Scientific Institute of Public Health

Section Epidemiology Unit of Cancer Epidemiology

Working document Evaluation Breast Cancer screening

programme

IPH/EPI REPORTS Nr. 2005 – xxxProtocol for the evaluation of the Breast Cancer screening programme

Section Epidémiologie, August 2005; Bruxelles (Belgique) Institut scientifique de Santé publique, ISP/EPI REPORTS N 2005 – xxx

N° de Dépot: D/2005/xxxx/xx

Working document Evaluation Breast Cancer screening programme

Breast Cancer evaluation working group: Marc Arbyn (Institut Scientifique de Santé Publique, Wetenschappelijk Instituut Volksgezondheid), Murielle Deguerry (Observatoire de la Santé et du Social, Commission Communautaire Commune de Bruxelles Capitale - Observatorium voor Gezondheid en Welzijn van Brussels Hoofdstedelijk Gewest) Valerie Fabri (Agence Intermutualiste, Intermutualistisch Agentschap) Cinthia Lemos (Institut Scientifique de Santé Publique, Wetenschappelijk Instituut Volksgezondheid) Françoise Renard (Foundation Registre du cancer - Stichting Kankerregister ) Élisabeth Van Eycken (Foundation Registre du cancer - Stichting Kankerregister ) Anne Vandenbroucke (Centre Communautaire de Référence, Communauté Française) Pieter Vandenbulcke (Vlaams Agentschap Zog en Gezondheid, Vlaamse Gemeenshap) Herman Van Oyen (Institut Scientifique de Santé Publique, Wetenschappelijk Instituut Volksgezondheid),

Institut scientifique de Santé publique – Wetenschappelijk Instituut Volksgezondheid

Rue J. Wytsman 14

1050 Bruxelles Belgique

Tél: 02 642 57 50 Fax: 02 642 54 10

e-mail: cinthia.lemos@iph.fgov.beSite web: http://www.iph.fgov.be/epidemio/

IPH/EPI REPORTS Nr. 2005 – xxx

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PROTOCOL FOR EVALUATION OF THE BREAST CANCER SCREENING PROGRAMMES

1. Introduction.......................................................................................4 2. Breast cancer screening in Belgium......................................................6 3. The use of surrogate indicators ...........................................................9 4. Objectives .......................................................................................11 5. Material and methods .......................................................................11 6. Output and reporting........................................................................14 7. Bibliographic references....................................................................14 Annex 1 – Working group for the Evaluation of the Breast Cancer screening programmes in Belgium...........................................................................20 Annex 2- Indicators for the evaluation of breast cancer screening programme.............................................................................................................21 Annex 3 - Definition of the indicators for the evaluation .............................24 Annex 4– Results of screening programme evaluations by country..............35 Annex 5 - Time schedule for the evaluation...............................................36 Annex 6 - Budget....................................................................................36 Annex 7 - Health procedures related to screening, diagnosis and treatment of breast cancer, ........................................................................................37 Annex 8 TNM pathological classification ....................................................39 The anatomy pathology classification of the breast tumour lesions is done following the size of the primary tumour, measured in mm, the presence of regional lymph node metastasis and the presence of distant metastasis, making the Tumour-Nodule-Metastasis (TNM) classification (57). .......................................................................................39 Annex 9 - The effect of mammography screening in breast cancer mortality 40 Annex 10 - Abbreviations.........................................................................48

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1. Introduction

Worldwide, cancer is one of the main causes of morbidity and mortality. Every year, there are more than 10 millions new cancer cases and 6 million deaths. From all cancers, 1 million are women who are diagnosed with a breast cancer, and half of it occurs in high income countries of North America, West Europe, Australia, and New Zealand(1). Based on the year 2000 estimations of the International Agency for Research on Cancer (IARC) and the European Network of Cancer Registry (ENCR), in Europe, there are 350.000 new breast cancer cases diagnosed and 130.000 deaths. In Belgium during 1998, the last year with national cancer registry data available, there were 6.628 new invasive breast cancer registered. The incidence of breast cancer in Belgium, after standardisation by the European population (ESR), was 109.33 per 100.000 women, one of the highest in Europe (2). The study of the breast cancer mortality trend in Belgium had shown an increase going from 25-27 to 35-36/100.000 in the decades 1950-1980 (3). For 1997, there were 2.416 women deaths due to breast cancer registered by the National Institute of Statistics.

Figure 1 - Evolution of age-standardized rates for mortality from breast cancer in Belgium and neighbouring countries, standardized using the European reference population, 1950-1999.

15

20

25

30

35

40

45

1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000

Year

ASR

(dea

ths

/ 100

000

wom

en-y

ears

)

Belgium England & Wales France Germany The Netherlands

In the cancer registry report for Flanders, the standardised incidence rate (ESR) for invasive breast cancer showed was 137.3/100.000 in 2000 (2). The most comprehensive study on survival rates of breast cancer patients is the EUROCARE II study, published in 1999. The five-year survival rate of women suffering from breast cancer

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varied between 81% (Sweden and France) and 58% (Poland and Slovakia). This disparity was primarily ascribed to differences in access to and quality of breast cancer treatment (4). The European Against Cancer programme was launched, on the initiative of the heads of state or governments of the European Community, in a meeting hold in Milan in June 1985. After this meeting, in its Resolution of 7/07/1986(5), the Council expressed its political will to implement a European programme of action against cancer. This initiative was taken up and enhanced by the three consecutive European action plans to fight cancer, the "Europe against Cancer" (EAC) programmes” of 1987-89, 1990-94 and 1996-2002. The early aim of the Europe against cancer action was a 15% reduction in mortality rates from cancer by the year 2000 (6). As a result of the first “Europe Against Cancer” action plan, the Breast Cancer screening network (EBCN) was set up in 1990, in order to extend mammography screening throughout Europe. In 1992, the network of European experts submitted the first edition of the “European Guidelines for Quality Assurance in Mammography screening”, which resulted in technically improved mammography equipment and progress in quality assurance (6). The second edition was published in 1996, with new guidelines for quality assurance in the epidemiology and pathology of breast cancer screening (7). Then in 2001, the third edition was published, with new sections added to reflect the radiologist and radiographers training requirements and data collection system, as well the surgical aspects of the diagnosis and management of small screen detected cancers. The “European Guidelines for quality assurance of breast cancer screening and Diagnosis”, fourth edition, now on press, kept the focus on screening of breast cancer while supporting the provision of effective diagnostic services and the setting up of specialist breast units for treatment of women with breast lesion. The new edition of the guidelines support the implementation of the European Parliament resolution 2003/878/EU which recommended the member states to fight against breast cancer as a health policy priority (8).

Figure 2 - Breast cancer incidence and mortality in Europe, year 2000 estimates, using the European standard population as reference,

0 20 40 60 80 100

LatviaEstonia

RomaniaPolandGreece

SpainPortugal

LithuaniaSlovenia

ItalyAustriaNorway

LuxembourgSwitzerland

IcelandMalta

IrelandGermany

United KingdomFinland

SwedenBelgiumFrance

DenmarkThe Netherlands

Age adjusted rate/100.000

MortalityIncidence

Source: European Network Cancer Registries - Cancer Fact sheets on Breast cancer in Europe(9).

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The breast cancer screening programme was organised in Belgium, after the signature in the 25 October 2000, of the protocol of collaboration between the communities and the federal government, but the phase of implementation start between June 2001 – June 2002(10). The Intermutualistic Agency report presented that the proportion of women from the target age group, who had a mammography in the last two years (2002-2003) was 52% for Flanders and 49% for Walloon and Brussels regions(11). The proportion of women from 50 to 69 years old, who had a mammography (screening or non-screening mammography) in Belgium increased from 43% in 2001-2002, before the organisation of the screening programme, to 54% during the first screening round period 2002-2003. The National Health survey(12) organised by the Scientific Public Health Institute (IPH) in 2001 demonstrated the existence of socio-economic barriers to ensure the access to the use of mammography following a gradient of socio-economical status.

2. Breast cancer screening in Belgium The pilot projects of breast cancer screening From 1989, several loco-regional initiatives developed pilot screening programmes in Belgium(13). Early as in 1995, Leuven and Brussels provincial pilot projects were members of the European breast cancer network (EBCN)(14) (15) . This earlier provincial experience influences the actual practice of breast cancer screening in Belgium. The organization of the screening programme by mammography in Belgium The national breast cancer screening policy, the principles of collaboration between the health authorities at national and communities’ level, and the basis of organization of the breast cancer screening programme in Belgium were defined by the protocol of agreement from the 25 October 2000(10), published at the Official Bulletin, the Belgian Monitor, at the 22 December 2000. Further, there was a complementary act which oriented the transmission of data and the evaluation of the breast cancer screening programme, signed on the 30 th May 2001 (16) published on the 10 august 2001. Following this agreement, the target population for the screening programme was defined as the women from 50 to 69 years, inscribed in a health insurance and with a record at the national population register. Additionally, on the 23 may 2001, a new code (450192 and 450214) was created for the reimbursement of the screening mammography and the second reading. This two procedures are restricted to women belonging to the target age group (17). In the Inter-ministerial conference of the 13 June 2005 (18) , the federal public health ministry and the communities signed the prorogation for 5 years to the amendment of the protocol of the 25 October 2000, about the implementation of the breast cancer-screening programme in Belgium. The new inter-ministerial agreement is applicable retrospectively starting on January 2004. The breast cancer screening programme structure In Belgium, the screening programme was incorporated in the existing health services. The breast cancer-screening network is considered as having a decentralised structure, which uses the general radiology unities (fixed and mobiles) and the available health services for screening and follow up.

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From the beginning of the organised screening until September 2005, a network of 297 screening unities is being set-up in Belgium, subdivided in three regional programmes in Flanders, Brussels and Walloon. The community’s health authorities have the responsibility for the organisation of the screening programmes and the invitation of the target population. In Flanders, the screening network was organised in 171 mammography unities, and 5 screening centres, with 34-second readers, recently reassembled in a consortium (www.borstkankeropsporing.be)1(19). For the Brussels region(20), a specific protocol of agreement to orient the implementation of the breast cancer screening programme in Brussels was signed on the 6 Mai 2002 between the CCC/GGC of Brussels and the Flemish and French communities. Actually, in the Brussels region there are 32 certified radiological screening centres and the activities are coordinated by Brumammo ( www.brumammo.be)(21). At the Walloon region (22), there is a network of 91 screening unities situated in the French speaking community and 2 others under the responsibility of the German speaking community. The Walloon network is coordinate by five provincial coordination centres and the community centre of reference (CCR)( www.mammotest.be). The federal level is responsible for the reimbursement of the screening mammography fees through the National Institute for health insurance and sickness (INAMI/RIZIV) and the evaluation on the national level of the programme performance under responsibility of the Scientific Public Health Institute (IPH). The invitation system The invitation to participate in the breast cancer-screening programme in Belgium is done through two pathways: by the sending of an invitation letter to the women belonging to the target or eligible population address or by the prescription for a screening mammography (or mammotest) by the general practitioner or gynaecologist. The management of the invitation system is under responsibility of the screening centres (Flanders), or provincial coordination centres (Walloon) or Brumammo (Brussels) who receives a list of the target population from the social security cross point database (BCSS/KCZ) (23) or by the Flanders administration. At the beginning in June 2001, when the screening programme started in Flanders the only way of participation was by means of a prescription from the GP or gynaecologist, as the first path. Three months later, a second pathway was organised progressively, by the sending a nominal invitation letter with a fixed appointment in one of the certified mammography unity. In Brussels at the beginning of the screening programme from June 2002, the prescription by a medical practitioner was the single mode of invitation, few months later the system of sending a letter of invitation started in February 2003. In Walloon region the breast cancer-screening programme started also in June 2002 with the prescription of the screening mammography by medical doctors. Three months later from September 2002 the system of sending of an invitation letter started. Via this letter, the women are invited to take an appointment in one of the certified radiological unity presented in an annex to the invitation letter. Only for the Flanders region, every woman resident belonging to the age group is invited to participate in the breast-screening programme, at contrary in the other programmes only the

