinic of Wolfsburg participated regularly in the benchmarking of the German Society of Cervical Pathology and Colposcopy Research Group (Arbeitsgemeinschaft Zervixpathologie und Kolposkopie) of the German Society of Gynecology and Obstetrics (Deutsche Gesellschaft fur ¨ Gynakologie ¨ und Geburtshilfe; DGGG). The data of participating gynecological offices were compared by an independent third party. In the case of any deviation, gynecologists were contacted and asked for clarification. Women with invasive cervical carcinoma were treated according to the S2-guideline of the German Gynecological Oncology Research Group (Arbeitsgemeinschaft Gynakologische ¨ Onkologie; AGO) and the recommendations of an interdisciplinary tumor board. At differential colposcopy, verified CIN 2 or CIN 3 lesions were treated surgically either with LLETZ (large loop excision of the transformation zone) or laser conization. In women who desired to have children and were under the age of 40 years, in lieu of treatment, a CIN 2 lesion could also be observed. 4. Results 4.1. Participation From February 2006 to December 2008, 16,724 women with a median age of 47.7 years participated in the project; 8,691 women were recruited in the year 2006, 5,672 women in 2007 and 2,361 women in 2008. Based on 14,012 women living in Wolfsburg, age ≥30 years, client of the BKK, and with no hysterectomy (target population), the participation rate after 34 months was 87.2%. Main exclusion criteria were hysterectomies (22.1%). There were 6,599 participants who lived in the urban fringe and not in Wolfsburg. However, we did not observe any difference in acceptance, continued participation or distribution of disease between residents of Wolfsburg and women living in the neighborhood. The acceptance among women attending gynecological offices appeared to be very high with more than 99%. 4.2. Findings 93.3% of the women were double (Pap smear and HC2) negative, 1.27% had a negative HC2 test but a positive Pap smear, 4.65% had a positive HC2 test with a normal cytology, and 0.75% were HPV-HR positive and had atypical Pap smears at recruitment (Fig. 2). HPV test Pap smear
HPV test Pap smear HPV-HR neg Pap neg
HPV-HR neg Pap pos
HPV-HR pos Pap neg
HPV-HR pos Pap pos
Repeat HPV+Pap after 5 years Routine exam annually
ASCUS/LSIL Observation HSIL Colposcopy
Repeat Pap 6 mo Repeat HPV Pap/HPV-HR pos Colposcopy
Colposcopy (immediate)
HPV-HR neg Pap neg 93.33%
Fig. 1. Patients pathways in the Wolfsburg Cervical Cancer Prevention Project (women >29 years; N = 16,724).
3.6. Quality control procedures and guideline-conform therapy The findings of all participating women were collected in a central data base at the clinic of Wolfsburg. Adherence to the patient screening and treatment pathways was supervised by regularly centralized requesting. This encompasses a regular supervision of the adherence to the designated pathways based on the central database. In case women were not invited for colposcopy as scheduled or the findings were not controlled, an automatically
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HPV-HR neg Pap pos
HPV-HR pos Pap neg
1.27%
4.65%
HPV-HR pos Pap pos 0.75%
Fig. 2. General findings in the 3-year follow-up.
4.3. CIN and invasive cervical cancer There were 417 (2.48%) of the women referred to colposcopy, of whom 151 had unsuspicious findings. 104 were diagnosed with CIN 3 or worse, including 8 with adenocarcinoma in situ, and 8 women had cervical cancer (Fig. 3). Only 11 of the 104 CIN 3+ cases were classified correctly as PapIVa or worse on cytology. At highest risk for a CIN 3-lesion or invasive cervical cancer were those women who had a positive HC2 test and abnormal Pap smear (41.9%). There were no cases of CIN 3-lesions in women who were double negative (Pap negative/HC2 test negative) or in HC2 negative women.
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analyzed for the participants who were recruited in 2006 because the full observational course for women with positive HC2 tests but normal cytology takes more than a year from initial findings to colposcopy. There were 50 out of 55 women with a positive HC2 result and atypical Pap smear finding who were transferred within 6 months to colposcopy (90.9% compliance). There were 333 out of 379 participants (87.9%) who tested positive for HPV but had normal Pap smears and 92 out of 104 (88.5%) women with negative HC2 results but atypical Pap smears were followed according to the defined pathways.
NED CIN 1 CIN 2 CIN 3 ACIS Ca
4.6. Therapy Overall, 181 women needed further treatment following colposcopical assessment. All 8 patients with invasive cancers underwent specific oncologic treatment. All 96 women with CIN 3, 63 patients with CIN 2 and 14 participants with CIN 1 were treated either by LLETZ or laser conization.
Fig. 3. CIN and invasive cervical cancer in the 3-year follow-up. NED: No evidence of disease; CIN: Cervical intraepithelial neoplasia; ACIS: Adenocarcinoma in situ of the cervix; Ca: Carcinoma.
