Introduction

Breast cancer in Uganda is the third commonest cancer in women coming only next to cancer of the cervix and Kaposi's sarcoma. The incidence of breast cancer in Uganda has doubled from 11: 100,000 in 1961 to 22:100,000 in 1995^1,2,. Many patients are often seen in late stages thus the outcome of treatment is mostly unsatisfactory. The present day knowledge of this disease does not have any effective primary prevention. It is thus imperative that efforts should be made to detect the disease in its early stages. Mammography has been found to be useful but it is not feasible for mass screening in Uganda, as there is a limited number of units accessible to the general public.

It also explains why mammography screening is unlikely to be effective today. All health professionals and members of the public will find these revelations disturbingly illuminating. It will radically transform the way healthcare policy makers view mammography screening in the future. II European guidelines for quality assurance in cervical cancer screening – Second edition This document has been prepared with financial support from the European Communities through the Europe Against Cancer Programme (European Cervical Cancer Screening Network) and the EU.

Public education towards Breast Self Examination (BSE) should be propagated because it is practical and affordable ³.

These guidelines were compiled by the Uganda Breast Cancer working group whose objectives are to improve the quality of life of the breast cancer patients and their families by working towards encouraging early detection; harmonize treatment, referral of patients and to create a reference document for health workers dealing with breast cancer. In addition it aims at creating awareness about breast cancer to health workers and the community and to be part of the National Cancer Society creating a breast cancer registry and cancer control program.

This edition is an updated version of the one published in 2003⁴. This version highlights the importance of Breast Self Examination (BSE), which is still practical and affordable though it is discouraged in other resource rich settings. It includes a section on pathological specimen reporting in an effort to information sharing and therefore decision making. It includes a section on prognostication. It presents a relaxed view on and recommends Breast conserving surgery a different stand from the previous edition and lastly it presents a one-page reader friendly, at a glance overview of Breast cancer treatment for easy reference by the user.

Objectives of these guidelines

• To assist women and their doctors to make decisions on managing breast cancer
• To provide information for physicians handling breast specimen.
• To present the many treatment options open to patients with breast cancer

Methods

This is a consensus document, a result of a team of mostly Uganda experts reviewing the past guidelines, incorporating new ideas accruing from accumulated experience through a multidisciplinary clinic that runs weekly over a seven year period dealing with Ugandans Cancer patients.

Breast self- examination (BSE) detection of breast cancer ⁵6⁶

The woman stands in front of a mirror, puts up her arms and observes her breasts; she may note wrinkling of skin, elevation of the nipple, and a mass may also be seen. Then the woman lies flat on her back, puts one hand behind her head and uses the opposite hand to palpate the opposite breast.

If she notices any abnormality she should seek attention of health care provider immediately. In premenopausal women BSE should be done on every 10^th day of the menstrual cycle.

Triple assessment of symptomatic cases

This is essential before treatment is undertaken and includes clinical evaluation, breast imaging and histopathological examination, it is done for any patient suspected to have breast cancer.

i. Clinical assessment

History of a mostly painless breast mass, nipple discharge especially if from one duct, nipple or skin retraction, axillary mass, arm swelling, hair loss and development of other symptoms with reference to possible metastatic disease. A past medical history of breast disease and family history of breast cancer should be sought.

The reproductive history is also important. This should include age at menarche, menstrual history, age at first pregnancy, and age at on set of menopause, number of pregnancies and abortions, breast-feeding duration and history of contraceptive pill use. Physical examination should include weight, height and surface area (BMI). The local examination should be done with the patient both in sitting and in supine positions. One should look for breast masses, skin and nipple changes, axillary and supraclavicular lymph nodes as well as arm swelling.

ii. Breast imaging

Patients are divided into 3 categories:

• Patients for testing including those with a family history of breast cancer, benign disease, follow up after surgery or those more than 45 years of age.
• Patients for image guided interventional procedures.

Imaging procedures offered include: mammography, breast ultrasound, galactography and pnuemocystography. Mammography is the imaging technique of first choice in symptomatic patients. The ages at which mammography should be done were adopted depending on our clinical experience and may be reviewed. Mammography is done for the symptomatic group for those over 25 years, and testing is done for those over 30 years. The BISM system of reporting a mammogram is recommended.

European Guidelines For Quality Assurance In Mammography Screening 2nd Edition 2017

Normal -1. Benign lesion- 2. Indeterminate- 3. Suspicious- 4. Malignant- 5.

iii. Pathological examination

• Fine needle aspiration cytology Biopsy has a high degree of accuracy ^7,8 and with minimal discomfort⁹ when malignant cells are noted and definitive surgery may go ahead based on this provided the results are in agreement with the clinical and/or mammography assessment. For impalpable lesions, ultrasound or mammography guided fine needle aspiration (FNA) is advocated.
• Open biopsy Frozen section histology can be used during biopsy but this is not practiced in Uganda at the moment.

Staging

Staging investigations include bilateral mammography to exclude multifocal or bilateral disease, breast ultrasound for accurate tumor size assessment and other tests. Full blood count, urea & electrolytes, liver function tests and baseline chest X-ray. The routine uses of liver ultrasound, skeletal survey and skeletal scintigraphy in asymptomatic women has very low yield and does not improve survival or quality of life. The TNM classification of breast cancer is recommended^{10, 11}.

Treatment

Like in all cancers the diagnosis of breast cancer is frightening and exposes the patient and her family to psychosocial trauma. Adequate counseling, pain and other symptom control should be part and parcel of the entire management strategy. Good counseling enables the patient and her family to cope with the stress that is part and parcel of cancer. It enables them to adjust their life styles. For example if she was the breadwinner some one else may have to take up that role as she undergoes treatment. Counseling should continue during treatment and follow up.

Management of early breast cancer Ductal carcinoma-in-situ (DCIS)

We recommend wide excision (Breast Conserving Surgery) and adjuvant radiotherapy as effective methods of treating DCIS ^{12, 13, 14} unless in presence of multicentric tumors in more than one quadrant, or diffuse malignant looking micro calcifications through out the breast¹⁵. The other relative contraindication to breast conserving surgery is pregnancy, previous radiotherapy to breast area and collagen vascular disease of BCS is not possible or feasible a mastectomy is done.