1 Draaiboek Vlaams bevolkingsonderzoek naar borstkanker, administratie gezondheidszorg van de Vlaamse Gemeesnchap.

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women who have the national health insurance (INAMI/RIZIV) are beneficiaries of the screening mammography. The quality assurance of the mammography The quality assurance of the screening mammography is guarantee by the application of technical standards and by the organisation of the double reading, following the recommendations of the European Guidelines for quality assurance in mammography screening (24). The communities and the CCC/GGC of Brussels are the responsible for the accreditation of the mammography units and the screening centres. The periodical radiographic and technical quality control is under responsibility of the screening centres (Flanders) or communitarian reference centre (Walloon) or Brumammo (Brussels) under supervision of the communities. Other initiatives were developed to strengthening the quality of the screening test, as the training of radiologist and the establishment of standardised data collection tools. The screening mammography is performed in two views, for initial and subsequent screening rounds. In Belgium the opportunistic screening, which follows the usual care without application of the screening standards of quality, is a common medical practice that is used by many radiologist, gynaecologist and general practitioners. The follow-up of women with abnormal screening mammographies The general practitioners or gynaecologists have to assure that the follow up of women found with abnormal signs in the screening mammography is realised in the usual health care. In the protocol of 25th October 2000, the different partners agreed to ensure that the screening mammography results would be send to the chosen general practitioner or/and gynaecologist, the professionals responsible for the follow-up. Still, the same protocol considered that screening is not justifiable if the follow up is not assured. Several initiatives were developed to ensure the quality of the follow up by the three screening programmes. First by the development of a standard result letter, that is sent to the general practitioner and/or gynaecologist responsible for given the mammography results and eventually, orientation for further assessment to the women found with abnormal screening mammography. In Flanders, the letter of result is send directly to the screened women, independently of the results. When the mammography presents signs indicating abnormalities, the screened women receives the recommendation to contact her doctor for further assessment. Another action to ensure the quality of the follow up is the standardisation of the data collection about the follow up of the women with an abnormal mammography. The screening centres (Flanders) or provincial coordination centres (Walloon) or Brumammo (Brussels) are responsible for the transmission of results to the primary care physician and for the collection of the follow up data. In 2003 in Belgium, the Royal decree that defined the standards for oncology care was published, to improve the quality of care of cancer patients (25). By this decree the hospital and/or oncology services should establish quality guidelines, which provides the orientations for diagnosis, treatment and follow up of cancer patients. This could be an opportunity to standardise guidelines for the follow up of women with abnormal mammography or for the management of breast cancer patients. Another initiative to ensure the quality of the follow up of women with breast pathology in Belgium is under discussion in the Belgian Senate (26). The new project of law presented on the 26 September 2005 adapts to the Belgian health care, the European Parliament resolution

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of 2003(27) and the standards recommended by the European society of mastology (EUSOMA), in how to guarantee that the diagnostic of breast pathology follows established quality standards. European recommendations about the follow-up of women with abnormal mammography The European society of mastology (EUSOMA) established standards for the creation of the specialised breast clinics(28), guidelines for quality assurance of the breast lesions diagnosis(29), etc. Additionally, the European breast cancer network proposed the standards for surgical treatment of mammography detected breast lesions (30). An Audit System on Quality of Breast Cancer Treatment (QT) was created to help monitoring of breast cancer diagnosis, treatment and follow-up. A multidisciplinary team from the European Breast Cancer Network, sponsored by the “Europe Against Cancer Programme developed the audit system. The outcome measures include those defined by the Third edition of the European Guidelines for Quality Assurance in Mammography Screening (2001) and the European Society of Mastology (EUSOMA). The QT includes several parts such as screening, further assessment, surgery, pathology, radio, hormone, chemotherapy and follow-up. The software can be downloaded at the EUSOMA website, http://www.eusoma.org/Engx/BreastUnits/Default.aspx?cont=qt. Adverse effects of breast screening The adverse effects of breast screening programme are mainly related to the false positive results, which are inevitable in screening, with a large variation between different screening programmes. Fortunately, between 50 to 90% of women who are referred for further assessment after a positive screening mammography will prove not have breast cancer. These false positive mammograms generate anxiety, additional medical visits and diagnostic tests. Overdiagnosis is the term used to describe the detection of cancers that would never have been found without screening. Patients who have such slow growing cancers experience only the harm related to screening: the anxiety associated with the diagnosis of cancer and the complications related to the therapy. From the experience in the randomized trials of mammography, between 5 to 25% of the cancers detected by mammography may represent overdiagnosis. Overdiagnosis increases the cost of screening and complicates the evaluation of the programme. Evidence from clinical studies suggests that a proportion of ductal carcinomas in situ (DCIS) will progress to invasive cancer. Some 20% of women in whom breast cancer is diagnosed have a DCIS, the treatment of such lesions will prevent development of an invasive cancer. The greatest opportunity for reducing false-positive results is in improving radiological quality standards, including the interpretation skills of the radiologist. The exposure to radiation is a known risk factor for breast cancer; because of this the exposure of women to the radiation from mammography should be the lowest compatible with adequate image quality. The risk of radiation-induced breast cancer decreases with age and is particularly low for women after the menopause (1).

3. The use of surrogate indicators All measures of performance of breast cancer screening programmes are compared with targets or expected values, which are derived from the results from the randomized controlled trials. The application of the performance indicators based in the results of the RCT trials, adjusted to the local conditions, allows the prediction of the eventual reduction in the breast cancer mortality likely to be achieved in a national or community screening programme(1).

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However the expected reduction in mortality will be observable only after several years of the introduction of the screening program, for this reason, surrogate indicators were proposed to evaluate the quality of the screening programs and to estimate the expected impact on mortality. When estimating the impact of mammography screening in the breast cancer mortality reduction in Belgium, the contribution of the both types of screening (organised and opportunistic) by mammography should be analysed. Following the European guidelines for quality assurance (24), the minimum indicators for assessing the performance of a breast cancer-screening programme are:

− Participation rate, − Technical repeat rate, − Recall rate, − Additional imaging rate at the time of screening, − Proportion of pre-treatment diagnosis of the malignant lesions, − Image-guided FNAC procedures with insufficient results, − Benign to malignant biopsy ratio − Proportion of women re-invited within the specified screening interval.

In Belgium, the Royal decree from the 23 may 2001, which established the reimbursement of the screening mammography does not authorize the combination of another medical procedure with the screening mammography, excluding the possibility of measure the additional imaging rate at the time of screening (17). The screening programme effectiveness depends on a high participation rate, the respect of the inter-screening interval (every 24 months) and the quality control of the screening test. Additionally, the screening programme should guarantee that every women found with abnormal mammography must have an adequate follow-up (1) . The measurement of the early surrogate indicators and the follow of their evolution over time, can predict the reduction in breast cancer mortality, like the interval cancer rate, cancer detection rate, the distribution of the stage at diagnosis of screen-detected cancers, the proportion of screen detected invasive cancers < 10 mm, the proportion of screen detected invasive cancers stage II or more, and the proportion of screen-detected cancers without lymph node metastases (24). The European guidelines for quality assurance in mammography screening (24) was elaborated upon the experience acquired since 1988 through the European Breast Cancer Network(EBCN)(31) and European Reference Organization for Quality Assured Breast screening and Diagnostic services (EUREF) (32). This document is at the European level, the reference document for the organisation and evaluation of the breast cancer screening programmes. Furthermore, the European Network of Cancer Registry (ENCR) published the reference for the evaluation and monitoring of the screening programmes through the strengthening of the link between screening programmes and the cancer registry (33). In general, the outcomes of a cost-effectiveness analysis of breast cancer screening programme are defined as the number of breast cancer deaths prevented and the number of life years gained by participating in the screening(34;35). The most important benefit of an effectiveness breast cancer-screening programme is a reduction in breast cancer mortality, together with life-years gained in relatively good quality. If screening is effective, it also leads to a reduction in advanced stage disease. This is important not only from the point of view of reduced costs due to less radical treatment but especially from the perspective of improved quality of life, less morbidity(36). Many factors determine the favourable or unfavourable effect of screening, and possibly, its cost-effectiveness. Important variables are improved prognosis of cases detected at screening, the predictive value of the screening test and the detection of DCIS that would have progressed to invasive carcinoma.

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The cost of systematic breast cancer screening can be divided roughly into those for organizing and implementing the programme, those for assessment of women found with abnormal mammography, including false positive results, those for additional primary treatment and savings in treatment costs due to a decreased number of cases of advanced disease(37).

4. Objectives General objective To evaluate the effectiveness and quality of the breast cancer screening programme in Belgium Specific

a) To measure the participation in the screening programme b) To assess the quality of the screening process c) To measure the impact of screening d) To compare the global results achieved, at national and regional level, to the

international targets e) To measure the cost related to the screening programme

i. Cost Screening ii. Cost Diagnosis iii. Cost Treatment iv. Number of deaths prevented by screening

5. Material and methods Material The Pre-requisite for the evaluation For the global breast cancer screening programme evaluation to be done the following activities should be implemented:

o Utilisation of standardised forms for data collection o Use of National Social Insurance Number (NISS) as personal identifier for

every record to enable to coupling of the different databases o Authorisation from the Health and Social security committee for privacy

protection to link the screening, IMA databases and cancer registry o Update of the cancer registry of Belgium

Data sources, data collection and transmission The amendment to the protocol of the 25th October 2000 (16) published on the 10 august 2001, established the screening programmes and defined the use and modes of data transmission to ensure the execution, monitoring and evaluation of the screening activities. By this document, the Scientific Public Health Institute is the organization responsible for the evaluation at federal level, in direct collaboration with the breast cancer evaluation-working group (Annex 1). The screening programme is allowed to use the social security number (NISS) as personal identifier, to ensure the evaluation of the screening programme. The further use of personal data collected during screening and follow up of women with abnormal mammography, diagnosis and treatment of breast cancer patients should be done in agreement with the law of 8 December 1992, on privacy protection and confidentiality (38). It was established that the mammography unities should obtain an informed consent for the future use of the personal data for the management and evaluation of the screening programme. Data sources required

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• Population data of the target population: women 50 to 69 years old, per year of birth

and municipality, source: National population register, « Banque carrefour pour la Sécurité sociale » and Population Database from Flanders

• Data about screening of breast cancer by mammography, source: dataset regional screening programmes

• Data from the reimbursement claims for the screening, diagnosis and treatment using the INAMI/RIZIV nomenclature codes and prices, source: Intermutualistic Agency

• Data on breast cancer cases, source: National cancer registry • Data on breast cancer deaths, source: National Institute Statistics and the Vlaamse

administratie gezondheidszorg (gezondheidsindicatoren) • Data on the participation by mode of invitation, socio-economic determinants and

demography by provinces, source: National Health Interviews 1997, 2001, 2004 (IPH),

Existing databases and forms

1. National register (women 50-69 years old, by municipality) 2. INAMI/RIZIV register 3. Intermutualistic Agency • Registry of the reimbursement claims from the INAMI/RIZIV for screening, diagnostic

and treatment of breast cancer 4. Cancer registry • Cancer registry form

5. Mortality registry • Deaths certificate for women, general and specific mortality by breast cancer 6. Borstkankerscreening in Vlanderen: • Extraction from the Flemish administration of the web-based application HERACLES, 7. Programme de dépistage du cancer du sein en Communauté française et

communauté germanophone • Extraction of French and German Communities Data base, 8. Centre de coordination de la Région bruxelloise, Observatoire de la santé

et du social, CC Commune de Bruxelles Capitale et Brumammo • Extraction of the database Brumammo

The screening programmes databases in Flanders, Walloon and Brussels The screening programmes established a list of variables to be registered about the screening test and the follow up of the mammography test. The data collection is done with the use of the national register number as the personal identifier, making possible the exchange of data with the objective to perform the evaluation of the quality of the screening programmes. The Prevention unit of the Flanders Ministry of Health developed web-based application HERACLES. This tool generates the invitation and screening result letters, and permits the registration of the screening activities. Later the records of the management system produce a report that becomes the Flanders administration dataset. These 64 variables characterise the target population, the participation path, the mammography results (first, second or third readers), the recall and their reason, the additional imaging, the screen detected cancer characteristics, the timing of results transmission to the referent medical doctor and to the women concerned, the results of the investigation of women with abnormal mammography, the screening round of participation and the interval in months between the actual screening mammography and the previous screening mammography.