4.4. Follow-up control of the HC2 test
5. Discussion
Altogether, 781 women (4.65%) had a positive HC2 test and a normal Pap smear. Repeat testing after one year demonstrated that 46.3% of these participants cleared HPV infections and had a negative HC2 result. Of the 328 women with a persistent HR-HPV infection, 38 women were diagnosed with CIN 3/carcinoma. Ten of these women had a suspicious cytology after 12 months, 28 women had a consistent normal cytology (Pap I/II).
As many studies have conclusively indicated, testing for the DNA of high-risk types of HPV is more sensitive than conventional cytology in detecting cervical pre-cancerous lesions.8 This scenario strongly supports the adoption of HPV DNA testing for cervical screening but raises the essential question about the best way to use the test in organized primary cancer prevention programs. We report here the 3-year follow-up data of the Wolfsburg Model, showing that cytology in combination with HPV testing yields very good risk stratification with a better and earlier detection of CIN 3+ lesions. The risk for CIN 3 or invasive cervical cancer was highest among the group with positive HC2 test and abnormal cytology (41.9%). For women with an unsuspicious Pap smear but
4.5. Adherence of patient pathways As shown in Fig. 4, 15,605 of the 16,724 participants were double negative (Pap negative/HC2 test negative). Adherence to the established patient screening and treatment pathways can be best
16,724 participants
15,605 women HPV negative Pap normal
213 women HPV negative Pap positive
781 women HPV positive Pap normal
125 women HPV positive Pap positive
36 colposcopy or histopathology
8 colposcopies
287 colposcopies
116 colposcopies
No case
No case
Fig. 4. Results 2008: detailed patient pathways with number of all cases and controlled women.
52 CIN3+
52 CIN3+
A. Luyten et al. / Journal of Clinical Virology 46 (2009) S5–S10
positive HC2 test there was a moderate risk for CIN 3/invasive cancer of 6.9%. No case of CIN 3+ was found among women with initially normal cytology and negative HC2. In our project, we offered a routine cervical screening protocol encompassing conventional cytology plus HPV testing with HC2 to all women. Participants with negative results on cytology and HC2 were re-tested after 5 years instead of annual intervals, as is usually the case in Germany. When both tests were positive, women were called immediately for colposcopy. In women with a normal Pap smear but positive HC2 test, cytology was repeated after 6 months, and HC2 testing after 12 months. These defined patient screening pathways seemed to be adequate for women with a high risk (cytology and HC2-test positive) and with no risk (double negative). In the year 2008, there were no cases of cervical cancer in 8,691 women who were recruited in 2006, while the general incidence in women outside the Wolfsburg project did not change or even increased. The incidence for cervical cancer for women above 30 years in Germany is 24/100,000.11 The incidence for women older than 30 years living in Wolfsburg and not taking part in the project was 25/100,000 in the year 2006, and 27/1000,000 in the year 2008. However, a major weakness of the model is the poor performance of cytology in detecting CIN 3+ among HC2 positive/Pap negative women. We identified 28 women with CIN 3+ including 4 ACIS and 3 invasive cancers who had 3 normal Pap smears within 12 months but a persistent positive HC2 test. This underlines that the poor sensitivity of Pap smears is related rather to a system immanent weakness than to a lack of quality control. Cytopathologists were aware of the positive HC2 results, the majority of follow-up smears were liquid based, the quality of samples was stated to be sufficient and the majority of smears were reclassified as normal on review. More detailed information will be the subject of another publication. Furthermore only 11 out of 104 CIN 3+ cases were diagnosed correctly by cytology alone. The remaining 93 cases would have received either a delayed diagnosis or even gone undetected until malignant progression. Other authors (Dillner 2008,7 Bulkmans 20073 ) proposed primary HPV screening with secondary cytology triage on all HC2-positive cases. However our data suggest that even as a triage test Pap smear might be not the best choice. HPV 16 and 18 have been proved to be associated with a significantly increased risk for development of CIN 3 among women with normal cytology.13,14 Therefore, HPV genotyping in conjunction with HR-HPV testing testing could be a better option to detect women at risk than repeated HC2 testing alone or cytology follow-up. A triage of HC2-positive patients using p16INK4a ELISA or immunocytochemistry appears to be another alternative to identify women with underlying high-grade disease.15 As shown in the 3-year follow-up data of the Wolfsburg project, the defined patient pathways and extended screening intervals proved to be feasible in identifying women with increased risk for cervical cancer, which could be minimized by appropriate control or minimal-invasive treatment. By focusing resources on those women who really need a more intensive care, one can avoid unnecessary examinations with false positive results in the majority of women without risk for cervical cancer (93.3% in our project). This approach does also translate into saving costs, as a Health Technology assessment for the German Federal Ministry of Health concluded: compared with the actual annual Pap smear screening, HPV testing in combination with cytology screening within 5 years intervals for double negative women would be cost efficient even if annual gynecological consultation would be continued.16 The reasons for that are reduced numbers of Pap smears in general, and false negative results in particular. In addition, the current approach of histological evaluation of an abnormal Pap smear by using traditional cold knife conization without prior colposcopy