Mammography detected ductal CIS or palpable ductal CIS with no multicentric or diffuse micro calcifications qualifies for breast conserving surgery and axillary dissection ^16,17

The likelihood of axillary involvement in DCIS is about 2–3% and axillary dissection is therefore not recommended 12, 16, 17.

Role of sentinel mode biopsy is unresolved in literature and not yet available in Uganda. Routine use of tumor matters, imaging for metastases and LFT tests in DCIS is not useful and discouraged ¹⁸.

Post operative Clinical reviews

We recommend 3–6 monthly follow up for first year then annually for life, unless concerns or complications arise¹⁷. Postoperative mammography may be done after 1 year when surgery and postoperative treatment changes resolve after that 2 yearly if possible

Lobular carcinoma in situ (LCIS)

Lobular carcinoma in situ is generally considered a pre cancerous condition. It is lobular because the cancer is confined to the lobules (the glands that secrete milk). Lobular carcinoma is situ is an unusual histological pattern of non-invasive neoplastic disease of the breast¹⁸.

Lobular carcinoma in situ is frequently multicentric and bilateral and there is evidence that it is associated with an elevated familial risk of breast cancer¹⁹. We offer a wide excision and give tamoxifen for a 2 to 5 year period. Prophylactic mastectomy is an option.

Paget's disease ^20,21

Paget's disease of the breast is a rare malignancy of the nipple-areola complex^{22, 23}; it is manifested by progressive eczematoid changes of the areola with persistent soreness or itching ²⁴. It is mostly associated with at underlying ductal carcinoma in-situ or invasive carcinoma even when there is no palpable mass or mammography findings ^25,26.

Simple mastectomy and adjuvant radiotherapy are given as well as tamoxifen. If breast-conserving therapy is a choice it must be carefully indicated²⁴.

Invasive breast cancer

Surgery

Surgery with or without radiotherapy remains the mainstay of treatment for early breast cancer. Surgical treatment may consist of tumor excision with surrounding margins or mastectomy (removal of the entire breast tissue and the fascia overlying pectoralis major muscle). Breast conserving surgery should be followed by radiotherapy as it has been shown that local recurrence is minimized ^12,14

T₁N_oM_o and T₂N_oM_o tumors (T< 3cm) may be considered for breast conserving surgery plus radiotherapy. The tumor-free margin should not be less than 10mm at surgery. If the tumors are central, breast-conserving surgery could be done if other factors allow like tumor breast size ratio.

Patients should have mastectomy if these cancers are multifocal or central or larger than 3 cm ^16,17.

The mastectomy incision should be short and transverse to ease execution of radiotherapy. Physiotherapy of the ipsi-lateral shoulder joint should start on the first postoperative day to ease radiotherapy planning.

Adjuvant radiotherapy

A number of patients may fail to get radiotherapy because of socio-economic constraints and the long distances they may have to travel. However, health workers throughout the county should know that most of the patients would need radiotherapy after surgery. Adjuvant radiotherapy is required to reduce the risk of local recurrence ^18,25. There is evidence it improves survival²⁶. In circumstances where the clinical and histopathological information is not sufficient we recommended that radiotherapy to the chest wall and supra-clavicular region be given in all patients that have had mastectomy.

To reduce the risk of shoulder joint fixation and arm oedema, the axilla should not be irradiated in patients that have had proper axillary clearance, With proper planning, radiotherapy to the chest wall should avoid irradiating the heart and more than 3 cm of lung tissue. Adjuvant radiotherapy is also indicated in localized non-invasive breast cancer where wide local excision has been done. Adjuvant radiotherapy to the chest wall following mastectomy with axillary clearance is given in many centers when the primary tumour is more than 5cm or is T₄, or when the surgical margins are unclear, or if four or more axillary lymph nodes have tumour in them.

Adjuvant systemic therapy

Adjuvant systemic treatment is recommended in almost all patients in Uganda except ductal carcinoma in situ, lobular carcinoma in-situ, Paget's disease and patients for which it may be contraindicated for medical reasons. All patients with lobular carcinoma in situ should have tamoxifen after wide local excision or mastectomy. Cytotoxic chemotherapy and hormonal therapy are recommended in all other patients. The chemotherapy should start immediately after surgery and be augmented by radiotherapy.

Neoadjuvant chemotherapy can be given to down- stage the tumour before local treatment (radiotherapy or surgery) can be offered. The dose of tamoxifen is 20 mg once daily for as long as 2 – 5 years. Active drugs include: methotrexate, 5-fluoro-uracil, anthracycline antibiotics and cyclophosphamide. Adjuvant therapy with tamoxifen, cytotoxic drugs and ovarian suppression all reduce the risk of recurrence, risk of cancer in the other breast and death in women under 50 years of age, with node positive and node negative breast cancers.

Tamoxifen alone reduces recurrence and improves overall survival in all age groups. Elderly patients and those patients in poor performance status should ideally not be given cytotoxic chemotherapy, but they may benefit from hormonal treatment. Tamoxifen is withheld while patients are receiving tamoxifen.

Follow up after treatment for early breast cancer

The aim of follow-up is to detect recurrence at an early stage, and thus improve chances of salvage treatment, to screen for a new primary in the opposite breast, to detect and manage treatment related toxicity, and to provide psychological support.

It is recommended that palliative care team such as Hospice Uganda get involved with breast cancer patients as early as possible. Hospice is able to offer psychosocial support, drugs for pain and other symptom control. It is also recommended that more health workers (doctors and nurses) be trained in palliative care delivery to be able to offer the necessary support quite early during the patient's illness.

Patients who have had mastectomy should have mammography of the opposite breast every 2 years. For those that have had breast-conserving surgery, mammography of both breasts should be done every year. The incidence of local recurrence in a conserved breast is 10–15% in Europe.

Patients should be seen at 3 and 6 months following radiotherapy and then once every year for life or at any time that they develop symptoms.