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For Brussels, the office for Health and Social Affairs together with Brumammo, developed a database of 213 variables to be able to register: the identification of the eligible women, the mammography test quality, the results per reader, the follow-up advise and the transmission of the results to the referent medical doctor. The French Community centre of reference that coordinates screening programme in Walloon developed in collaboration with the IPH a database named ARTEMIS. It was conceived to assist the management of the screening programme at provincial and community level. Nowadays this database is under revision, it will include the screening data and the results of the follow up of the women who had an abnormal mammography. The Intermutualistic Agency database from the reimbursement of medical acts concerning the screening, diagnosis and treatment of breast cancer The Intermutualistic Agency was created by the health insurance organisations, as a non-governmental organisation to collect analyse and study the social security medical acts reimbursement data. The National Health Insurance Institute refunds the mammographies (screening and diagnostic), the further assessment and diagnosis and treatment. The breast cancer databases from the Foundation for the National cancer registry In 1983, a cancer registry was created under auspices of the Public Health and Social Security Ministries, the Health Insurance organizations, and the Belgium Association against cancer. The new cancer register collects data about the cancer cases to characterise the: age, sex, residence, cancer type (histology, morphology, TNM stage) and initial treatment. Later in 1996, the different sources of data (health insurance organisations, hospitals, pathology laboratories) were reassembled in a network of registration managed by the National Cancer Registry. Since 1997, the Flemish cancer registry reached a high level of exhaustivity and data quality. A similar effort should be taken to strength the network of cancer notification sources in the French community and the region of Brussels. In July 2005, a new foundation for cancer registry was created in Belgium (39). This new organisation aims to improve the quality of the cancer registration, and it will make cancer declaration obligatory from the hospitals, medical doctors and pathology laboratories. All provincial or regional cancer registries will be incorporated in the new national foundation for cancer registry network. Method The evaluation method was foreseen, in the preliminary protocol, in function of the level of the screening programme execution (40). At the screening centres (local level), the process evaluation should be done, to assess the functioning of the programme. At the communities of Flanders and Walloon and at the CCC/GGC of Brussels, they should verify the results related to the screening programme participation, the quality of the screening test and the follow-up of the abnormal mammography women and evaluation of the regional or provincial screening programme by comparing the results to European standards. The global evaluation done by the Scientific Institute of Public Health, Cancer Epidemiology unit, will focus on the assessment of programme effectiveness; by comparing the general results to European standards and by relating the benefit with the resources expend. The IPH presented a request of authorisation to have access to individual coded data, from the screening programmes and Intermutualistic Agency, to the Privacy Protection Commission (Health and Social security sub-committee). At the first phase of the breast cancer evaluation, the participation and the quality of screening process will be assessed using the individual coded databases from the screening

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programmes. Besides that, the Intermutualistic Agency database will be used to study the coverage of women from the target age group by the non-screening mammography and the estimation of the cost of screening, further assessment, diagnosis and treatment of breast cancer cases. Later, for the subsequent phases, all the screening indicators will be measured, after the merging of the screening databases and Intermutualistic agency databases will be done with the Belgium Cancer Registry. The measurement of the indicators for the evaluation will take into account the different screening rounds: initial and subsequent. The screening programmes will provide their databases in a regular basis, following their own data format and structure (dataset common of three databases, in annex). The Intermutualist Agency will provide, periodically, the individual coded data about the medical acts related to screening, diagnosis and treatment of breast cancer (list of INAMI/RIZIV 2006 codes in annex). Subsequently, the data linkage between the screening centres databases and the cancer registry database will be under responsibility of the Health Authorities of the Communities and the Foundation for cancer registry. After the merging of the databases, the resulting database will be provided for analysis at the Cancer Epidemiology unit of the IPH.

6. Output and reporting Periodically, at least four times a year, the working group for the breast cancer evaluation will meet to monitor the progress of evaluation. At the last meeting of the year, the Cancer Epidemiology Unit of the Scientific Public Health Institute will present an annual report about the results of the breast cancer evaluation. The reports about the evaluation of breast cancer screening will be submitted for approval by the working group before the results can be presented to the public or to the different health authorities at national and community level. The planned outputs about the breast cancer evaluation will be the production of an annual report, scientific articles to be submitted for publication and abstracts to present the evaluation results at International Conferences.

7. Bibliographic references (1) IARC. Breast Cancer Screening. Lyon: IARC, 2002.

(2) Van Eycken E, De Meyer L, Van de Walle G, Van Horenbeek D, Renson M. Kankerincidentie in Vlaanderen 1997-1999. D/2002/9738/I, 1-70. 2002.

(3) Arbyn M, Capet F, Abarca M. Trend of breast cancer mortality in Belgium.

IPH/EPI-REPORTS 26, 1-75. 2002. Brussels, Scientific Institute of Public Health.

(4) Quinn MJ, Martinez-Garcia C, Berrino F. Variations in survival from breast

cancer in Europe by age and country, 1978-1989. EUROCARE Working Group. Eur J Cancer 1998; 34(14 Spec No):2204-2211.

(5) Council of Europe. Resolution of the Council and the Representatives of the Governments of the Member States, meeting within the Council, of 7 July 1986, on a programme of action of the European Communities against cancer. Off J Eur Union , 1-3. 23-7-1986.

(6) Jons K. Report on breast cancer in the European Union (2002/2279/INI).

A5/0159/2003, 1-17. 7-5-2003.

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(7) European Guidelines for Quality Assurance in Mammography Screening. 2nd edition ed. I-1 tot III-26: 1996.

(8) The Council of the European Union. Council Recommendation of 2 December on Cancer Screening. Off J Eur Union 2003; 878(L327):34-38.

(9) Tyczynski JE, Bray F, Maxwell-Parkin D. Breast cancer in Europe. ENCR Cancer Fact Sheets 2002; 2:1-4.

(10) Ministère des Affaires Sociales dlSPedl, Ministerie van Sociale zaken VeL. Protocolakkoord tot samenwerking tussen de Federale Overheid en de Gemeenschappen inzake mammografische borstkankerscreening - Protocole visant une collaboration entre l'Etat Fédéral et les Communautés en matière de dépistage de masse du cancer du sein par mammographie . Belgisch Staatsblad/Moniteur belge 2000-3316, 42720-42721. 25-10-2000. 22-12-2000.

(11) De Gauquier K, Remacle A, Fabri V, Mertens R. Campagne

Borstkankersreening periode 1999-2002. 2, 1-85. 2004. Intermutualistisch Agentschap.

(12) Capet F, Arbyn M, Abarca M. Mammografische opsporing van borstkanker

in België: analyse van de gezondheidsenquêtes 1997 en 2001. IPH/EPI-REPORTS 8, 1-59. 1-4-2003. Brussels, Scientific Institute of Public Health.

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15

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Oyen H et al. Evaluation du dépistage du cancer du sein en Belgique. 1-11. 2001. Brussels, Belgium.

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groupe de travail sur l'intégration des processus de dépistage et de diagnostic de l'Initiative canadienne pour le dépistage du cancer du sein. Health Canada, editor. 1-42. 1997. Quebec.

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Annex 1 – Working group for the Evaluation of the Breast Cancer screening programmes in Belgium In 2001, when the protocol of collaboration was signed to create the screening programme, the federal health authorities and the communities recognised the importance to keep a group of expert to ensure the evaluation of the screening programme. The breast cancer screening working group responsible for the evaluation was renewed, is composed by: Marc Arbyn (Institut Scientifique de Santé Publique, Wetenschappelijk Instituut Volksgezondheid), Murielle Deguerry (Observatoire de la Santé et du Social, Commission Communautaire Commune de Bruxelles Capitale - Observatorium voor Gezondheid en Welzijn van Brussels Hoofdstedelijk Gewest) Valerie Fabri (Agence Intermutualiste, Intermutualistisch Agentschap) Françoise Renard (Foundation Registre du cancer - Stichting Kankerregister) Cinthia Lemos (Institut Scientifique de Santé Publique, Wetenschappelijk Instituut Volksgezondheid) Françoise Renard (Foundation Registre du cancer - Stichting Kankerregister ) Elysabeth Van Eycken (Foundation Registre du cancer - Stichting Kankerregister ) Anne Vandenbroucke (Centre Communautaire de Référence, Communauté Française) Pieter Vandenbulcke (Vlaams Agentschap Zog en Gezondheid, Vlaamse Gemeenshap) Herman Van Oyen (Institut Scientifique de Santé Publique, Wetenschappelijk Instituut Volksgezondheid),

20

Annex 2- Indicators for the evaluation of breast cancer screening programme

Table 4 – Participation, quality of screening, and sources of data

European Guidelines standards

Data sources Performance indicators

Acceptable Desirable Screening database

Cancer registry

IMA database

Participation rate − First − Subsequent

Regular attendance rate

> 70% > 70%

> 95%

> 75% > 75%

100%

+

+

+

+ Recall rate

− First − Subsequent −

Benign to malignant biopsy ratio

− First − Subsequent (regular

screening)

Positive predictive value of biopsy

− First − Subsequent

Cancer detection rate/1.000 − First − Subsequent

Invasive cancer/total cancers detected at screening

< 7% < 5%

< 1:1 < 1:1

>50% >75%

> 6 > 3

90%

< 5% < 3%

< 0.5:1 < 0.2:1

80-90%

+

+

+

+

+

+

+

+

+

+

21

Table 4– Quality of the screening process including the delays, and sources of data

European Guidelines

standards Data sources Surrogate indicators

Acceptable Desirable Screening database

Cancer registry

IMA database

Prevalence/ expected incidence ratio

− First − Subsequent

Proportion of in situ cancers − First & subsequent

Proportion of invasive cancers =< 10 mm

− First − Subsequent

Proportion of cancers with negative nodal status (N-)

− First − Subsequent

Proportion of advanced cancers (Stage II or more)

− First − Subsequent

Interval cancer rate/ background incidence rate

− (0-11m) − (12-23m)

Women reinvited within the specified screening interval (%)

3 x IR 1.5 x IR

10%

>20% >25%

70% 75%

25% 20%

30% 50%

>95%

> 3 x IR > 1,5 x IR

10-20%

> 25% > 30%

> 70% > 75%

< 25% < 20%

< 30% < 50%

100%

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Delay between screening mammography and the mammography results Delay between mammography result and offered assessment Delay between assessment and issuing results (>90%) Delay between decision to operate and date offered for surgery

1 5 w.d.

5 w.d.

< 5. w.d.

< 15 w.d.

10 w.d.

3 w.d. -

< 10 w.d.