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contributes to the relatively high cost of cervical cancer screening in Germany of €268.5 million per year.17 The acceptance of the Wolfsburg screening model was high; less than 1% of the women attending gynecologic practices who met the inclusion criteria did not want to participate. As a survey among the participating office-based gynecologists has shown, the annual screening was obtained as frequent as usual with no drop in participation rate, as some had expected. On the contrary, 83.3% of the women included in the Wolfsburg project in the year 2006 visited their gynecologists at least once in 2007/2008, compared to 56.6% of women who were not clients of the German health insurance BKK. Approximately 87.2% of the target population (living in Wolfsburg, age ≥30 years, client of the BKK, no hysterectomy) participated in the Wolfsburg project. Based on the existing data, the estimated number of hysterectomised women accounts for 22.1% of the target age group with a variation between 19% and 25%. Therefore, the participation rate could also range between 86% and 88%. However, this is a much better result than the German average participation in cervical cancer screening which is 45–48% for the annual screening rounds and less than 65% for attendance within 3 years. In addition, the awareness of the yearly gynecological examination was improved. The results presented here once more support the implementation of HR-HPV DNA testing as the sole primary screening test in the German screening routine, with cytology reserved for women who test HPV positive, and allowing the safe extension of the interval between cervical screenings in women with negative results both on cytology and HPV DNA-testing. This approach may reduce morbidity and mortality of cervical cancer and will avoid over-referral to colposcopy as well as mistreatment and therefore maintain sustainable costs. Acknowledgements: The authors would like to thank the German BKK, Willy-Brandt-Platz 1, 38440 Wolfsburg, for assistance in performing the pilot project. In addition, we would like to thank the following participating gynecologist: F. Asper, C. Bock, T. Buttner, ¨ E. Schrage, H. Czuczwara, G. Djatschenko, H. Eckert, M. von Freymann, J. F. Nicolai, E. Grunwald, D. Muller, ¨ Y. Hahn, I. Hettmer-Bothmann, M. Jifi, B. Kastner, ¨ B. Kayser, H. Kieslinger, R. Konigsmann, ¨ F. Schmidt, D. Levi, S. Engisch, A. Metzner, A. Miethe, N. Muller, ¨ U. Penner, A. Reinartz, E.-M. Rieck, D. Suerdieck, G.-P. Schmidt, H.-G. Muller, ¨ T. Schnabel, H.-P. Schulze, N. Trabulsi, B. Wanninger, A. Weishaupt, I. Werner, G. Wolbern. ¨ Competing interests: K. Ulrich Petry receives speaker honoraria from QIAGEN. References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108. 2. Walboomers JMM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. 3. Bulkmans NW, Berkhof J, Rozendaal L, van Kermenade FJ, Boeke AJP, Bulk S, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370:1764–72. 4. Ronco G, Segnan N, Giorgi-Rossi P, Zappa M, Casadei GP, Carozzi F, et al. Human papillomavirus testing and liquid-based cytology: results at recruitment from the New Technologies for Cervical Cancer randomized controlled trial. J Natl Cancer Inst 2006;98:765–74. 5. Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al. Human papillomavirus versus Papanicolaou screening tests for cervical cancer. N Engl J Med 2007;357:1579–88. 6. Naucler P, Ryd W, Tornberg ¨ S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007;357:1589–97.
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7. Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ 2008;13:337, a1754. 8. Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006;119:1095–101. 9. Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand MH, et al. Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries. Vaccine 2008;26(Suppl 10): K29–41. 10. Luyten A, Theiler KG, Pietralla M, Braun BE, Reinecke-Luthge ¨ A, Petry KU. Primary HPV-screening project in Wolfsburg, Germany. Experience over 18 months. Geburtsh Frauenheilkd 2008;68:268–73. 11. Krebs in Deutschland 2003–2004. H¨ aufigkeiten und Trends. Eine gemeinsame Veroffentlichung ¨ des Robert Koch-Instituts und der Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. 6. uberarbeitete ¨ Auflage, 2008. 12. Petry KU, Menton S, Menton M, van Lonen-Frosch F, de Carvalho Gomes H, Holz B, et al. Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients. Br J Cancer 2003; 88:1570–77.
13. Khan MJ, Castle PE, Lorincz A, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005;97:1072–79. 14. Kjaer SK, Høgdall E, Frederiksen K, Munk C, van den Brule AJ, Svare E, et al. The absolute risk of cervical abnormalities in high-risk human papillomaviruspositive, cytologically normal women over a 10-year period. Cancer Res 2006; 66:10630–6. 15. Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, Gillio-Tos A, De Marco L, et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2008;9:937–45. 16. Mittendorf T, Nocon M, Roll S, Muhlberger ¨ N, Sroczynski G, Siebert U, et al. HPV-DNA-Diagnostik zur Zervixkarzinomfr¨ uherkennung. Koln: ¨ Deutsche Agentur fur ¨ HTA des DIMDI Report. Schriftenreihe Health Technology Assessment 2007, Band 58. 17. Petry KU, Breugelmans JG, Benard S, Lamure E, Littlewood KJ, Hillemanns P. Cost of screening and treatment of cervical dyskaryosis in Germany. Eur J Gynaecol Oncol 2008;29:345–9.