Special groups or circumstances

• Patients with locally advanced breast cancer were surgery is not possible, systemic treatment or radiotherapy or both should be considered.
• Local recurrence after breast conserving surgery; salvage mastectomy and systemic chemotherapy should be given; if recurrence is small and the breast is large a second breast conserving surgery can be considered.
• Local recurrence after mastectomy — local excision, radiotherapy if not previously delivered and chemotherapy.
• In Metastatic breast cancer the main aim is to alleviate symptoms and maintain the highest possible quality of life. Biphosphonates significantly reduce skeletal related events. They are recommended for use whenever possible²⁸. Clodronate reduces risk of new bony and visceral metastases ^23,29 Visceral brain metastases are treated with radiotherapy and corticosteriods³⁰.
• Breast cancer during pregnancy requires a multi-disciplinary approach involving surgeons, oncologists and obstetricians. Termination of pregnancy is not necessary, as it does not improve survival. Radiotherapy and chemotherapy should be avoided during pregnancy.

After 32 weeks, induced delivery followed by conventional treatment is recommended.

Prognostic factors and Pathology reporting

It is clear that most important prognostic factors in breast cancer remain the traditional histopathological features of tumor size, lymph node stage and histological grade. ^{30, 31, 32, 33}

Standardized Pathology reports to include the following information:

Gross description

1. Nature of specimen — core biopsy, excisional biopsy (lumpectomy), re-excision, quadrantectomy, simple mastectomy, modified radical mastectomy.
2. Dimensions — overall
3. Tumour description: Mass/masses/no mass, size (3 dimensions), contour, texture, location and distance from nearest margin
4. Remainder of breast tissue, nipple, skin if present
5. Frozen section diagnosis — if one was done

Diagnosis

1. Histological type
2. Margins of resection

Comments

1. Tumour size
2. Extensive intraductal component — if present in a specimen that is less than a total mastectomy
3. Lympho-vascular invasion — peri-tumoral and/or dermal, if present
4. Other significant disease — if present (e.g. a typical ductal hyperplasia, Paget's disease of the nipple, biopsy site changes, papillomatosis)
5. Other tumor markers ancillary studies
6. If information required for prognosis is not available or cannot be adequately assesses (e.g. No nodes submitted, margins not assessable), this should be stated specifically in the report.

• Rationale for Surgery — Eliminate source and local control of tumor, hemorrhage and discharge
• Rationale for Radiotherapy — Local control, control of pain and destruction at distant sites
• Rationale for Chemotherapy — Systemic and local control of disease
• Rationale for Hormonal — Systemic, local control of disease and preventive as well.
• Tamoxifen failure is when a recurrence occurs while on treatment
• Tamoxifen for 2–3 yrs followed by Anastrozole is an option as is Anastrozole straight way if can be afforded
• A sandwich arrangement of 3 cycles of chemo then radiotherapy followed by the last 3cycles of chemotherapy
• CAF is used for the young (<50yr) and or with poor tumor grades, CMF is for the elderly and or those with favorable tumor grades

Recent Advances: Trails for use of Anastrozole instead of Tamoxifen, Molecularly targeted therapies e.g. HER 1 Inhibition — gefitnib, Lapatinib, HER 2 Inhibition — trastuzumab and Anti-angiogenic agents — bercizumab and taxanes for metastatic disease.

Conclusion

This guidelines document is a consensus document a result of work by a team of mostly Ugandan experts with hands on experience over the past seven years involved in the management of Breast Cancer patients. The first edition published in 2003 was deemed to be useful to the target audience; it has been referred to by students in training among others and cited in other publications. This updated version is enriched to capture changing view and much easier to reference.

This shared work underpins our continued commitment to do the best we can with what we have for the good of our patients in a resource-limited environment like Uganda. Mp3 free download music.

Uganda Cancer Working Group

• A.M. Gakwaya, Senior Consultant Department of Surgery, Mulago Hospital.
• P. Baguma, Consultant Radiologist Department of Radiotherapy Mulago Hospital.
• J. B. Kigula-Mugamba, Consultant Radiologist Department of Radiotherapy Mulago Hospital.
• E. Kiguli-Malwadde, Senior Lecturer Department of Radiology Makerere University.
• H. Nalwoga, Medical Officer Special Grade Department Mulago Hospital.
• J. Jombwe, Medical Officer special Grade Department of Surgery Mulago Hospital
• M. Galukande Specialist General Surgeon department of Surgery, Mulago hospital
• Orem, Consultant Oncologist Uganda Cancer Institute Mulago hospital.
• A. K. Luwaga, Consultant Radiologist Department of Radiotherapy Mulago hospital.
• I. Luutu, Consultant Radiologist Department of radiotherapy Mulago hospital
• A. Merriman, Palliative care physician Hospice (Uganda)
• P. Kiondo, Medical Officer Special Grade Department of Obstetrics and Gynecology Mulago hospital.
• A. Kanyike, Specialist Radio Therapist, Department of Radiotherapy Mulago Hospital.

​

TNM Stage	Treatment surgery	Options			Remarks
		Radiotherapy	Chemotherapy (CAF/CMF)	Hormonal (Tamoxifen)
1. DCIS tumor	Wide excision (1)	√(2) 50/25/5	X	√ Routine use (1b)	If multiple or >3cm do mastectomy
2. LCIS	Wide excision (1)	X	X	If ER+ PgR + 2–5 (2) fails.	Anastrozole if Tamoxifen years Prophylactic mastectomy is an option
3. Pagets disease	Simple Mastectomy (1)	√(3) 50/25/5	X	(2) ER+ PgR+	Anastrozole if Tamoxifen fails
4. ToN1Mo	Excise nodes (1)	X	√ (2)	X	Chemotherapy if nodes positive 5FU, adriamycin & Cisplatin
5. T1–2NoMo <3cm	Wide excision plus Nodal sampling (1)	(3) 50/25/5	√(2)If Nodes positive	√ (3)ER+ PgR+	Anastrozole if Tamoxifen fails
>3cm	Simple mastectomy plusAxillary clearance (1)	√(3)Minus axilla	√(2)Nodal positive	√ (3)ER + PgR+	Anastrozole if Tamoxifen fails
6. T12N1Mo> 3cm	Simple Mastectomy and Axillary clearance (1)	√(3) 50/25/5	√(2)	√ ER+ PgR+	Anastrozole if Tamoxifen fails
7. T3.T4No-3Mo (1 or 2)	α Toilet Mastectomy (1 or 2)	α Neoadjuvant	√(1or 2 or 3)	√ ER+ PgR+(4)	Downstage first if it flaps inadequate
8. Any T&N M1	Surgery mostly not indicated	√(2)Local control Breast and distant sites	√(1)50/25/5	√ ER+ PgR+(3)	For visceral metastases use chemo, for bone & brain metastases give radiotherapy