+

+

+

+

+

+

+

+

Sources: Adapted from Schaffer et al, 1996, Rev Epidem et Santé Publique) (33) • European Guidelines for quality assurance in mammography screening, 3 rth edition (24) • Rapport du groupe de travail sur l’intégration des processus de dépistage et de diagnostic de l’Initiative

Canadienne pour le dépistage du cancer du sein (41), • Quality assurance in the diagnosis of breast cancer (29)

22

Table 4– Quality of the screening process, and sources of data

Data sources Performance indicators Screening database

Cancer registry

IMA database

Screening mammography coverage rate Proportion of women who had a mammography False positive rate at screening Screening sensitivity Screening specificity Absolute rate of advanced cancer detection Absolute rate of small cancer) detection Evolution of prognostic factors in target population overt time Interval between first reading of the screening mammography and the 2nd and 3rd reading results

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Table 4– Cost effectiveness Analysis and sources of data

Data sources Cost effectiveness analysis Screening database

Cancer registry

IMA database

Mortality database

Cost Screening Cost Assessment and Diagnosis Cost Treatment Number of deaths prevented by screening

+

+

+

+

+

+

+

+

+

23

Annex 3 - Definition of the indicators for the evaluation Absolute rate of advanced cancer detection: Percent change in proportion of advanced cancers (stage II-IV) detected as compared to the background situation (before screening) Context: Early predictor of the impact of screening on breast cancer mortality. The assumption is that a decrease in the rate of advanced cancers will allow for a reduction in breast cancer morbidity and mortality. Absolute rate of small cancer detection: Percent change in proportion of small cancers (< 10 mm) detected as compared to the background situation (before screening) Context: Evidence of ability of screening to advance the diagnosis of cancer an earlier stage. May indicate overdiagnosis due to screening. Benign to malign biopsy ratio: The ratio of pathologically proved benign lesions to malignant lesions for the women who had an open core biopsy or surgery. As well named the ratio of biopsy detection. It may vary between initial and subsequent screening rounds. Context: an indication of the quality of the pre-surgery assessment. Ratio benign/malign tumours: Number of benign tumours detected / Number of malign tumours detected by open core biopsy: 1 Further related indicators: Biopsy rate Definition: the proportion of the women with a breast biopsy from the women who had a screening mammography Context: an indication of the quality of the pre-surgery assessment. Biopsy rate: Number of women who had a biopsy/ Number of women who underwent screening mammography x 10.000 Further indicators: Benign biopsies/10 000 women screened: (EV09) Number of women who underwent a biopsy with a benign result/ Number of women screened x 10.000 Cancer detection rate: Proportion of women who had a pathologically proven breast cancer detected among those who underwent a screening mammography. Context: The cancer detection rate is the key indicator in the evaluation of the screening programme, showing the performance of the screening programme. It has to be considered in relation to the recall rate, cancer detection rate and the background incidence rate. In the framework of the organised screening, the cancer detection rate should be higher than the background incidence of cancer, before the development of the organised screening programme, as some cancers will have remained asymptomatic in the absence of screening. The cancer detection rate is usually much higher in the initial screening (detection of prevalent cancers) than the subsequent screening rounds. CDR: Number of cancers detected/ Number of screening mammography x 1.000

24

Further indicator: The overall cancer detection rate represents the performance of a screening programme but also reflects the age structure of the population being screened. To provide a more sensitive measure of performance the age-specific detection rate per 5 year age groups. Age-specific detection ratio= cancer detection rate in a 5 year age-group/ background expected breast cancer incidence in that age group in the absence of screening. The incidence rate for breast cancer in the denominator should reflect the expected incidence rates in the absence of screening. The expected incidence rate should increase slightly by each screening year, because it reflects the annual increase in the estimated background incidence (24). Standardized Detection Ratio(SDR)= ratio of the number of screen detected invasive cancers divided by the expected number of screen detected invasive cancers. The SDR measures the ratio of screen detected invasive cancers to the number of expected, if the screening programme was detecting invasive cancers at a similar rate as achieved by the Swedish two county (STC) randomised controlled trial. Following the STC study results the relative breast cancer mortality risk was 0.70 with 95% CI (0.58-0.85) for the women who participate regularly at the screening. The Standardized Detection Rate (SDR) is a measure of the screening performance which provides the opportunity to estimate the likely final reduction in breast cancer mortality owed to the screening programme (42) (43). Cost analysis: to evaluate the screening related cost, all immediate cost related to screening and follow up imaging, biopsy and the treatment of a breast pathology discovered during screening should be analysed. Only direct medical cost will be evaluated, excluding non medical direct cost (transport), or indirect cost (e.g., time lost from work) associated to screening (44) Cost screening mammography: defined the expenses related to the invitation, organisation and performance of the screening mammography, prescription and provision of the screening mammographies results. Cost further assessment or diagnosis: cost related to the assessment depending on the number of recalled or referred screen-positive cases and secondly on the setting in which the further diagnostic assessment is carried out. In general the higher the recall rate, the higher the false positive screen results. Diagnostic fees: any clinical evaluation fee (GP, gynacologist, radiologist, oncologist, surgery, pathologist, laboratory, etc), diagnostic cytology, pathologist or analytical investigation, fees reimbursed for additional diagnostic imaging and breast intervention procedures. Diagnostic imaging: defined as imaging used to evaluate either a clinical problem (disclosed during screening session) or a mammography abnormality identified at interpretation of screening views. Specific examinations should include subsequent additional mammography (within days to weeks of initial screening mammography), short interval follow-up mammography (3-12 months after screening mammography), ultrasound and MRI. Breast intervention procedures should be defined as fine needle biopsy cytology, imaging guided core-needle biopsy, open core biopsy or excisional biopsy. Cost Treatment: The direct cost related to the global treatment of breast cancer: surgery, chemotherapy, hormone therapy, adjuvant therapy, rehabilitation therapy, psychological support, etc; can be expressed as the cost savings associated with finding breast cancer at an earlier stage.

25

Cost of the medical procedures: related to the deficit in observed breast cancer deaths. This cost can be expressed in terms of breast cancer deaths prevented per year per woman invited for screening, per mammography, per biopsy, per breast cancer detected at screening. In the first years of implementation of a screening programme, the treatment costs will rise owing to the increase in breast cancer detection. Thereafter, when most women have been invited for incidence screening (first round), the number of breast cancers detected in an advanced stage can be expected to decrease, and the costs of extensive breast cancer treatment can be saved(36). Delay between a screening mammography and the mammography results: time interval that starts at the date of the screening mammography and finishes when the mammography result is send to the referent doctor Delay between mammography result and offered further assessment: time interval which starts at the date of the advice for further assessment and finishes when the women had been informed of the need of further assessment (notification by the referent doctor). Diagnostic interval (delay between assessment and issuing results): time interval which starts at the date of the advice for further assessment and finishes when after the complete further assessment a final diagnosis result is given (date of biopsy or start of therapy). Context: The long waiting times for the diagnostic after the information of an abnormal mammography finding is associated with anxiety, personal and family distress. Acute anxiety due to the long delays between the abnormal mammography result and the diagnosis and treatment of breast cancer had been previously described(45). Eligible population: all women eligible to attend for screening on the bases of age, geographical location and social security status. (This definition can change in time: If merging with the cancer registry: minus the woman with breast cancer before ten years ago). Evolution of prognostic factors in target population overt time: Evolution of TNM and breast tumour stage in women who had a screening mammography, an opportunistic (diagnostic) mammography and unscreened population over time Context: The more favourable the distribution of prognostic factors in screen-detected cancers with respect to clinically detected cancers, the larger the potential impact of the programme. False positive rate at screening: Proportion of women with no evidence of cancer after the complete follow up in usual care from the women who were recalled and underwent a further assessment. Context: The harm of false-positive mammograms relates to the additional testing, invasive procedures and anxiety that would never have happened in the absence of screening. The challenge is to minimize both while still detecting those cancers for which early diagnosis and treatment can alter the clinical course of disease. The false positive women are those who have a histological proven benign lesion. False positive rate at screening: Number of women with a negative further assessment/ Number of women who were recalled for further assessment after an abnormal mammogram False Positive rate at screening= % of all mammograms requiring further assessment x (1-PPV)

26

Further assessment negative: further assessment completed in usual care with no evidence of breast cancer in a woman recalled for further assessment because of an abnormal mammography signs Evidence: The review of the literature suggests that characteristics relating to the women and to the mammography process are involved. Age is inversely related to the false positive rate, and the use of post-menopausal hormonal replacement, which increase breast density, and a previous breast biopsy increases the risk of false positive result. Interval between first reading of the screening mammography and the 2nd / 3rd reading of the screening mammography: time interval that starts at the date of the first reading screening mammography and finishes when the 2nd / 3rd reading mammography result is available. Interval cancers rate: Number of cancers appearing in between two screening rounds in women who screened negative at the previous screening round Context: Measures ability of screening to advance the diagnosis of cancer as well as screening sensitivity. Interval cancers rates are inversely proportional to the expected reduction in breast cancer mortality. They are potentially useful means of evaluating the performance of a screening programme and the appropriateness of the screening interval being used. The cancer registry is essential for identifying interval cancers. Sensitive record linkage between the cancer registry and screening programme is necessary to ensure that cases are not missed. It should be possible to classify all cancers registered in women of the screening age range, into one of the following categories: screen detected cancers, interval cancers, cancer in invited but non participant woman, cancer in irregular participant, and cancer in non-invited woman (46). Interval cancers rate: Number of interval cancers/ woman-years at risk x 10.000 The number of interval cancers is defined as the cancers diagnosed following a negative screen, including those cancers missed by screening. Also, in the interval cancers will be integrated some cancers newly occurring since the last negative screen. The definition of an interval cancer can have an important effect on the calculated interval cancer rates. If a programme is falling behind in the invitation schedule and re-invitation women beyond the agreed screening interval, should interval cancers that occur during this “slippage time”, (i.e. beyond three years) be included as interval cancers. The interval cancers occurring in the slippage time should be taking into account in the evaluation of the overall success of a screening programme, but they should be not included in the evaluation of the effectiveness of the screening test in detecting cancers arising outside the screening interval (47). The woman-years at risk can be defined by three methods ((48):

• Method 1, the number of women screened negative, • Method 2, adjusting the number of women screened negative at three times periods

by removing women who had been re-screened or diagnosed with cancer before that time period.

• Method 3 takes into account the person-time elapsed between the date of the last negative screen and the date of re-screening or diagnosis of cancer, truncated at 3 years if this occurs later than 3 years.

Lives saved by screening mammography or total number of deaths prevented by screening mammography: the difference of the cumulative death

27

rate from breast cancer in women who have being screened minus women without a screening mammography SMP= screening mammography participant NSP= no screening mammography rSMP = cumulative death rate from breast cancer screening participant: number of deaths from breast cancer in women who participate in the organised screening by mammography (regular attendants) rSMP=dSMP/NSMP

rNSP = cumulative death rate from breast cancer no screening participant: number of deaths from breast cancer in women who did not participate in the organised screening by mammography rNSP=dNSP/NNSP Number of deaths prevented in the screened women (Dp)(49) Dp= NSMP * rNSP - dSMP

Confidence intervals (CI) can be estimated by assuming that the number of deaths as poisson random variables, though the estimation of the variance the 95% CI of the deaths prevented can be calculated. Participation rate: Proportion of the women who underwent a screening mammography via the 2th mode within 24 months after invitation, who belonged to the target population and who had received a letter of invitation. Participation Rate (%) (Biannual)= Number of women who underwent a screening mammography within the interval of two years period after an invitation letter/Number of women belonging to the target population who were invited for the screening mammography x 100 Further related indicators: Completeness of the variable by which mode the women participate: Number of women participants who had the mode of invitation registered/ total number of participants Participation rate by 5 years age group: number of women who underwent a screening mammography by 5 year age group/ number of women who have received a letter of invitation or a medical prescription of screening mammography, by 5 year age group. Indicators can be stratified by age, period, place, screening round, social status, etc… Predictive Positive Value (PPV) for the screening mammography: refers to the ratio of lesions that are truly positive to those tested positive (true and false positive). Context: It is intimately affected by the prevalence of breast cancer (< 1%). For breast cancer screening programmes, we can expect a low positive predictive value and a very high negative predictive value for the screening mammography. The Positive predictive value of specific interventions can be calculated for the screening mammography and in the further assessment of abnormal mammography (additional imaging, recall, cytology, recommendation for open biopsy). Results can be expected to vary between initial and subsequent screening examinations.