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Journal of Clinical Virology j o u r n a l h o m e p a g e : www.elsevier.com/locate/jcv
Risk-adapted primary HPV cervical cancer screening project in Wolfsburg, Germany – Experience over 3 years a Alexander Luytena , Sarah Scherbringa , Axel Reinecke-Luthge ¨ , Bernd Erich Brauna , Martina Pietrallab , b a, Klaus Theiler , K. Ulrich Petry * a Klinikum
der Stadt Wolfsburg, b Mecklenburger Str. 7, Wolfsburg, Germany
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summary
Keywords: Primary cervical cancer screening Pap smear Cytology High-risk human papilloma virus HPV testing HC2 test
Background: Currently, the German cervical cancer screening program encompasses an annual cytological Papanicolaou (Pap) smear. However, primary screening for cervical cancer using human papillomavirus (HPV) DNA testing detects cervical pre-cancerous lesions with a significantly higher sensitivity than the Pap smear-based cytology. Objectives: In order to develop viable modalities for primary cervical screening incorporating DNA testing for high-risk (HR) types of HPV, we started a pilot project in the city of Wolfsburg, Germany, in February 2006. This program provided a risk-adapted HPV testing-based strategy with defined patient pathways and extended screening intervals for women of 30 years or older. We report here the data of a 3-year follow-up. Study design: In the context of the usual routine screening at their office-based gynecologists, women were offered conventional cytology plus the Hybrid Capture 2 (HC2) HPV DNA test. Women with inconspicuous cytological findings (Pap I/II) and negative HC2 test were re-tested after 5 years but continued their annual gynecological examinations. When cytology and HC2 were positive, women were immediately referred to colposcopy. In women with a negative cytology but positive HC2 test, Pap smear was repeated after 6 mo and HC2 testing after 12 mo, and women were called for colposcopy if the HC2 test was persistently positive. Results: From February 2006 to December 2008, 16,724 women agreed to participate in the project. Overall, 906 (5.41%) had positive HC2 results and 338 (2.02%) showed atypical Pap smears at recruitment. There were 417 (2.48%) women referred for colposcopy, 104 of whom were diagnosed with cervical intraepithelial neoplasia (CIN) 3 or worse, including 8 invasive cancers and 8 adenocarcinoma in situ (ACIS). No case of CIN 3 or worse occurred in HC2 negative women. Conclusions: The presented risk-adapted Wolfsburg Cervical Cancer Prevention Project (“Wolfsburg Model”) has been shown to be effective and feasible in identifying women at risk and for avoiding unnecessary procedures for those who are double negative, thus allowing longer screening intervals and cost savings. Acceptance rates for the program were high for both participating women and gynecologists. © 2009 Elsevier B.V. All rights reserved.
Abbreviations ACIS: AS-CUS: CIN: CIS: HC2 test: HPV: HR: HSIL: LSIL:
Adenocarcinoma in situ of the cervix Atypical squamous cells of undetermined significance Cervical intraepithelial neoplasia Carcinoma in situ Hybrid Capture 2 test Human papilloma virus High-risk High-grade squamous intraepithelial lesion Low-grade squamous intraepithelial lesion
* Corresponding author. Prof. Dr. K. Ulrich Petry, Frauenklinik im Klinikum Wolfsburg, Sauerbruchstr. 7, 38440 Wolfsburg, Germany. Tel.: +49 5361 801270; fax: +49 5361 801613. E-mail address: [email protected] (K.U. Petry). 1590-8658 /$ – see front matter © 2009 Elsevier B.V. All rights reserved.
Pap smear: Papanicolaou smear RLU: Relative light units 1. Background Cervical cancer remains the second most common tumor after breast cancer in women worldwide1 despite screening with the Papanicolaou (Pap) cervical cytologic test has been available for more than 50 years. Around two thirds of cervical cancers are squamous cell carcinoma (SCC), followed by adenocarcinoma. There are three systems used to classify several pre-malignant and benign cytological cervical abnormalities: • The World Health Organization (WHO) describes cervical dysplasia as mild, moderate, or severe as well as a separate category for carcinoma in situ (CIS).