Key:

Numbers in (1) signify sequence of events, what comes first, 2^nd and 3^rd

ER+ estrogen receptor — positive

PGR+ Progesterone Receptors — positive

References

European Guidelines For Quality Assurance In Mammography Screening 2nd Edition Edition

Abstract

European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises ∼250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community.

summary document

Cancer is common in older people but cancer of the uterine cervix primarily affects younger women, with the majority of cases appearing between the ages of 35 and 50, when many women are actively involved in their careers or caring for their families. In the European Union (EU) 34 000 new cases and >16 000 deaths due to cervical cancer are reported annually [1, 2].

The burden of cervical cancer is particularly high in the new member states. The highest annual world-standardised mortality rates are currently reported in Romania and Lithuania (13.7/100 000 and 10.0/100 000, respectively) and the lowest rates in Finland (1.1/100 000). Governmental authorities, parliamentary representatives and advocates should be aware that the substantially higher dimension of this public health problem in the east of the EU requires special attention.

Among all malignant tumours, cervical cancer is the one that can be most effectively controlled by screening. Detection of cytological abnormalities by microscopic examination of Pap smears and subsequent treatment of women with high-grade cytological abnormalities avoids development of cancer [3].

Cytological screening at the population level every 3–5 years can reduce cervical cancer incidence up to 80% [4]. Such benefits can only be achieved if quality is optimal at every step in the screening process, from information and invitation of the eligible target population to performance of the screening test and follow-up, and, if necessary, treatment of women with screen-detected abnormalities.

Quality assurance of the screening process requires a robust system of programme management and coordination, assuring that all aspects of the service are performing adequately. Attention must be paid not only to communication and technical aspects but also to qualification of personnel, performance monitoring and audit, as well as evaluation of the impact of screening on the burden of the disease.

Population-based screening policy and organisation conforming to evidence-based standards and procedures provide the overall programmatic framework essential to implementation of quality assurance and are therefore crucial to the success of any cervical cancer screening programme.

Establishment of screening registries and linkage of individual screening data with cancer registry data, taking into account appropriate data protection standards and methods, are essential tools of monitoring and evaluation.

The first edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening [5] established the principles of organised population-based screening and was pivotal in initiating pilot projects in Europe. A number of countries have in the meantime developed organised population-based screening approaches, which are illustrated in Section 2.4.2 of the second edition [6]. It is hoped that this new guideline edition will have a greater impact on those countries in which opportunistic, rather than organised, population-based screening has been the preferred model in the past.

Transformation of these programmes to the population-based approach with quality assurance at all appropriate levels has the potential to substantially improve the accessibility, the effectiveness and the cost-effectiveness of the respective services. At the same time, substantial numbers of unnecessary screening examinations could be avoided by adhering to the interval for cervical cancer screening recommended in the European guidelines (3–5 years) [7, 8]. Towards this end, considerable attention has been given to the essential aspects of developing an organised population-based programme policy that minimises the adverse effects and maximises the benefits of screening.

The current recommendations are also particularly relevant to planning new cervical cancer screening programmes in Europe. Different solutions fulfilling the recommended methodological standards need to be implemented in different countries and regions with diverse levels of resources and general health care infrastructure.

More than a decade has passed since the publication of the first guideline edition. The current expanded edition therefore also includes extensive updates on technical details and documentation, as well as assessment of new technologies, e.g. liquid-based cytology (LBC), automated interpretation of Pap smears and testing for human papillomaviruses (HPVs). The scope of the current guideline has also been extended to include comprehensive instructions prepared by a multidisciplinary team of experts for general practitioners, gynaecologists and cytopathologists. Much more extensive recommendations on follow-up, diagnosis and management of women with positive cervical cytology have been added. This necessitated the incorporation in the second edition of a separate chapter on techniques and quality assurance in histopathology and, for the first time, detailed guidance for clinicians in dealing with abnormal cytology, including management according to the severity of cytological abnormalities and management of histologically confirmed cervical epithelial neoplasia.

A major further addition has been the inclusion of uniform indicators for monitoring programme performance and for identifying and reacting to potential problems at an early time. The indicators deal with screening intensity, test performance and diagnostic assessment and treatment and address aspects of the screening process that influence the impact as well as the human and financial costs of screening. Standard tables have been provided for documenting screening policies and for tabulating the person-based data used to generate the uniform performance indicators. The availability of these standardised tools will substantially improve data comparability and the exchange of experience and results between screening programmes in Europe. Such exchange, in turn, is essential to effective Pan-European collaboration in implementing and continuously improving the quality and effectiveness of cervical cancer screening programmes.

Cervical cytology still is the cornerstone of cervical cancer prevention programmes in Europe, although new perspectives for other screening technologies are developing rapidly. The principles of quality assurance, performance monitoring and evaluation and many of the procedures and methodological standards laid down in the current guideline edition are of equal relevance to cervical cancer screening on the basis of other conceivable methods. It is therefore expected that the publication of the updated and revised second edition will also promote rigorous standards in the evaluation and application of new screening technologies, thereby improving the effectiveness of cervical cancer prevention in Europe.

Over the short and medium term, screening for cervical cancer precursors and management of screen-detected lesions will remain the most effective tool for cervical cancer prevention in Europe. However, the field of cervical cancer prevention is rapidly developing due to better understanding of the natural history of the disease. Persistent infection with one of 13–16 oncogenic HPV types is now known to be a key prerequisite for development of cervical cancer [9, 10]. The overwhelming evidence linking HPV infection to cervical cancer has prompted the development of test systems to detect its nucleic acids as well as prophylactic and therapeutic vaccines.