28

PPV= Number of cancers detected/ Number of women with a positive test who underwent the complete further assessment Further indicators: PPV of additional imaging: The number of cancers detected as a proportion of the women with positive results in additional imaging. Further assessment does not include additional mammograms for technical reasons (repeat screening tests). In practice, the denominator corresponds to those women who, after additional imaging, undergo invasive tests for diagnostic confirmation PPV of cytology: The number of cancers detected as a proportion of the women with positive cytology (suspicion of malignancy). In practice, the denominator corresponds to those women who, undergo biopsy after cytology for diagnostic confirmation PPV of recall: The number of cancers detected as a proportion of the women who were physically recalled further assessment (but excluding those for technical recall). PPV of recommendation for open biopsy: The number of cancers detected as a proportion of the women who were recommended for open biopsy. Predictive Positive Value (PPV) for the screening mammography: refers to the ratio of lesions that are truly positive to those tested positive (true and false positive). Context: It is intimately affected by the prevalence of breast cancer (< 1%). For breast cancer screening programmes, we can expect a low positive predictive value and a very high negative predictive value for the screening mammography. The Positive predictive value of specific interventions can be calculated for the screening mammography and in the further assessment of abnormal mammography (additional imaging, recall, cytology, recommendation for open biopsy). Results can be expected to vary between initial and subsequent screening examinations. PPV= Number of cancers detected/ Number of women with a positive test who underwent the complete further assessment Further indicators: PPV of additional imaging: The number of cancers detected as a proportion of the women with positive results in additional imaging. Further assessment does not include additional mammograms for technical reasons (repeat screening tests). In practice, the denominator corresponds to those women who, after additional imaging, undergo invasive tests for diagnostic confirmation PPV of cytology: The number of cancers detected as a proportion of the women with positive cytology (suspicion of malignancy). In practice, the denominator corresponds to those women who, undergo biopsy after cytology for diagnostic confirmation PPV of recall: The number of cancers detected as a proportion of the women who were physically recalled further assessment (but excluding those for technical recall). PPV of recommendation for open biopsy: The number of cancers detected as a proportion of the women who were recommended for open biopsy.

29

Prevalence/expected incidence rate: ratio of cancer detection rate, at initial and subsequent screening rounds, to the expected background incidence. Context: Measures the number of cancer detected by screening which (in the absence of over-diagnosis) should have been detected clinically at some later point in time. One of the most important contributions of the evaluation of the screening programmes is to show the evolution of breast cancer incidence following the introduction of organised screening. The underlying premise of screening is that it allows for the detection of more cancers at earlier stage, thus causing an apparent increase in cancer incidence at the prevalent or initial rounds of screening. When the estimation of the background incidence is difficult, another way to calculate the P/I rate is using the sensitivity and sojourn time, as: Prevalence at 1st screen/expected incidence rate: screening sensitivity x sojourn time Sojourn time or the pre-clinical detectable phase (PCDP), is the length of time the breast lesion is detectable by the screening mammography before the clinical phase. For the breast cancer affecting women between 50-69 years old, the mean sojourn time was described as 3.7 years, with a 95% CI (3.44-4.17) (50) Proportion of ductal carcinoma in situ detected: Proportion of ductal carcinoma in situ of the total cancers detected throughout screening, by initial and subsequent rounds Context: It is important to distinguish non-invasive and invasive cancers, as a high rate of detection of invasive cancers is the principal measurement of interest. Ductal carcinoma in situ detection rate: Number of ductal carcinoma in situ cancers detected/ total number of cancers detected by screening mammography Proportion of screening detected invasive cancers: Proportion of screening detected invasive cancers of the total invasive cancers detected during screening. Context: The progression of breast cancer can be halted by early detection of invasive cancer and treatment. By stopping the progress of the disease, screening can prevent a significant proportion of breast cancer deaths. Proportion of screening detected invasive cancers (%)= Number of screening detected invasive tumours according to the best data from pathological, histological and radiological reports/total cancers detected during screening, by initial and subsequent rounds, Proportion of screening detected invasive cancers <10mm: Proportion of screening detected invasive cancers measuring less than or equal to 10mm of diameter of the total invasive cancers detected during screening. Context: The progression of breast cancer can be halted by early detection and treatment. By stopping the progress of the disease, screening can prevent a significant proportion of breast cancer deaths. The basic mechanism for the prevention of deaths by screening is the reduction in the incidence rate of advanced tumours. Tumour size is an indicator of earlier detection and therefore a prognostic variable used to predict the outcome in terms of mortality (51). It indicates the ability of screening programmes to advance the diagnosis of cancer to an earlier stage. Tumour size is probably the most relevant early indicators of the effectiveness of breast cancer screening; this information is available in most cases in the cancer registry. The role of tumour size is well established as a predictor of case survival and consequently in the effect of screening to reduce breast cancer mortality.

30

Proportion of screening detected invasive cancers <10mm (%)= Number of screening detected invasive tumours measuring less than or equal to 10mm of diameter according to the best data from pathological, histological and radiological reports/total invasive cancers detected during screening, by initial and subsequent rounds, Proportion of screening detected cancers node-negative: Proportion of invasive cancers that are node negative of the total number of invasive cancers with axillary lymph nodes with anatomy-pathology investigation, at initial and subsequent rounds Context: The proportion of cases with positive nodes is strongly related to tumour size, and this relation is the same in screen detected as in clinically detected cases (52). Proportion of screening detected cancers node-negative: Number of invasive cancers with axillary lymph node negative/ number of invasive cancers with axillary lymph nodes with anatomy-pathology investigation x 100 Proportion of stage II+/total cancers detected: Proportion of invasive cancers at advanced stage,TNM II or more/ total of cancers detected during screening, by initial and subsequent rounds Context: A prerequisite for a reduction in breast cancer mortality is a more favourable stage distribution in screen-detected cancers compared with clinically diagnosed cancers. Tumours size and axillary lymph node involvement of invasive cancers are of central importance; they are assessed preferably after surgery (pT and pN) The categorisation of size according to pathological diameter is based on the TNM classification (UICC 1997). Proportion of advanced cancers: Number of invasive tumours presenting a TNM stage of II or more, according to the best data from pathological, histological and radiological reports/total invasive cancers detected during screening, by initial and subsequent rounds, Proportion of women that have undergone mammography: the proportion of women belonging to the eligible population who underwent a mammography within the interval of two years Context: The ECHI project, the use of mammography in the population was defined as one of the disease prevention indicators (53). Interesting to measure the migration between diagnostic to screening mammography. Proportion of women that have undergone mammography: Number of women who underwent a mammography in the two years period/ eligible population (population file from the BCSS/KCZ) x 100 Recall rate: Proportion of women who had a screening mammography and were recalled for further assessment due to the detection of an abnormal mammography signs. The abnormal mammography classification been based in the radiological reading of the presence of: (3) an abnormality of undetermined significance, (4) features suspicious of malignancy and (5) malignant features. The women recalled because the mammogram presented inadequate technical quality are excluded in the computation of recall rate. Context: the recall rate is a valuable indicator, which shows the quality of the mammography image and the reading. The recall rate is usually higher during the initial screening round, when existing tumours (prevalent) are detected than during subsequent screening (incident tumours).

31

Recall rate: Number of women who had received the recommendation of further assessment due to abnormal mammography signs/ Number of women who underwent a screening mammography x 100 Further related indicators: Technical recall rate: Number of mammogram repeated because of a technical inadequacy of the screening mammogram/ Number of women who underwent a screening mammography x 100 Regular attendance rate: proportion of women who undergo a new mammography test within the period of (24+6)30 months since the preceding test, for the women who remains as target population and have not a proven breast cancer Context: It is the regular participation (at least every two years) to the screening programme what increases its advantages. Until now, there is no indication that the benefit of screening is lost if the subsequent screening is done within an interval maximum of six months after the advisable screening interval. Regular attendance rate: At = 1 – (p0p1p2…pt) When pt = 1 – qt

qt=et / n t n*t= nt ½ ct

At = the cumulative probability estimated of return between the start and the end of the study interval which starts at time t pt = the proportion of women that are not screened between t 0 and t 30 qt= the proportion of women regular participants between t 0 and t 30

et= is the number of women which returned during the study interval which starts at time t

nt= is number of women present at the start of the study interval which starts at time t

ct= is the number of cases censured (due to death, breast cancer or the age limit of 68 years during the interval which starts at time t) Screening interval (proportion of women reinvited within the specified screening interval): the proportion of women screened within the fixed interval between two screening rounds, in months. Context: Population screening programmes usually aim at screening each woman at regular intervals, normally between 1 and 3 years. In this situation, cancers would be detected at each screening test, and clinically detected cancers would present in each of the intervals between screening rounds. The larger the interval between screens, the larger the proportion of cancers that will present clinically in the intervals (interval cancers) and the lower the overall sensitivity of the screening approach will be. For women aged 60-69, the predicted reductions in mortality with 3-yearly, 2-yearly and annual screening are predicted to be 34%, 39% and 44%, respectively (54) ,

Screening mammography coverage rate: Proportion of women belonging to the target population who underwent a screening mammography within the interval of two years

32

Context: The target group should participate in the screening activities in a sufficient number for the programme to be able to decrease the breast cancer mortality. In the randomized control trials where the breast cancer mortality reduction was described, the rate of participation was 70% or more (55). Screening mammography coverage rate: Number of women who underwent a screening mammography in the two years period/ target population (mean population in the first and second year according to the population register, or the population on 1 day of the second year) x 100 Screening programme sensitivity: The screening program sensitivity is the probability that a case in the PCDP at any time during the ongoing screening programme (and ending at the last screen) will be diagnosed following a positive test. Context: There is the need to differentiate between test sensitivity and programme sensitivity. The mammography sensitivity is the probability that a tumour in the preclinical detectable phase will be diagnosed after a positive screening test. There are a number of ways in which sensitivity can be estimated; all require knowledge of the rate of interval cancer following a negative screen, since these will include those missed by screening. However, interval cancers will also include some cancers newly arising since the last negative screen, and the proportion of the latter will increase with increasing time since a negative test (56). Screening sensitivity= Screen detected cancers/ (Screen detected cancers+Interval cancers ) S= Number of screen-detected cancers I= Number of cancers diagnosed in the interval of 24 months after the screen (interval cancers) Evidences: The traditional method is likely to overestimate sensitivity, since a number of cancers detected by screening may not otherwise appeared in the interval. Further indicator: Screening mammography sensitivity is the ability of a screening test to detect true cases of breast cancer. Proportion incidence method for estimating sensitivity calculates the rate of interval cancers as a proportion (p%) of the expected cancer incidence in the absence of screening. The sensitivity is then estimated as (100-p%). The expected incidence can be estimated from the historical incidence rates (background incidence rate before the organised screening) (33). Screening specificity: is the proportion of women without breast cancer and that had a normal screening mammography Context: To derive an estimate of specificity would require that each person dismissed as having a negative screening test is followed for ascertainment of subsequent negativity, and that those who are recalled for additional investigation following the screening test are regarded as potentially all having a malignancy. In practice ascertainment of specificity is frequently made on the basis of the results of initial mammograms. Screening specificity: ratio of truly negatives screening examinations per those who are truly negative plus false positive. Truly negative screening mammography= is a negative screening mammography which remains negative after the complete further assessment is done in the usual care, False positive screening mammography= is a positive screening mammography which after complete further assessment in usual care becomes negative (biopsy).

33

Approximate specificity: is the proportion of women who did not develop breast cancer (T-) by the total women who had a screening mammography minus the breast cancer cases (TP) Biopsy

Mammography (+) (-) (+) a b (-) c d Approximate specificity = (Negative test/N –TP) = c+d/b+c+d= Specificity = d/b+d Target population: all women eligible to attend for screening on the bases of age and geographical location. Considered as the mean population in the first and second year according to the population register, or the population on 1 day of the second year.

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Annex 4– Results of screening programme evaluations by country Table 5 – Performance indicators of the evaluation of screening programmes in nine countries.