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• The term cervical intraepithelial lesion (CIN) was developed to emphasize the spectrum of abnormality in these lesions, and to help standardize treatment. It classifies mild dysplasia as CIN 1, moderate dysplasia as CIN 2, and severe dysplasia and CIS as CIN 3. • The most recent Bethesda system divides all cervical epithelial precursor lesions into two groups: low-grade squamous intraepithelial lesion (LSIL) corresponds to CIN 1, and a high grade SIL (HSIL) encompasses both CIN 2 and CIN 3. The presence of high-risk human papillomavirus (HR-HPV) infection in virtually all cervical cancers2 has led to the suggestion that testing for HPV DNA should be included in existing cervical cancer-screening programs to further prevent the disease. Up to now, a number of large-scale randomized controlled trials and meta analyses have shown that HPV DNA testing as a primary screening parameter yields a higher sensitivity compared to the cytology Papanicolaou (Pap) smears.3–8 Cuzick et al. recently reported that primary cervical screening with the Hybrid Capture 2 (HC2) HPV DNA test (QIAGEN, Gaithersburg, USA) generally detects more than 90% of all CIN 2, CIN 3 or cancer cases, and is 25% relatively more sensitive than cytology at a cut-off of atypical squamous cells of undetermined significance (ASC-US) or LSIL if ASC-US is unavailable, but is 6% relatively less specific.9 The higher sensitivity offers several potential advantages, especially reduced cervical cancer rates and extended screening intervals for HR-HPV negative women due to the long interval of 8 to 50 years10 from initial HPV infection to the development of invasive disease. Given these facts, routine screening for cervical cancer based on Pap smears should ideally detect all high-grade neoplasia in a given population, while testing for HPV, as the causative agent of cervical cancer, should identify all individuals either having prevalent cervical neoplasia or of being at risk for developing incident cancer within the next decade. Combining both methods should enable a reliable risk stratification of the screened population and allow for the development of a risk-adapted screening program. In Germany, a yearly Pap smear based-routine cervical cancer screening program was established in 1971; it is available to all women 20 years of age or older and is covered by statutory health insurance. Although this screening has undoubtedly led to a large reduction of the disease, with 6200 annual new cervical cancer cases11 Germany still has one of the highest incidence rates in Western Europe, higher than in neighboring countries with similar socio-economic structures such as France, Italy and the Netherlands. Main disadvantages of the German screening concept based on annual Pap smears are the following: • low specificity of the routine cytology: as shown in the Hannover– Tuebingen prospective cohort study, more than 13% of healthy women attending for all annual screening rounds received at least one false positive result within five years12 • low sensitivity of the routine cytology: less than 50% will be detected by a single time Pap smear12 • poor colposcopy standards: cold knife conization without colposcopy is the standard of care in atypical Pap smears (HSIL and repeated LSIL/ASCUS) Therefore, a considerable effort was made to develop adequate screening protocols incorporating DNA testing for high-risk HPV types into existing cervical cancer screening programs to improve their quality and success.
Wolfsburg Cervical Cancer Prevention Project (“Wolfsburg Model”) were: • reduction in the incidence of cervical cancer • risk-adapted, preferably minimal-invasive diagnostics – the introduction of HPV DNA testing as a cervical cancer screening test for women 30 years and older provides an important tool for risk stratification – colposcopical assessment of women with an assumed high risk of having high-grade cervical neoplasia • establishment of defined and guideline-structured patient pathways with quality control • improvement in cervical cancer screening adherence In an earlier publication with 18 months of follow-up, we demonstrated that the acceptance of the screening concept was high with less than 1% of the screening population refusing to participate.10 In addition, there was a good selection of women at risk for cervical disease, the study demonstrated a better and earlier detection of CIN 3+, and there was a low transferral rate.10 Here we report the data based on the 3 years of follow-up since the initiation of the study. 3. Study design 3.1. Project partner The Deutsche BKK as well as the clinic of Wolfsburg/Germany and the health organizations in the German cities of Wolfsburg, Gifhorn and Braunschweig were partners for the project. Officebased gynecologists could only take part in the project if they were clients of one of these organizations. 3.2. Participants Women were eligible for the project if they were 30 years or older, a client of the Deutsche BKK and gave their written informed consent. In addition, data concerning pariety, contraception, smoking, and gynecological history of all participating women were collected. Exclusion criteria were a history of atypical Pap smear in the preceding year, previous cervical cancer or conization, hysterectomy and pregnancy. All participating women were intensively informed by their gynecologists about the screening project and the causal relation between HPV and cervical cancer. ¨ The ethics committee of the Arztekammer Niedersachsen was informed, but did not see a need for a formal opinion since the project did not involve a trial but an evidence-based pivotal project in the routine screening process. Associated scientific studies concerning new diagnostic procedures received opinions of the ethics committee without any objections. 3.3. Cytology As usual, all cervical smears were taken at each gynecological practice. All smears were analyzed at one of the cytology laboratories normally used by each participating gynecological office, and reported in accordance with the Second Munich Cytological Classification (Table 1). The “PapIIw” (w = wiederholen = repeat) is a widely used category although it is not an official cytological classification. It is employed by cytologists to describe inadequate specimens, minimal changes, koilocytes in the absence of further abnormalities or AS-CUS.