Primary prevention by prophylactic vaccination against the HPV types that are causally linked with most cervical cancers in Europe is likely to become a feasible option for cervical cancer control, provided the current cost of inoculation regimens is substantially reduced.

While prophylactic vaccination, primarily in young girls, may provide important future health gains, cervical screening will need to be continued [11]. Neglecting cervical cancer screening due to the current availability of a vaccine could paradoxically lead to an increase in cancer cases and deaths.

Development of comprehensive European guidelines on prevention of cervical cancer that appropriately integrate screening and vaccination strategies is a key aim of the next phase of guideline development activities supported by the EU Health Programme.

guideline development process

The current updated and expanded second guideline edition has been prepared by a multidisciplinary team of experts appointed by the European Commission from the former European Cervical Cancer Screening Network (ECCSN) established under the Europe Against Cancer Programme. In addition to the cytopathologists, epidemiologists, general practitioners, gynaecologists, histopathologists, virologists and specialists in social science serving as editors and authors, experts from outside ECCSN were also invited to write, review and contribute to the development of the second edition. Besides the input of the 48 experts from 17 member states directly involved in the production of the guidelines, numerous comments and suggestions were provided by experts attending meetings held in Denmark, Finland, Greece, Hungary and Luxembourg from 2003 to 2006 by ECCSN and the European Cancer Network (ECN) in which the former cancer screening networks have been consolidated.

A draft-revised guideline was made available for public consultation on the internet in December 2003. The results of this consultation were incorporated into a new draft, which was reviewed by experts invited by the International Agency for Research on Cancer (IARC) to Lyon, France, in June 2005. Two or three reviewers were invited for each chapter, in order to comment on the contents and to ensure that all relevant references available had been considered. The further revised guideline content was subsequently discussed with screening experts from 23 member states and 1 applicant country of the EU at the ECN meeting in February 2006. Since then, IARC has provided technical and scientific support to the editorial board and the authors for the final preparation of the guideline document.

The final recommendations and standards of best practice in the revised and updated second guideline edition are on the basis of the expert consensus in the editorial board after the above-mentioned consultations and discussions. They take into account the available evidence of screening and diagnostic procedures and programmes. For assessing evidence of effectiveness, two criteria were used: study type and study outcomes. Study types were ranked from high- to low-level evidence as follows: (i) randomised clinical trials, (ii) observational studies: case–control studies and cohort studies and (iii) correlational studies (time trends, geographical comparisons). Outcomes of studies were ordered as follows: (i) reduction of mortality from cervical cancer, (ii) reduction of incidence of invasive cervical cancer, (iii) reduction of incidence of cervical intraepithelial neoplasia (CIN) 3 or cancer (CIN3+), (iv) increased detection of high-grade histologically confirmed CIN (CIN3+ or CIN2+), (v) increased test positivity rate without or with small loss in positive predictive value for CIN2+. Throughout this guideline, scientific evidence on which the recommendations are based is indicated by references in the text. Where no observed data were available, outcomes simulated by mathematical models and expert opinion were accepted as lowest level of evidence.

The authors conducted systematic literature searches and used available systematic reviews and published meta-analyses. Publication of the handbook for cervical cancer prevention by the IARC Working Group on the Evaluation of Cancer Preventive Strategies in 2005, which included several ECN experts, was also helpful. Several pioneering population-based randomized trials have been conducted in recent years, or are currently being conducted, in various member states: LBC (Italy, The Netherlands), automated cytological screening (Finland); HPV-based versus cytology and combined (cytology + HPV) screening (Finland, Italy, The Netherlands, Sweden, UK). The results available from these trials were taken into account during the preparation of the second guideline edition up to July 2007. In addition, several meta-analyses were carried out to assess the level of evidence of new screening or management methods: LBC versus conventional cytology; HPV testing in triage of minor cytological lesions to identify women needing further follow-up, in follow-up after treatment of CIN to predict success or possible failure of treatment and in primary screening. In the meta-analyses carried out for the current guideline edition, it was only possible to assess cross-sectional outcomes (outcome types 4–5); an insufficient number of trials had reached longitudinal outcomes before final closure of chapter revisions in mid-2007. One additional meta-analysis concerned obstetrical adverse effects of treatment of precancerous lesions.

Due to the rapid accumulation of evidence on new technologies and prevention strategies, review and updating of the current guidelines has already been initiated under the current EU Health Programme [European Cooperation on Development and Implementation of Cancer Screening and Prevention Guidelines (ECCG-ECN)].

fundamental points and principles

screening policy

• The Council of the EU has recommended implementation of population-based cervical cancer screening programmes to the EU member states, with quality assurance at all levels and in accordance with European guidelines [12].

• Screening recommended by the European Council and the European Guidelines is set up as a population-based public health programme, with identification and personal invitation of each woman in the eligible target population. In addition to invitation, the other steps in the screening process and the professional and organisational management of the screening service, including quality assurance, monitoring and evaluation, are well defined by programme policy, rules and regulations at the regional and national level.

• Designing a cervical cancer screening programme includes defining the screening policy, i.e. choosing the screening test systems, determining the target age group and the screening interval between normal test results (3 or 5 years) and establishing follow-up and treatment strategies for screen-positive women, taking into account the variation in background risk in target populations and the natural history of the disease, which is characterised by a rather long detectable preclinical period and substantial regression rates of the precancerous lesions.

• Cervical cytology is the currently recommended standard test for cervix screening, which should start in the age range 20–30 [12, 13], but preferentially not before age 25 or 30 years, depending on the burden of the disease in the population and the available resources [13, 14]. It is recommended to continue screening at 3- to 5-year intervals until the age of 60 [13, 15] or 65 [4, 5]. Stopping screening in older women is probably appropriate among women who have had three or more consecutive previous (recent) normal cytology results.

• Special attention should be paid to the problem of older women who have never attended screening as they exhibit increased risk for cervical cancer.

• Opportunistic screening, which takes place in clinical settings and depends on the initiative of the individual woman or her doctor, should be discouraged. Such activities are often characterised by high coverage in selected parts of the population which are screened too frequently, coexisting with a low coverage in other population groups with less socioeconomic status, and heterogeneous quality, resulting in limited effectiveness and poor cost-effectiveness.

screening organisation, monitoring and evaluation

• The programme design must permit evaluation. An experimental design that is suitable for evaluation of new screening policies in organised settings is recommended.