Sources:

Screen Canada (1)

Luxembourg (2)

France (3) Australia (4) Sweden (5) Finland (5) United Kingdom

(5)

The Netherlands

(5)

Denmark (6)

Age group 50-69 50-64 50-69 50-69 40-69 50-59 50-64 50-69 50-69Period 1997-

19981992-2000 1989-

20001996-1998

1988-1992

1987-1997

1998-1999

1990-1999

1991-1999

first 11-54.7 30-59 43 51-54 87 89 74 79 71%subsequent 78 87 69%first 11.1 11 7.6 5.5 7subsequent 6.2 6 4.4 5.6 3.9first 43.8 53.1subsequent 50.8 65.6first 15.9 1.1 12subsequent 16.6 0.6 6.5first 1.6:1 1.3:1subsequent 2.2:1 1.0:1.0first 6.7 7.9 5.6 5.93 7.0 3.7 6.8 6.5 11.9subsequent 4.2 8.2 4.2 3.59 6.3 3.7 5.3 3.6 6.3

first 19.7 1.4 14.3 11 11 23 15 11subsequent 2.2 14.5 15 11 19 14first 78.5 71 76 67 61 77subsequent 72.9 83 67 69 79.3first 37.8 31.5 35.3 18.6 11 33 22 27 36

subsequent 37.3 14.6 21 33 24 31 42first 29.1

subsequent 30.9

Indicator

VPP biopsy

Rate of recall (%)

Participation rate

Cancers in situ

Cancer detection rate per 1.000 screens

Ratio tumour benign/malign for

Biopsy rate

Countries

Cancers invasifs <=10 mm N- %

Cancers <= 10 mm %

Cancers invasifs N- %

(1) Programmes organisés de dépistage du cancer du sein au Canada, Rapport de 1997-1998, Health Canada. (2) Le programme Mammographie - une expérience sur 10 ans. Fondation Luxemburgeoise contre le Cancer. (3) Dépistage du cancer du sein, Evaluation su suivi épidémiologique, situation au décembre 2000. INVS. (4) Breastscreen Australia - achievement report 1997-1998, Australian Institute of Health and Welfare. (5) Broeders, MJM, et al, European Breast Cancer Network (EBCN), Eur J Cancer Prevention 2005, 14:107-116. (6) Vejborg,I. et al, Early outcome of mammography screening n Copenhagen 1991-1999, J Med Screen 2002,9:115-119.

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Annex 5 - Time schedule for the evaluation Table 6. Time schedule for the evaluation of the breast cancer-screening programme by mammography

Activities 2005 2006 2007 2008 2009 2010 Renew of the evaluation team X Review evaluation protocol X Centralisation of screening databases At community level Transfer of databases to IPH

X

Request of Privacy commission authorisation for data linkage

X X

Update of follow up database X X X X X X Update of cancer registry X X X X X X Assessment of the screening performance and surrogate indicators

− Participation − Quality of screening − Impact of screening on cancer

epidemiology − Screening efficiency

X X

X X X X

X X X X

X X X X

X X X X

Reporting and dissemination of results X X X X X

Annex 6 - Budget This IPH should constitute a multidisciplinary team to perform the evaluation of the breast cancer-screening programme in Belgium. This team will be in charge of networking, data management and reporting, in collaboration with the working group for the Evaluation Breast Cancer screening programme. Table 7. Budget for the evaluation of the screening programme per year in EUROS, for five years. Descriptions 2006 2007 2008 2009 2010 Total Epidemiologist 65.000 65.000 65.000 65.000 65.000 325.000 Data Manager 25.000 25.000 25.000 25.000 25.000 125.000 Secretary 25.000 25.000 25.000 25.000 25.000 125.000 Subcontract 12.000 12.000 12.000 12.000 12.000 60.000 Informatics equipment

5.500 0 0 0 6.000 11.500

Consumables 2.000 2.000 2.000 2.000 2.000 10.000 Running fees (5%)

6.725 6.450 6.450 6.450 6.750 32.825

TOTAL( EURO) 141.225 135.450 135.450 135.450 141.750 689.325

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Annex 7 - Health procedures related to screening, diagnosis and treatment of breast cancer, Table 8- Health procedures and codes, INAMI/RIZIV 2006

Codes Health procedures 450096 – 450100

Mammographie par sein y compris les clichés axillaires éventuels (quel que soit le nombre des clichés) Mammographie per borst, inclusief de eventuele okselclichés (ongeacht het aantal clichés)

450192 – 450203

Mammographie des deux sein dans le cadre d’un examen de masse organisé par une autorité Mammographie van beide borsten, in het kade van een door een overheid georganiseerd bevolkingsonderzoek

450214 – 450225

Deuxième lecture de mammographie de dépistage, des deux seins, dans le cadre d’un examen de masse organisé par une autorité Tweede lezing van een screeningsmammographie van beiden borsten, in het kade van een door een overheid georganiseerd bevolkingsonderzoek

461090 - 461101

Mammographie par sein y compris les clichés axillaires éventuels (quel que soit le nombre des clichés), par médecins agréés spécialiste non radiologue Mammographie per bort, inclusief de eventuele okselclichés (ongeacht het aantal clichés), de genesheren die zijn erkend voor een ander specialisme dan rönthendiagnose

460132 – 460143

Echographie d’un sein ou des deux sein Echografieën van één of beide borsten

469394 – 469405

Echographie bidimensionnelle d’un ou des deux seins Echographieën bidimensionele van één of beide borsten

459793 –459804

Echographie combinées d’au moins deux régions anatomiques différents : contenu d’autres organes et les seins Echographie combinatie van minstens 2 verschillende anatomische regio’s: schedelinhoud en borst

459476-459480

Examen d’IRM d’un ou des deux seins, minimum 3 séquences, avec ou sans contraste, avec enregsitrement sur support soit optique, soit électromanétique NMR-onderzoek van één of beide mamae, minstens drie sequenties, met of zonder contrast, met registratie op optische of electromagnetische drager

227091 - 227102

Biopsie incisionnelle de la glande mammaire Incisie voor biopsie van de borstklier

355670 - 355681

Ponction de la glande mammaire pour examen cytologique ou injection Punctie van de borstklier voor cytologisch onderzoek of inspuilting

355913 - 355924

Supplément aux prestation 355670-355681 lorsque celles-ci sont effectuées sous contrôle échographique ou radiographique Bijkomend honorarium bij de verstrekkingen 355670-355681 wanner zij uitgevoerd worden onder echographische of radiologische controle

227032 – 227043

Exérèse d’une tumeur ou d’un kyste de la glande mammaire Verwijderen van een gezwel of cyste uit de borstklier

227054 - 227065

Mammectomie partielle ou tumorectomie associée à un curage ganglionnaire axillaire Gedeeltelijke mammectomie of tumorectomie, geassocieerd met een curage van de okselklieren

Codes Health procedures

226995 – 227006

Intervention selon Halsted ou Pattey Ingreep volgens Halsted of Pattey

226973 - 226984

Intervention selon Halsted ou Pattey avec examen anatomopathologique extemprané

37

Ingreep volgens Halsted of Pattey met extempore pathologisch-anatomisch onderzoek

226951 - 226962

Intervention selon Urban Ingreep volgens Urban

226936 - 226940

Evidement ganglionnaire de l’aisselle Uitruiming van okselklieren

227010 - 227021

Exérèse d’un tumeur située au-dessus du fascia dans les parties molles mais avec résection totale de l’organe dans lequel se situe la tumeur Verwijderen van een gezwel uit de weke weefses boven de spierfascia maar met volledige resectie van het orgaan waarin het gezwel is gelegen

588254-588265

Honoraires pour l’examen anatomo-pathologique par inclusion et coupe, d’autant de prélèvements que nécessaire, quel que soit le nombre de coupes et quel que soit le nombre d’organes examinés, y compris l’examen macroscopique éventuel, pour les prélèvements suivants: Biopsie des organes profonds siuivants:… sein et ganglion lymphatique…, etc Honorarium voor het pathologisch-anatomisch onderzoek door inclusie en coupe, van zoveel prelevementen als nodig, ongeacht het aantal coupes en ongeacht het aantal onderzochte organen, en met inbegrip van het eventueel macroscopisch onderzoek voor volgende prelevementen: Biopten van volgende diepe organen: ….borst, lymfklier,….etc

588276-588280

Honoraires pour l’examen anatomo-pathologique par inclusion et coupe, d’autant de prélèvements que nécessaire, quel que soit le nombre de coupes et quel que soit le nombre d’organes examinés, y compris l’examen macroscopique éventuel des pièces opératoires suivantes: exérèse de ganglion lymphatique, évidement ganglionnaire axillaire unilatéral, biopsie par incision du sein, tumorectomie du sein, …etc Honorarium voor het pathologisch-anatomisch onderzoek door inclusie en coupe, van zoveel prelevementen als nodig, ongeacht het aantal coupes en ongeacht het aantal onderzochte organen, en met inbegrip van het eventueel macroscopisch onderzoek voor volgende operatiestukken : lymfklierexerese, eenzijdige lymfeklier okselevidement, incisionele borstbiopsie, borsttumorectomie,…etc

588291 - 588302

Honoraires pour l’examen anatomo-pathologique par inclusion et coupe, d’autant de prélèvements que nécessaire, quel que soit le nombre de coupes et quel que soit le nombre d’organes examinés, y compris l’examen macroscopique éventuel des pièces opératoires suivantes : mammectomie partielle avec évidemment ganglionnaire, mammectomie totale avec ousand évidemment ganglinnaire,…etc Honorarium voor het pathologisch-anatomisch onderzoek door inclusie en coupe, van zoveel prelevementen als nodig, ongeacht het aantal coupes en ongeacht het aantal onderzochte organen, en met inbegrip van het eventueel macroscopisch onderzoek voor volgende operatiestukken: partiële mammectomie met okselklier uitrioming, totale mamectomie met of zonder oksleklier uitruiming,…etc

Codes Health procedures 588416-588420

Honoraires pour l’éxamen cytopahologique pour la recherche de cellules néoplasiques (après frottis et/ou inclusion), de prélèvements non précisés dans les prestations 588350-588361 ou 588394-588405, quel que soit le nombre de frottis et :ou d’inclusions, par prélèvement Honorarium voor het cytopathologisch onderzoek voor het opzoeken van neoplastische cellen (zowel na uitstrijken en/of insluiten), van afnamen niet gespecifieerd in the verstrekkingen 588350-588361 en 588394-588405, ongeacht het aantal uitstrijkpreparaten en/of insluiten, per afname

350372-350383

Rapport d’une concertation oncologique multidisciplinaire avec la participation d’au moins trois médecins de spécialités différentes sous la direction d’un médecin coordinateur et reprenant la description du diagnostic

38

et du plan de traitement Shriftelijk verslag van een multidisciplinair oncologisch consult met deelname van minstens drie geneesheren van verschillende specialismen onder leiding van een genesheer-coordinator, met beschrijving van de diagnose en van het behandenlingsplan

350394-350405

Participation à la concertation oncologique multidisciplinaire Deelname aan een multidisciplinair oncologisch consult

350416-350420

Participation à la concertation oncologique multidisciplinaire par le médecin traitant qui n’est pas membre de l’équipe hospitalière Deelname aan een multidisciplinair oncologisch consult door de behandelende arts die geen deel uitmaakt van de ziekenhuisstaf

Annex 8 TNM pathological classification The anatomy pathology classification of the breast tumour lesions is done following the size of the primary tumour, measured in mm, the presence of regional lymph node metastasis and the presence of distant metastasis, making the Tumour-Nodule-Metastasis (TNM) classification (57). Primary tumour (T) is classified as follows: pTx primary tumour cannot be assessed pT0 no evidence of primary tumour pTis carcinoma in situ: intraductal carcinoma, or lobular carcinoma in situ, or Paget disease of the nipple with no tumour pT1 Tumour 20 mm or less in greatest dimension

pT1mic micro invasion 1 mm or less in greatest dimension pT1a tumour more than 1 mm but not more than 5 mm in greatest dimension pT1b tumour more than 5 mm but not more than 10 mm in greatest dimension pT1c tumour more than 10 mm but not more than 20 mm in greatest dimension

pT2 tumour more than 20 mm but not more than 50 mm in greatest dimension pT3 tumour more than 50 mm in greatest dimension pT4 tumour any size with direct extension to chest wall or skin

pT4a Extension to chest wall pT4b Oedema (including peau d’orange), or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast pT4c Both 4 a and 4b above pT4d Inflammatory carcinoma