2. Objectives In February 2006, a pilot project was started in the city of Wolfsburg, Germany, offering regular routine screening for cervical cancer to women who are clients of the Deutsche BKK, a large German health insurance company. The primary aims of the
3.4. HPV DNA testing All primary HPV DNA testing was done using the HC2 test at the clinical diagnostic laboratory of the clinic of Wolfsburg. Digene cervical samplers (cervical brushes and small tubes with STM for
A. Luyten et al. / Journal of Clinical Virology 46 (2009) S5–S10 Table 1 Correlation between second Munich classification and the Bethesda system a Munich classification
Bethesda correlate
PapI/II
Normal/inflammatory
PapIII
ASC-H and AGUS – cannot exclude high-grade disease or cancer
PapIIId
CIN 1–2
PapIVa
CIN 3 – carcinoma in situ
PapIVb
Carcinoma in situ – microinvasive carcinoma
PapV
Microinvasive carcinoma – invasive carcinoma
Unofficial classification PapIIw a
Includes inadequate and ASC-US
Modified from Petry KU et al.,12 Br J Cancer 2003;88:1570–77).
transportation) were used. The HC2 test is the first FDA-approved in vitro diagnostic test for primary HPV testing in the screening setting (specific for women 30 and older). In the Wolfsburg project, only the HR-HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, included in the HC2 test, were evaluated. Samples were considered positive if they attained or exceeded the FDA-approved threshold of 1.0 pg HPV DNA ml−1 , which corresponds to 1.0 relative light units (RLU). 3.5. Patient pathways Women with negative results on both cytology (Pap I/II) and HC2 test were asked to continue their annual gynecological examination but without a Pap smear (Fig. 1). Cytology and the HPV testing would be repeated after 5 years. In women with a positive Pap smear (PapIIw, III, IIID) but a negative HC2 test, cytology was repeated after 6 months. In the case of persistent atypical Pap smears, women were referred to colposcopy. In the case of negative cytology (Pap I/II), annual Pap smears were recommended and cytology in combination with HPV testing after 5 years. In women with Pap I/II but positive HC2 test, cytology was repeated after 6 months and 12 months, and HC2 test after 12 months. In the event of positive findings, women were immediately referred to colposcopy. In unsuspicious results, there was an annual cytology testing and afterwards cytology and HC2 after 5 years. All women with PapIIw, III, IIID and positive HC2 test as well as women with Pap IV/V cytology regardless of the HC2 result were referred immediately to colposcopy.
generated request by the project headquarter followed. In the case of any discrepancy, the gynecologist was informed. The colposcopy clinic of Wolfsburg participated regularly in the benchmarking of the German Society of Cervical Pathology and Colposcopy Research Group (Arbeitsgemeinschaft Zervixpathologie und Kolposkopie) of the German Society of Gynecology and Obstetrics (Deutsche Gesellschaft fur ¨ Gynakologie ¨ und Geburtshilfe; DGGG). The data of participating gynecological offices were compared by an independent third party. In the case of any deviation, gynecologists were contacted and asked for clarification. Women with invasive cervical carcinoma were treated according to the S2-guideline of the German Gynecological Oncology Research Group (Arbeitsgemeinschaft Gynakologische ¨ Onkologie; AGO) and the recommendations of an interdisciplinary tumor board. At differential colposcopy, verified CIN 2 or CIN 3 lesions were treated surgically either with LLETZ (large loop excision of the transformation zone) or laser conization. In women who desired to have children and were under the age of 40 years, in lieu of treatment, a CIN 2 lesion could also be observed. 4. Results 4.1. Participation From February 2006 to December 2008, 16,724 women with a median age of 47.7 years participated in the project; 8,691 women were recruited in the year 2006, 5,672 women in 2007 and 2,361 women in 2008. Based on 14,012 women living in Wolfsburg, age ≥30 years, client of the BKK, and with no hysterectomy (target population), the participation rate after 34 months was 87.2%. Main exclusion criteria were hysterectomies (22.1%). There were 6,599 participants who lived in the urban fringe and not in Wolfsburg. However, we did not observe any difference in acceptance, continued participation or distribution of disease between residents of Wolfsburg and women living in the neighborhood. The acceptance among women attending gynecological offices appeared to be very high with more than 99%. 4.2. Findings 93.3% of the women were double (Pap smear and HC2) negative, 1.27% had a negative HC2 test but a positive Pap smear, 4.65% had a positive HC2 test with a normal cytology, and 0.75% were HPV-HR positive and had atypical Pap smears at recruitment (Fig. 2). HPV test Pap smear
HPV test Pap smear HPV-HR neg Pap neg
HPV-HR neg Pap pos
HPV-HR pos Pap neg
HPV-HR pos Pap pos
Repeat HPV+Pap after 5 years Routine exam annually
ASCUS/LSIL Observation HSIL Colposcopy
Repeat Pap 6 mo Repeat HPV Pap/HPV-HR pos Colposcopy
Colposcopy (immediate)
HPV-HR neg Pap neg 93.33%
Fig. 1. Patients pathways in the Wolfsburg Cervical Cancer Prevention Project (women >29 years; N = 16,724).
3.6. Quality control procedures and guideline-conform therapy The findings of all participating women were collected in a central data base at the clinic of Wolfsburg. Adherence to the patient screening and treatment pathways was supervised by regularly centralized requesting. This encompasses a regular supervision of the adherence to the designated pathways based on the central database. In case women were not invited for colposcopy as scheduled or the findings were not controlled, an automatically
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HPV-HR neg Pap pos
HPV-HR pos Pap neg
1.27%
4.65%
HPV-HR pos Pap pos 0.75%
Fig. 2. General findings in the 3-year follow-up.