• The success of a screening programme requires adequate communication with women, health professionals and persons responsible for the health care system.

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• Moreover, a well-organised screening programme must reach high population acceptance and coverage and must ensure and demonstrate good quality at all levels.

• The communication strategy for cervical cancer screening must be underpinned by robust ethical principles and ensure that the information developed is evidence based, ‘women centred’ and delivered effectively, taking into account the needs of disadvantaged groups and enabling women to make an informed choice about participation at each step in the screening process [16].

• Population-based information must be established for continuous monitoring of screening process indicators. An appropriate legal framework is required for registration of individual data and linkage between population databases, screening files and cancer and mortality registers. Indicators of screening programme extension and quality need to be published regularly.

• The information system is an essential tool for managing the screening programme; computing the indicators of attendance, compliance, quality and impact; and providing feedback to involve health professionals, stakeholders and health authorities.

new screening technologies

• An observation that a new screening method detects more precursor lesions than the standard Pap smear does not sufficiently demonstrate improved effectiveness. Due to frequent regression of precursor lesions, high specificity is also required to avoid anxiety, unnecessary treatment and side-effects. Evidence of effectiveness should preferentially be on the basis of reduction of cancer morbidity and mortality. Nevertheless, reduction in incidence of grade 3 cervical intraepithelial neoplasia (CIN3) is a surrogate indicator of effectiveness.

• Before routine implementation of a new screening strategy, the feasibility, cost-effectiveness and quality assurance should be verified and the necessary training and monitoring should be organised. A randomised screening policy, which permits quality-controlled piloting of a new test or procedure in the context of an organised screening programme, is a particularly powerful tool for timely evaluation under real-life conditions.

cytological methods.

• The occurrence of false-negative and unsatisfactory Pap smears has prompted the development of LBC and automated screening devices. The quality of the evaluation of the performance of these technologies often was poor and rarely on the basis of histologically defined outcomes using randomised study designs. In general, the proportion of unsatisfactory samples is lower in LBC compared with conventional cytology, and the interpretation of LBC requires less time. The cost of an individual LBC test is considerably higher, but ancillary molecular testing, such as high-risk HPV testing in the case of atypical squamous cells of undetermined significance (ASC-US), can be carried out on the same sample. The economic advantage of LBC due to the reduction of recalls for a new sample depends on the existing rates of inadequate Pap smears, which are highly variable throughout Europe.

• An Italian population-based randomised study recently confirmed that the sensitivities of LBC and conventional cytology are similar [17].

• Computer-assisted screening using LBC is currently being evaluated, but insufficient evidence is available for guidelines.

HPV detection.

• Several applications for HPV DNA detection have been proposed: (i) primary screening for oncogenic HPV types alone or in combination with cytology; (ii) triage of women with equivocal cytological results; (iii) follow-up of women treated for CIN to predict success or failure of treatment.

• HPV infections are very common and usually clear spontaneously, especially in younger women. Detection of HPV DNA thus carries a risk of unnecessary colposcopies, psychological distress and possibly of overdiagnosis. The need to carry out cervical cancer screening in an organised programme, rather than in an opportunistic setting, therefore applies particularly to screening on the basis of HPV testing.

• Evidence from randomised studies and meta-analyses shows that triage of women with equivocal cytological lesions by HPV testing with the Hybrid-Capture 2 assay is more sensitive and equally specific in finding high-grade CIN compared with repeat cytology. There is also evidence indicating that HPV DNA detection predicts treatment failure more quickly than cytological follow-up.

• The high sensitivity of current HPV DNA detection methods yields very high negative predictive values even for adenocarcinoma precursors that often escape cytological detection. Recent cohort studies indicate a prolonged duration (up to 10 years) of the negative predictive value of HPV testing. Nevertheless, further longitudinal research is necessary, preferably in an organised setting guaranteeing optimal follow-up, using randomised designs and targeting relevant outcomes.

• Current randomised controlled trials may demonstrate lower cumulative incidence of CIN3 and invasive cervical cancer as joint or separate outcomes in HPV-negative compared with cytology-negative women. The results of these trials are needed before screening policies for general primary HPV screening can be recommended in Europe. Such policies would also have to ensure that possible increases in the detection and management of less severe lesions are kept to an appropriate minimum. Introduction of primary HPV screening will require appropriate triage and counselling of HPV-positive women.

• As for any screening policy, future recommendations on primary HPV screening should not be made without specifying the age group to be targeted, the screening interval and the essential elements of quality assurance required for programme implementation.

• Piloting with validated HPV DNA testing can be recommended if carried out in an organised screening programme with careful monitoring of the quality and systematic evaluation of the aimed outcomes, adverse effects and costs. Women <30 years of age should not be screened for HPV, due to the high rate of viral clearance. Rollout towards national implementation can be considered only after the pilot project has demonstrated successful results with respect to effectiveness (relative sensitivity, positive predictive value of the screening test, triage and diagnostic assessment) and cost-effectiveness and after key organisational problems have been adequately resolved.

• HPV screening in an opportunistic setting is not recommended because adherence to appropriate intervals and requisite quality control cannot be adequately assured under such conditions.

guidelines for cytology laboratories

• Professional and technical guidelines must be followed to assure the collection and preparation of an adequate cervical cell sample [18].

• The quality of a cervical cytology laboratory depends on adequate handling and staining of the samples, screening and interpretation of the slides and reporting of the results. An appropriate balance must be achieved between the best patient care possible, laboratory quality assurance and cost-effectiveness [19].

• Uniform grading of cellular abnormalities is an essential condition for registration and comparisons over time and between different settings. Laboratories should apply only a nationally agreed terminology for cytology that is translatable into the Bethesda Reporting System [20]. The CIN terminology should be reserved for describing histology.

guidelines for histopathology

• Histopathology provides the final diagnosis on the basis of which treatment is planned and serves as the gold standard for quality control of cytology and colposcopy. It is also the source of the diagnostic data stored at the cancer registry and used for evaluation of screening programmes. It is therefore important that histopathology standards are monitored and are on the basis of CIN or other internationally agreed-upon terminology.