Regional lymph node involvement (N) is classified as follows: pNx regional lymph nodes cannot be assessed (not removed for study or previously removed) p N0 no regional lymph node metastasis pN1 metastasis no movable ipsilateral axillary node(s)

pN1a Only micrometastasis (none larger than 2 mm) pN1b Metastasis to lymph node(s), any larger than 2 mm)

pN1bi Metastasis to one to three lymph node(s), any more than 2 mm and all less than 20mm in greatest dimension pN1bii Metastasis to four lymph node(s), any more than 2 mm and all less than 20mm in greatest dimension pN1biii Extension of tumour beyond the capsule of a lymph node, metastasis less than 20mm in greatest dimension pN1biv Metastasis to a lymph node 20 mm or more in greatest dimension

pN2 metastasis to ipsilateral axillary node(s) fixed to one another or to other structures pN3 metastasis to ipsilateral internal mammary lymph node(s) Distant metastasis (M) is classified as follows:

39

Mx presence of distant metastasis cannot be assessed M0 no distant metastasis M1 distant metastasis (includes metastasis to ipsilateral supraclavicular lymph node(s)) Stage grouping Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage IIA T0 N1 M0 T1 N1 M0 T2 N0 M0 Stage IIB T2 N1 M0 T3 N0 M0 Stage IIIA T0 N2 M0 T1 N2 M0 T2 N2 M0 T3 N1 M0 T3 N2 M0 Stage IIIB T4 any N M0 any T N3 M0 Stage IV any T any N M1

Annex 9 - The effect of mammography screening in breast cancer mortality The aim of the breast cancer screening is to detect tumours in an early stage and through the treatment of less advanced lesions, decrease the associated mortality. The efficacy of the mammography as the test for the screening of breast cancer was demonstrated by the results of several randomized screening trials, showed in table 1. When interpreting the results of the RCT for breast cancer screening, there is some differences in the organisation of the studies that must be taking into account, like that they had different age groups at enrolment, that some evaluated different interventions: mammography or mammography associated with clinical breast examination (CBE), the screening intervals varied between 12 to 33 months and finally, the measurement of the outcome, reduction of breast cancer mortality, was estimated after a follow up period ranging from 11 to 20 years. Finally, with a screening attendance in the first round of at least 60%, and the continuous attendance remaining of at least 50% or higher, there was a risk reduction in breast cancer death measured by a relative risk lower than 1, varying from 0.68 to 0.97. In a meta-analysis the results for all age groups combined, after excluding the Edinbug trial, which is rated as poor in quality, the combined relative risk observed was 0.84 (95% CI 0.77-0.91), given an equivalent of 1.224 (95%CI 665-2.564) women needed to screen during in average 14 years to prevent one death from breast cancer(58). When the effectiveness of invitation to screen was compared to usual care in the same metanalytical study, the relative risk reduction was 0.81 (95% CI 0.73-0.89), and the number needed to invite to screening was 1.008 (95% CI 531-2.128). Further, the Swedish two county study was the only randomised screening trial, which showed a significant reduction in the risk of death by breast cancer, with a RR of 0.68, 95% confidence interval (CI) varying from 0.59-0.80, when women screened were compared to women not invited (52) (59).

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Figure 3 - Cumulative mortality from breast cancer in the invited and control groups, women 40-74 years, Swedish two county trial (60)

0

100

200

300

400

500

600

700

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Years since randomization (ys)

Cumulative mortality

Invited Control

When Nyström in 2002, looked about the age at start of screening as a factor influencing the magnitude of the reduction of the risk of death from breast cancer, it was found that the benefit was greater in the age group 60-69 years at entry (33%). Further, when looking at the 5-year age groups, there were statistically significant effects in the age groups 55-59, 60-64 and 65-69 years (RR=0.76, 0.68 and 0.69, respectively). The benefit in terms of cumulative breast cancer mortality started to emerge at about 4 years and continued to about 10 years(61).

Table 1. Results of the randomized screening trials

Indicators HIP(62) CNBSS-

1(63) CNBSS-2((64)

Edinburgh (65)

Gothenburg (61)

Stockholm (66)

Malmö(67) Swedish Two county(68)

Year study began

1963 1980 1980 1978 1982 1981 1976-1978

1977

Age of enrollment (y)

40-64 40-49 50-59 45-64 39-59 40-64 45-70 40-74

Study group

M + CBE x usual care

M + CBE x usual care

M + CBE x CBE

M + CBE x usual care

M x usual care

M x usual care

M x usual care

M x usual care

Screening interval (m)

12 12 12 24 18 24-28 18-24 24-33

Longest follow-up (y)

18 13 13 14 12 11 11-13 20

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Table 1. Results of the randomized screening trials

Indicators HIP(62) CNBSS-

1(63) CNBSS-2((64)

Edinburgh (65)

Gothen burg(61)

Stockholm (66)

Malmö(67) Swedish Two

county(68) Screening attendance (%) Round 1 Round 2-n

67 54-46

100 85-89

100 90-86

61 44

85 75-78

81 81

74 70

89 83-84

Relative risk (RR) for breast cancer death

0.79 0.97 1.02 0.79 0.76 0.91 0.82 0.68

RR 95% CI 0.74-1.27

0.78-1.33

0.60-1.02

0.56-1.04

0.65-1.27

0.67-1.00

0.59-0.80

Absolute risk reduction per 1000 women2

1.44 0.12 -0.09 1.02 0.88 0.29 1.71 1.81

Nr women needed to invite to screening to prevent one death

883 - - 980 1139 3468 584 553

M= mammography CBE= clinical breast examination Sources: Adapted from Humphrey, L. et al, Breast cancer screening: a summary of the evidence for the US preventive services task force, Ann Intern Med, 2002; 137:347-360. . When a meta- analysis was performed to evaluate the effect of screening using the results of eight case control studies, the authors found the odds ratios (OR) for breast cancer mortality of 0.42 to 0.75. As the value of the odds ratio is under 1, this means that there was a protective effect or in other words, a risk reduction of 58% to 25% when women participate in mammography screening. However, due to their design case–control studies are susceptible to present a number of biases, including self-selection bias. The most recent study conducted in Wales (69) used formal methods to adjust for self-selection bias, which resulted in a 25% breast cancer mortality reduction associated with screening, consistent with results of the randomised trials.

Table 2 Case-control study results

Study reference Age at invitation

Attendance first round

Breast cancer mortality (OR 95% CI)

Fielder 2004, Wales, UK Broeders 2004, Nijmegen, NL Miltenburg 1998, DOM, NL Van Dijck 1996, Nijmegen, NL Moss 1992, UK Friedman 1991, HIP New York, US Janzon 1990, Malmö, SE

50-64 35 + 50-69 65+

45-64 40-64 45-69

77 72 72 33 72 67 74

0.75 (0.49,1.14) 0.70 (0.46,1.04) 0.54 (0.37,0.79) 0.56 (0.28,1.13) 0.51 (0.27,0.98) 0.75 (0.60,0.93) 0.42 (0.22,0.78)

Sources: Adapted from Gabe R & Duffy,SW, Evaluation of service screening mammography in practice: the impact on breast cancer mortality, Annals of oncology 16 (supl 2):ii153-ii162, 2005.

2 Absolute risk reduction per 1000 women= meaning the absolute number of lives extended per 1.000 women screened.

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When eight cohort studies were pooled in a meta-analysis, the combined results confirmed the positive effect of breast cancer screening by mammography in the reduction of mortality, with a significant 28% (95% CI 37%-18%) reduction in the risk of death by breast cancer when women were invited and a 43%(95% CI 47%-38%) decrease in breast cancer mortality when women participated in the mammography screening.

Table 3- Cohort studies and non-randomised control trials

Breast cancer mortality (RR 95%CI) Study reference Age

range (years)

Attendance (%) Invitation Screening Screening

adjusted for self-selection

Cohort studies Olsen 2005, DK Tabar 2003, SE Anttila 2002, FI Paci 2002, IT Duffy 2002, SE Jonsson 2001, SE Jonsson 2000, SE Thompson 1994, US

50-79 40-69 50-59 50-69 40-69 50-59 40-49 40+

71 85 82 61 81 81 81 -

0.75(0.63,0.89) 0.59(0.53,0.66) 0.81(0.62,1.05) 0.75(0.54,1.04) 0.61(0.55,0.68) 0.84(0.67,1.05) 0.91(0.72,1.15)

-

0.60(0.49,0.74) 0.56(0.49,0.64)

- 0.63(0.42,0.94) 0.56(0.50,0.62)

- -

0.80(0.34,1.85)

0.70(0.55,0.90) 0.60(0.52,0.69) 0.75(0.52,1.09) 0.82(0.52,1.30) 0.61(0.54,0.69) 0.78(0.55,1.12) 0.88(0.61,1,26)

- Cohort studies combined RR 0.72(0.63,0.82) 0.57(0.53,0.62) Test heterogeneity p=0.003 p=0.87 Sources: Adapted from Gabe R & Duffy,SW, Evaluation of service screening mammography in practice: the impact on breast cancer mortality, Annals of oncology 16 (supl 2):ii153-ii162, 2005. The contribution of other factors in the reduction of breast cancer mortality The decrease in breast cancer mortality have been described in different countries, and the most likely explanations for these effect are supposed to be related to early detection of breast cancer by screening mammography and advances in treatment, like the application of improved case management guidelines and the use of adjuvant therapy (chemo and hormone therapy) and tamoxifen. It is recognised that some of the improvements in clinical care of breast lesions may be indirectly favoured by the implementation of an organised screening programme. Screening can reduce the rate of death from breast cancer only when followed by adequate treatment. Breast cancers tumours that are detected by screening before they metastasize can be cured by surgery, and breast cancer detected at an early stage of metastasis can be effectively treated by surgery and chemotherapy (60). In the last 20 years, the use of adjuvant chemotherapy and tamoxifen for all stages of breast cancer has increased. As an example, through the modelling of breast cancer mortality data from US from 1975 to 2000, the reduction in the breast cancer mortality rate that could be attributed to use of adjuvant therapy and/or screening were estimated. The adjuvant therapy contribution was estimated between 12 to 21 %, and that the participation in the screening programme alone reduced the breast cancer mortality rate of 7 to 23 percent, with a median of 15% (70). Additionally, when the benefit of screening by mammography was analysed, using the Swedish two county trial data with 85% attendance rate and 20 years of follow up (71), the average number of women needed to screening to save one life was estimated to be 465 (95% CI 324-819).

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Annex 9 Glossary of terms Absolute rate of advanced cancer detection: evolution of the proportion of advanced cancers (stage II+) detected as compared to the background incidence (before screening) Absolute rate of small cancer detection: Percent change in proportion of small cancers (< 10 mm) detected as compared to the background incidence (before screening) Absolute risk reduction per 1000 women: meaning the absolute number of lives extended per 1.000 women screened. Background incidence: underlying expected breast cancer incidence in the absence of screening Benefit of screening for breast cancer: reduction in the risk of dying of breast cancer. The benefit of screening for breast cancer lies in finding and treating, a cancer in an early stage that would have killed a women a few (or many) years later. Benign biopsies/10 000 women screened: Number of women who underwent a biopsy and had a benign result/ Number of women screened x 10.000 Biopsy rate: proportion of the women who had a breast biopsy and had a screening mammography Breast cancer: a pathologically proven malignant lesion that is classified as ductal carcinoma in situ or invasive breast cancer. Breast cancer mortality reduction: the reduction in breast cancer mortality rates due to screening at a given time after the start of the programme is complex to measure because in the absence of screening, breast cancer in a defined age-group is affected by different factors: cohort effects, improvements in treatment, presentation at an earlier stage, the attendant publicity and changes in death certificate. Cancer detection rate: The number of pathologically proven malignant lesions of the breast (in situ and invasive) detected in a screening round per 1.000 women screened in that round. This rate will differ for initial versus subsequent screening examinations. Cancers detected at intermediate mammography should be regarded as screen-detected cancers. Recurrent cancers detected for the first time at mammography screening, should also be regarded as screen-detected cancers since they will be identified and diagnosed in the same way as a primary breast cancer. Confidence interval: The computed interval with a given probability, e.g., 95%, that the true value of a variable such as a mean, proportion, or rate is contained within the interval. The confidence limits are the upper and lower boundaries of the confidence interval Needle Core biopsy (NCB): a percutaneous biopsy using a cutting needle to provide a core of tissue for histological assessment without the need for an operation. Micro core biopsy, macro core biopsy, vacuum-assisted biopsies are also included in this category. Performed with an automated biopsy guns or a vacuum-assisted systems (VACNB or mammotome). Vacuum Assisted Core Needle Biopsy (mammotome): when a larger volume of tissue is required for accurate diagnosis of low to moderate level suspicious micro calcifications. The biopsy probe incorporates a vacuum channel, with negative pressure and is positioned using image guidance. Coverage rate: Number of women belonging to the target population who underwent a screening mammography test in the framework of organised screening within the interval of two years/ Number of women belonging to the target age group (50-69 years) Diagnostic interval: time interval which starts at the date of the advice for further assessment due to abnormal findings at the screening mammography and finish when a final diagnosis is given after the complete further assessment tests set. Diagnostic mammography: a mammography applied to any women outside of the organised screening programmes. The diagnostic mammography can be performed as part of the further assessment of women with symptoms or signs of breast pathology or as opportunistic screening given to women in the target age group or not. Ductal carcinomas in situ (DCIS): Tumour non-invasive of the breast that develops on cells, which are only present in the walls of the galactophores ducts. Eligible women: all women eligible to attend for screening on the bases of age, geographical location and social security status. Evolution of prognostic factors (TNM and grade): Evolution of TNM and breast tumour stage in women who had a screening mammography, an opportunistic (diagnostic) mammography and unscreened population over time