4.3. CIN and invasive cervical cancer There were 417 (2.48%) of the women referred to colposcopy, of whom 151 had unsuspicious findings. 104 were diagnosed with CIN 3 or worse, including 8 with adenocarcinoma in situ, and 8 women had cervical cancer (Fig. 3). Only 11 of the 104 CIN 3+ cases were classified correctly as PapIVa or worse on cytology. At highest risk for a CIN 3-lesion or invasive cervical cancer were those women who had a positive HC2 test and abnormal Pap smear (41.9%). There were no cases of CIN 3-lesions in women who were double negative (Pap negative/HC2 test negative) or in HC2 negative women.
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analyzed for the participants who were recruited in 2006 because the full observational course for women with positive HC2 tests but normal cytology takes more than a year from initial findings to colposcopy. There were 50 out of 55 women with a positive HC2 result and atypical Pap smear finding who were transferred within 6 months to colposcopy (90.9% compliance). There were 333 out of 379 participants (87.9%) who tested positive for HPV but had normal Pap smears and 92 out of 104 (88.5%) women with negative HC2 results but atypical Pap smears were followed according to the defined pathways.
NED CIN 1 CIN 2 CIN 3 ACIS Ca
4.6. Therapy Overall, 181 women needed further treatment following colposcopical assessment. All 8 patients with invasive cancers underwent specific oncologic treatment. All 96 women with CIN 3, 63 patients with CIN 2 and 14 participants with CIN 1 were treated either by LLETZ or laser conization.
Fig. 3. CIN and invasive cervical cancer in the 3-year follow-up. NED: No evidence of disease; CIN: Cervical intraepithelial neoplasia; ACIS: Adenocarcinoma in situ of the cervix; Ca: Carcinoma.
4.4. Follow-up control of the HC2 test
5. Discussion
Altogether, 781 women (4.65%) had a positive HC2 test and a normal Pap smear. Repeat testing after one year demonstrated that 46.3% of these participants cleared HPV infections and had a negative HC2 result. Of the 328 women with a persistent HR-HPV infection, 38 women were diagnosed with CIN 3/carcinoma. Ten of these women had a suspicious cytology after 12 months, 28 women had a consistent normal cytology (Pap I/II).
As many studies have conclusively indicated, testing for the DNA of high-risk types of HPV is more sensitive than conventional cytology in detecting cervical pre-cancerous lesions.8 This scenario strongly supports the adoption of HPV DNA testing for cervical screening but raises the essential question about the best way to use the test in organized primary cancer prevention programs. We report here the 3-year follow-up data of the Wolfsburg Model, showing that cytology in combination with HPV testing yields very good risk stratification with a better and earlier detection of CIN 3+ lesions. The risk for CIN 3 or invasive cervical cancer was highest among the group with positive HC2 test and abnormal cytology (41.9%). For women with an unsuspicious Pap smear but
4.5. Adherence of patient pathways As shown in Fig. 4, 15,605 of the 16,724 participants were double negative (Pap negative/HC2 test negative). Adherence to the established patient screening and treatment pathways can be best
16,724 participants
15,605 women HPV negative Pap normal
213 women HPV negative Pap positive
781 women HPV positive Pap normal
125 women HPV positive Pap positive
36 colposcopy or histopathology
8 colposcopies
287 colposcopies
116 colposcopies
No case
No case
Fig. 4. Results 2008: detailed patient pathways with number of all cases and controlled women.
52 CIN3+
52 CIN3+
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positive HC2 test there was a moderate risk for CIN 3/invasive cancer of 6.9%. No case of CIN 3+ was found among women with initially normal cytology and negative HC2. In our project, we offered a routine cervical screening protocol encompassing conventional cytology plus HPV testing with HC2 to all women. Participants with negative results on cytology and HC2 were re-tested after 5 years instead of annual intervals, as is usually the case in Germany. When both tests were positive, women were called immediately for colposcopy. In women with a normal Pap smear but positive HC2 test, cytology was repeated after 6 months, and HC2 testing after 12 months. These defined patient screening pathways seemed to be adequate for women with a high risk (cytology and HC2-test positive) and with no risk (double negative). In the year 2008, there were no cases of cervical cancer in 8,691 women who were recruited in 2006, while the general incidence in women outside the Wolfsburg project did not change or even increased. The incidence for cervical cancer for women above 30 years in Germany is 24/100,000.11 The incidence for women older than 30 years living in Wolfsburg and not taking part in the project was 25/100,000 in the year 2006, and 27/1000,000 in the year 2008. However, a major weakness of the model is the poor performance of cytology in detecting CIN 3+ among HC2 positive/Pap negative women. We identified 28 women with CIN 3+ including 4 ACIS and 3 invasive cancers who had 3 normal Pap smears within 12 months but a persistent positive HC2 test. This underlines that the poor sensitivity of Pap smears is related rather to a system immanent weakness than to a lack of quality control. Cytopathologists were aware of the positive HC2 results, the majority of follow-up smears were liquid based, the quality of samples was stated to be sufficient and the majority of smears were reclassified as normal on review. More detailed information will be the subject of another publication. Furthermore