• Histopathologists should be aware of, and familiar with, the nature of cytological changes that may be relevant to their reports.

• The accuracy of the histopathological diagnosis of tissue specimens depends on adequate samples, obtained by colposcopically directed punch biopsies (with endocervical curettage if necessary) or excision of the transformation zone or conisation. An accurate histological diagnosis further depends on appropriate macroscopic description, technical processing, microscopic interpretation and quality management correlating cytological and histological diagnosis.

guidelines for management of screen-positive women

• A woman with a high-grade cytological lesion, a repeated low-grade lesion or an equivocal cytology result and a positive HPV test should be referred for colposcopy. The role of colposcopy is to identify the location of the abnormal cells, to target taking of biopsies and to decide whether any treatment is required. Colposcopy should only be carried out by adequately trained health professionals [21, 22].

• Guidelines are provided for the management of ASC-US and high-grade squamous intraepithelial lesions. Guidelines for low-grade squamous intraepithelial lesions (LSIL) are difficult to delineate because current evidence does not indicate that any method of management is optimal. Repeat cytology or colposcopy are acceptable options, but HPV testing as an initial management option is not sufficiently selective for all women with LSIL. However, HPV testing in older women with LSIL can be considered [21].

• https://rengol.netlify.app/hd-tune-pro-v560.html. Quality assurance and collection of data on patient management are important elements of the management and follow-up of women referred with an abnormal cervical smear [23].

• Colposcopy is sometimes proposed as an alternative screening method, but its specificity (and probably also its sensitivity) in primary screening is too low for this purpose.

complementary strategies of cervical cancer prevention

• Efforts to establish or improve cervical cancer screening should be planned and implemented in the framework of a comprehensive cancer control programme taking into account overall health care needs and priorities as well as feasible and cost-effective complementary preventive strategies, such as evidence-based primary prevention interventions [14, 24–26].

• As a matter of editorial policy, the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening provides recommendations on prevention of cervical cancer through early detection programmes for cervical lesions. An appendix on prophylactic HPV vaccination has been added to the second guideline edition in order to summarise the evidence available up to July 2007 but not to formulate European recommendations in this area [27]. There are two prophylactic HPV vaccines containing HPV16 and HPV18 licensed in the EU. These HPV types are causally linked with ∼70% of cervical cancers in Europe [28, 29]. Phase 2 and 3 trials have demonstrated strong immunogenicity and good safety profiles over the duration of the studies. Moreover, among girls and young women, aged 15–26 years not infected with those types at the time the vaccine was administered, excellent results were observed regarding protection against cervical cancer precursors and other diseases associated with the vaccine types, over the time span that data are available [27].

• European guidelines on HPV testing and vaccination are currently being developed in the framework of the ECCG-ECN project. In the meanwhile, it is important to note the uncertainty about the long-term efficacy of currently available vaccines as well as uncertainty about the future impact of oncogenic HPV types which are not targeted by currently available vaccines. Given current knowledge, population-based screening will continue to be necessary in coming decades in the cohorts of women already exposed to oncogenic HPV types. Screening fulfilling the quality assurance principles recommended in the current European cervical screening guidelines may also be necessary to adequately control cervical cancer in women vaccinated before exposure to HPV, although screening protocols and procedures will presumably require modification.

• As with any public health intervention, quality assurance of complementary strategies of cervical cancer prevention should also take into account organisational aspects essential to programme effectiveness and particularly cost-effectiveness. The potential importance of a population-based approach and programme monitoring and coordination to achieving and maintaining high coverage should not be overlooked. Resource limitations and the need to balance competing health priorities require adequate consideration of the marginal cost and benefit of combining cervical cancer screening and vaccination strategies. Consideration should also be given to the high costs of current HPV vaccines, which constitute a major barrier for several member states of the EU. The book containing the full guidelines and other EU documents on cancer screening can be downloaded free from the internet: http://ec.europa.eu/health/ph_determinants/genetics/keydo_genetics_en.htm

funding

EU: ECCSN (SPC.2002475), ECN (2004309), and ECCG-ECN (2006322).

disclosure

The travel grants received by MA from producers of HPV vaccines (GlaxoSmithKline and Sanofi-Pasteur MSD) ceased in 2008.

The views expressed in the publication are those of the authors; the European Commission is not responsible for any use which may be made of the information contained therein.

appendix 1

key performance indicators

A list of key performance indicators is provided for monitoring the screening process and for identifying and reacting to potential problems at an early time [30]. The indicators address aspects of the screening process which influence the impact as well as the human and financial costs of screening. The present parameters assume that cytology is used as the primary screening test, which is currently recommended. However, most of the present parameters may also be applied, with only small changes, if a different screening method (e.g. HPV DNA testing) is used. Depending on the respective screening test and the screening policy, the values of some parameters (e.g. detection rates of CIN, positive predictive values or specificity) will change. Before calculation of the recommended performance parameters, it is essential to verify key programme conditions which may influence the applicability and the further interpretation of respective parameters. As a minimum, the conditions indicated in Table 1 should be reported. For more information, see Annex 1 of Chapter 2 of the full guideline document [31].

Key characteristics of cervical cancer screening programme

1. Programme structure

1.1 Catchment area

1.2 Start date of the programme (month, year)

1.3 Youngest age targeted for screening

1.4 Oldest age targeted for screening

1.5 Recommended interval between negative tests (in years)

1.6 Groups (if any) not eligible to participate in screening (e.g. hysterectomised)a

1.7 Screening test

2. Does the programme invite

2.1 All women in the eligible target population, regardless of Pap test history?

2.2 All women in the eligible target population, except those who had a recent Pap test (within the past 6 months or 1 year)?

2.3 Only the women in the eligible target population who did not receive a Pap test within the recommended screening interval (3 or 5 years)?