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False positive rate at screening: proportion of women with no evidence of cancer after the complete follow up in usual care from the women who were recalled and underwent a further assessment. Fine needle aspiratory cytology (FNAC): is a biopsy procedure that uses a thin needle on a syringe to draw fluid and/or cellular material from a breast lesion, most frequently a fluid-filled cysts or remove clusters of cells from a solid mass. If the breast abnormality turns out to be solid or the fluid looks suspicious, an additional biopsy should be performed. For this procedure a fine gauge needle (22 or 25 gauge) is used and a syringe. Further assessment: Additional diagnostic techniques (either non-invasive or invasive) that are performed at usual care for medical reasons in order to clarify the nature of a perceived abnormality detected at the screening examination. Further assessment can take place on recall. Further assessment negative: a complete further assessment done at usual care, with no evidence of breast cancer in a woman recalled for further assessment because of an abnormal mammogram sign Initial screening: first screening examination of individual women within the screening program, regardless of the organizational screening round which women are screened. Interval cancer: a primary breast cancer which is diagnosed in a woman who has a screening test, with or without further assessment, which was negative for malignancy, either: before the next invitation to screening, or within a time period to a screening interval for a woman who has reached the upper age limit for screening. Interval cancer rate: The number of interval cancers diagnosed within the two years period since the last negative screening examination per 10.000 women screened negative. The rate of interval cancers can also be expressed as a proportion of the background (expected) breast cancer incidence rate in the screened group. Interval between an abnormal mammography result and the initial treatment: time interval which starts at the date when the women was advised to have a further assessment and finishes when a initial treatment is started (date of surgery or date of adjuvant therapy). Interval between an abnormal mammography result and the start of the further assessment: time interval which starts at the date of the advice for further assessment and finishes when the women was informed of the need of further assessment (notification by the referent doctor). Interval between a screening mammography and the result: time interval that starts at the date of the screening mammography and when the mammography result is send to the referent doctor. Interval between a screening mammography and the results of 2nd or 3rd reading: time interval which starts at the date of the screening mammography is performed and finish when the mammography result after reading is available. Invasive cancer: a cancer that cells have disseminate beyond the basal membrane of the galactophore or lobule of the breast. Invited women: all women invited in the period to which data refer, even if they have received a reminder, after the reception of an invitation letter. Odds ratio: The ratio of two odds or in the exposure-odds ratio for a set of case control data, it is the ratio of the odds in favour of exposure among the cases (a/b) to the odds in favour of exposure among the noncases (c/d), this is reduced to ad/bc. Open biopsy: refers to surgical removal of (part of) a breast lesion. Open biopsy rate: the number of women undergoing open biopsy as a proportion of all women who have a screening examination. This rate may differ for initial versus subsequent screening examinations. Opportunistic breast cancer screening: is that conducted after a prescription by a physician or a woman request rather than by an specified routine call and recall (an organized invitation system), registered as non screening or diagnostic mammography Overdiagnosis: term used to describe the detection of cancers that would never have been found without screening. Participation rate: Proportion of the women had a screening mammography who belonged to the target population and were invited to participate in the screening mammography Positive predictive value: refers to the ratio of lesions truly positive to those test positive. It is intimately effected by the prevalence of breast cancer estimated as < 1%, we can expect a low positive predictive and a very high negative predictive value for screening mammography. Positive predictive value of the screening mammography: The number of cancers detected as a proportion of the women with a positive screening test (abnormal screening mammography). In practice, the denominator

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corresponds to women undergoing further assessment, does not include additional mammograms for technical reasons (repeat screening tests) Prevalence/expected incidence rate: the ratio of the cancer detection rate, at initial and subsequent rounds, to the expected background incidence. Proportion: A ratio in which the numerator is included in the denominator or the ratio of a part to the whole, expressed as a "decimal fraction"' (e.g., 0.2), a fraction (1/5), or a percentage (20%). Proportion of screen detected invasive cancers (%): Proportion of invasive cancers of the total cancers detected throughout screening, by initial and subsequent rounds Proportion of screen detected invasive cancers that are ductal carcinoma in situ (%): Proportion of ductal carcinoma in situ of the total cancers detected during screening. Proportion of screen detected invasive cancer of <10mm (%): Proportion of invasive cancers measuring less than or equal to 10mm of diameter of the total invasive cancers detected during screening. Proportion of screen detected invasive cancer of <15mm (%): Proportion of invasive cancers measuring less than 15mm of diameter of the total invasive cancers detected during screening. Proportion of screen detected invasive cancer of <15mm grade 3 (%): Proportion of invasive cancers measuring less than 15mm of diameter of grade 3 of the total invasive cancers detected during screening. Proportion of screen detected cancers node-negative: Proportion of invasive cancers that are node negative of the total number of invasive cancers with axillary lymph nodes anatomo pathology investigation, at initial and subsequent rounds Proportion of screen detected cancers stade II+ (%): Proportion of invasive cancers at advanced stage (TNM II or more)/ total of invasive cancers detected during screening, by initial and subsequent rounds Proportion of women that have undergone mammography: Proportion of women belonging to the eligible population (50-69 years) who underwent a mammography within the interval of two years Rate: An expression of the relative frequency with which an event occurs in a defined population. Ratio biopsy benign/malign: The ratio between the numbers of benign tumours divided by the number of malign tumours, for the women who had an open core biopsy. As well named the predictive positive value of the biopsy or the ratio of biopsy detection. Recall rate: Proportion of women who had a screening mammography and were recalled for further assessment due to the detection of an abnormal mammography signs (initial and subsequent rounds) Regular attendance rate: proportion of women who had a new mammography test within the period of 30 months since the preceding test, for the women who remain eligible. Relative risk breast cancer death: The ratio of the risk of death by breast cancer among the exposed (screened) to the risk among the unscreened. RR = Mortality rate among screened /mortality rate among unscreened Screening interval: the ifixed interval between routine screens in months Screening mammography: a mammography applied to all women eligible in the framework of the organised screening programmes. Screening mammography coverage: proportion of the women who underwent a screening mammography who belonged to the target population Screening sensitivity: the screening programme sensitivity is the probability that a case I the PCDP at any time during the ongoing screening programme will be diagnosed following a positive test Sensitivity of the screening mammography: Number of cancers detected in the women participants in the screening programme (true positives)/ Number of cancer detected in screened women (true positives) and number of cancers detected during the inter-screening interval (false negatives). It is clear that to establish the sensitivity of the screening test, there must be a flawless system for identification and classification of all interval cancers (false negatives). Sojourn time: the probability of a cancer being detected at screening clearly depends on the length of time the lesion is detectable pre-clinically, i.e. the longer the sojourn time the greater the chance that the lesion is detected (50). Specificity of the screening mammography: Number of screening mammography which are normal (true negative)/ Number of normal mammographies and number of abnormal mammographies which become negative after complete further assessment (false positive)

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Subsequent screening: all screening examinations of individual women within the screening program following an initial screening examination, regardless of the organizational screening round in which women are screened. There are two types of subsequent screening examinations: at regular and irregular intervals. Standardized Detection Ratio= ratio of the number of screen detected invasive cancers divided by the expected number of screen detected invasive cancers. Target population: all women eligible to attend for screening on the bases of age and geographical location. Considered as the mean population in the first and second year according to the population register. Technical recall rate: proportion of women who had a screening mammography and were subjected to recall due to technical inadequacy of the mammograms, by screening round (initial and subsequent rounds) Women not participant: all women invited by the reception of an invitation letter but were not screened in a certified screening unit. Women not invited: all women belonging to the target age group, who are or not affiliated to a health insurance organization and have or not a record in the national population register, who have not received an invitation letter to participate in the organized screening. Women re-invited: all women invited in the period to which data refer, even if results of mammograms are not yet available who did not participate in the screening, and did not justify their refusals to participate and received another invitation letter (a reminder). Women screened: all women screened in the period to which data refer, even if results of mammograms are not yet available.

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Annex 10 - Abbreviations Asbl Non profitable Association BCE Breast Cancer Evaluation BCSS/KCZ Social Security Cross point bank Brumammo Breast cancer screening coordination centre of Brussels CBE Clinical Breast Examination CCC/GGC Commission Commune of the Community of Brussels/Gemeenschappelijke

Gemeenschapscommissie van het Brussels – Hoofdstedelijk Gewest. CCR Wallon Community Centre of Reference CDR Cancer detection ratio CI Confidence Interval CEU Cancer Epidemiology Unit DCIS Ductal carcinomas in situ EACP Europe Against Cancer Programme EBCN European breast cancer network EPI Epidemiology section ENCR European Network of Cancer registry ESR European standardized rate, using the European population EU European Union EUREF European Reference Organization for Quality Assured Breast screening and

Diagnostic services EUROCARE European study of cancer care EUSOMA European society of mastology FNAC Fine needle aspiration cytology GP General practitioner, referent medical doctor I interval cancers IARC International Agency for research on cancer IMA Intermutualist Agency INAMI/RIZIV National Institute for health insurance and sickness INVS National Institute of Health Surveillance (France) IPH Scientific Public Health Institute (Belgium) IR Incidence rate of breast cancer M Mammography - screening M months N- lymph node negative NHS National Health Services (United Kingdom) NHSBSP National Health Services Breast Screening Programme NKR or NCR National Cancer registry NISS National Social Security Number PCDP Pre-clinical screen-detectable phase PPV positive predictive vale pN axillary lymph node status pT tumour size assessed QT Audit System on Quality of Breast Cancer Treatment(EUSOMA) RCT Randomised Control Trials RMI Resonance Magnetic Image RR Relative risk or risk ratio S screen-detected cancers SBR histological grading system of breast cancer Scarff-Bloom-Richardson

grade I (well differentiated, best prognosis), grade II (moderate differentiated), grade III (poorly differentiated, fast growing tumours, worst prognosis)

SDR Standardized Detection Rate SIS equivalent to NISS from the social security information system number OR Odds ratio T- result of the screening test negative TN true negative, when a first screening test result negative remains negative after an

interval of observation (inter-screening interval) TNM stage The TNM system for breast cancer staging, the

T refers to the size of the Tumour, N describes how far the cancer has spread to nearby Nodes,

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M shows whether the cancer has Metastasized to other organs of the body To summarise the information, the TNM descriptions can be grouped together into Stages, labelled as I,II,III,IV.

TP true positive, abnormal screening test that after further assessment is c confirmed as an invasive breast cancer UICC International Union Against Cancer US United States of America w.d. working days y years

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© 2005 by Institut scientifique de Santé publique, Bruxelles (Belgique) Toute réproduction d’un extrait quelconque de ce livre, par quelque procédé que ce soit, et notamment par photocopie ou microfilm, est strictement interdite.

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