only 11 out of 104 CIN 3+ cases were diagnosed correctly by cytology alone. The remaining 93 cases would have received either a delayed diagnosis or even gone undetected until malignant progression. Other authors (Dillner 2008,7 Bulkmans 20073 ) proposed primary HPV screening with secondary cytology triage on all HC2-positive cases. However our data suggest that even as a triage test Pap smear might be not the best choice. HPV 16 and 18 have been proved to be associated with a significantly increased risk for development of CIN 3 among women with normal cytology.13,14 Therefore, HPV genotyping in conjunction with HR-HPV testing testing could be a better option to detect women at risk than repeated HC2 testing alone or cytology follow-up. A triage of HC2-positive patients using p16INK4a ELISA or immunocytochemistry appears to be another alternative to identify women with underlying high-grade disease.15 As shown in the 3-year follow-up data of the Wolfsburg project, the defined patient pathways and extended screening intervals proved to be feasible in identifying women with increased risk for cervical cancer, which could be minimized by appropriate control or minimal-invasive treatment. By focusing resources on those women who really need a more intensive care, one can avoid unnecessary examinations with false positive results in the majority of women without risk for cervical cancer (93.3% in our project). This approach does also translate into saving costs, as a Health Technology assessment for the German Federal Ministry of Health concluded: compared with the actual annual Pap smear screening, HPV testing in combination with cytology screening within 5 years intervals for double negative women would be cost efficient even if annual gynecological consultation would be continued.16 The reasons for that are reduced numbers of Pap smears in general, and false negative results in particular. In addition, the current approach of histological evaluation of an abnormal Pap smear by using traditional cold knife conization without prior colposcopy
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contributes to the relatively high cost of cervical cancer screening in Germany of €268.5 million per year.17 The acceptance of the Wolfsburg screening model was high; less than 1% of the women attending gynecologic practices who met the inclusion criteria did not want to participate. As a survey among the participating office-based gynecologists has shown, the annual screening was obtained as frequent as usual with no drop in participation rate, as some had expected. On the contrary, 83.3% of the women included in the Wolfsburg project in the year 2006 visited their gynecologists at least once in 2007/2008, compared to 56.6% of women who were not clients of the German health insurance BKK. Approximately 87.2% of the target population (living in Wolfsburg, age ≥30 years, client of the BKK, no hysterectomy) participated in the Wolfsburg project. Based on the existing data, the estimated number of hysterectomised women accounts for 22.1% of the target age group with a variation between 19% and 25%. Therefore, the participation rate could also range between 86% and 88%. However, this is a much better result than the German average participation in cervical cancer screening which is 45–48% for the annual screening rounds and less than 65% for attendance within 3 years. In addition, the awareness of the yearly gynecological examination was improved. The results presented here once more support the implementation of HR-HPV DNA testing as the sole primary screening test in the German screening routine, with cytology reserved for women who test HPV positive, and allowing the safe extension of the interval between cervical screenings in women with negative results both on cytology and HPV DNA-testing. This approach may reduce morbidity and mortality of cervical cancer and will avoid over-referral to colposcopy as well as mistreatment and therefore maintain sustainable costs. Acknowledgements: The authors would like to thank the German BKK, Willy-Brandt-Platz 1, 38440 Wolfsburg, for assistance in performing the pilot project. In addition, we would like to thank the following participating gynecologist: F. Asper, C. Bock, T. Buttner, ¨ E. Schrage, H. Czuczwara, G. Djatschenko, H. Eckert, M. von Freymann, J. F. Nicolai, E. Grunwald, D. Muller, ¨ Y. Hahn, I. Hettmer-Bothmann, M. Jifi, B. Kastner, ¨ B. Kayser, H. Kieslinger, R. Konigsmann, ¨ F. Schmidt, D. Levi, S. Engisch, A. Metzner, A. Miethe, N. Muller, ¨ U. Penner, A. Reinartz, E.-M. Rieck, D. Suerdieck, G.-P. Schmidt, H.-G. Muller, ¨ T. Schnabel, H.-P. Schulze, N. Trabulsi, B. Wanninger, A. Weishaupt, I. Werner, G. Wolbern. ¨ Competing interests: K. Ulrich Petry receives speaker honoraria from QIAGEN. References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108. 2. Walboomers JMM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. 3. Bulkmans NW, Berkhof J, Rozendaal L, van Kermenade FJ, Boeke AJP, Bulk S, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007;370:1764–72. 4. Ronco G, Segnan N, Giorgi-Rossi P, Zappa M, Casadei GP, Carozzi F, et al. Human papillomavirus testing and liquid-based cytology: results at recruitment from the New Technologies for Cervical Cancer randomized controlled trial. J Natl Cancer Inst 2006;98:765–74. 5. Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al. Human papillomavirus versus Papanicolaou screening tests for cervical cancer. N Engl J Med 2007;357:1579–88. 6. Naucler P, Ryd W, Tornberg ¨ S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007;357:1589–97.
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