2.4 Other, specify:

2.5 No invitations are issued?

3. Does the invitation include?

3.1 A pre-fixed, modifiable appointment

3.2 An invitation to get in touch to arrange an appointment

3.3 Other, specify:

4. Are noncompliers reminded?

4.1 All women

4.2 Some womenb

4.3 None

5. Diagnostic protocols

5.1 Cytology results for which repeat cytology is recommended

5.2 Cytology results for which referral for colposcopy is recommended

1. Programme structure

1.1 Catchment area

1.2 Start date of the programme (month, year)

1.3 Youngest age targeted for screening

1.4 Oldest age targeted for screening

1.5 Recommended interval between negative tests (in years)

1.6 Groups (if any) not eligible to participate in screening (e.g. hysterectomised)a

1.7 Screening test

2. Does the programme invite

2.1 All women in the eligible target population, regardless of Pap test history?

2.2 All women in the eligible target population, except those who had a recent Pap test (within the past 6 months or 1 year)?

2.3 Only the women in the eligible target population who did not receive a Pap test within the recommended screening interval (3 or 5 years)?

2.4 Other, specify:

2.5 No invitations are issued?

3. Does the invitation include?

3.1 A pre-fixed, modifiable appointment

3.2 An invitation to get in touch to arrange an appointment

3.3 Other, specify:

4. Are noncompliers reminded?

4.1 All women

4.2 Some womenb

4.3 None

5. Diagnostic protocols

5.1 Cytology results for which repeat cytology is recommended

5.2 Cytology results for which referral for colposcopy is recommended

Women with a recent Pap smear who fulfil eligibility criteria are included in the group of women eligible to participate in screening.

Specify, e.g. referral for colposcopy after repeated test? After HPV triage?

Key characteristics of cervical cancer screening programme

1. Programme structure

1.1 Catchment area

1.2 Start date of the programme (month, year)

1.3 Youngest age targeted for screening

1.4 Oldest age targeted for screening

1.5 Recommended interval between negative tests (in years)

1.6 Groups (if any) not eligible to participate in screening (e.g. hysterectomised)a

1.7 Screening test

2. Does the programme invite

2.1 All women in the eligible target population, regardless of Pap test history?

2.2 All women in the eligible target population, except those who had a recent Pap test (within the past 6 months or 1 year)?

2.3 Only the women in the eligible target population who did not receive a Pap test within the recommended screening interval (3 or 5 years)?

2.4 Other, specify:

2.5 No invitations are issued?

3. Does the invitation include?

3.1 A pre-fixed, modifiable appointment

3.2 An invitation to get in touch to arrange an appointment

3.3 Other, specify:

4. Are noncompliers reminded?

4.1 All women

4.2 Some womenb

4.3 None

5. Diagnostic protocols

5.1 Cytology results for which repeat cytology is recommended

5.2 Cytology results for which referral for colposcopy is recommended

1. Programme structure

1.1 Catchment area

1.2 Start date of the programme (month, year)

1.3 Youngest age targeted for screening

1.4 Oldest age targeted for screening

1.5 Recommended interval between negative tests (in years)

1.6 Groups (if any) not eligible to participate in screening (e.g. hysterectomised)a

1.7 Screening test

2. Does the programme invite

2.1 All women in the eligible target population, regardless of Pap test history?

2.2 All women in the eligible target population, except those who had a recent Pap test (within the past 6 months or 1 year)?

2.3 Only the women in the eligible target population who did not receive a Pap test within the recommended screening interval (3 or 5 years)?

2.4 Other, specify:

2.5 No invitations are issued?

3. Does the invitation include?

3.1 A pre-fixed, modifiable appointment

3.2 An invitation to get in touch to arrange an appointment

3.3 Other, specify:

4. Are noncompliers reminded?

4.1 All women

4.2 Some womenb

4.3 None

5. Diagnostic protocols

5.1 Cytology results for which repeat cytology is recommended

5.2 Cytology results for which referral for colposcopy is recommended

Women with a recent Pap smear who fulfil eligibility criteria are included in the group of women eligible to participate in screening.

Specify, e.g. referral for colposcopy after repeated test? After HPV triage?

Three groups of indicators can be distinguished:

• Screening intensity: the proportion of the target population actually screened within the recommended interval is the main determinant of the success of a screening programme. However, too frequent testing increases financial and human costs with only marginal gain in reduction of incidence and mortality. The duration of the recommended screening interval must therefore be taken into account in monitoring and evaluating screening intensity. Indicators include programme extension, compliance with invitation, coverage and smear consumption (Appendix Table 1).

• Screening test performance: essential indicators include the referral rates for repeat cytology and for colposcopy, as well as the positive predictive value of referral for colposcopy, the specificity of the screening test and the rate of detection of histologically confirmed CIN (Appendix Table 2).

• Diagnostic assessment and treatment: indicators include compliance to referral for repeat cytology and for colposcopy; treatment of high-grade lesions is also an essential performance indicator. The proportion of women hysterectomised for CIN serves as an indicator of extreme over-treatment (Appendix Table 3).

Widespread application of the following uniform parameters to report programme performance should facilitate collaborative studies and comparison between countries and regions and should thereby help to develop an evidence base for setting future Pan-European quality standards.

Screening intensity

https://crushgol.netlify.app/download-free-software-owon-oscilloscope-hack.html. Top 4 Download periodically updates software information of oscilloscope full versions from the publishers, but some information may be slightly out-of-date.

Screening intensity

Screening test performance

Screening test performance

Diagnostic assessment and treatment

Diagnostic assessment and treatment

definition of performance parameters in cervical cancer screening

The rationale and approach for calculation of the following parameters are provided in Sections 7.2–7.4 of Chapter 7 of the full guideline document [30]. Specific instructions are indicated in Section 7.5 of Chapter 7 and are reproduced below.

Most of the key performance indicators can be directly computed from the tables presented in the annex of Chapter 2 in the full guideline document (Full pdf guideline version [6]: http://bookshop.europa.eu/eubookshop/publicationDetails.action?pubuid=547021) [31]. However, a number of indicators are on the basis of the incidence of invasive cervical cancers in women with different screening history. These indicators provide a more direct evaluation of the impact of screening, but they need to be computed over longer periods of time and linkage of screening registry data with cancer registry data is required for some indicators; see also Section 5 in Chapter 2 in the full guideline document.

For short-term monitoring purposes, the calculations in the annex to Chapter 2 in ref. 31 are on the basis of annually aggregated data. Additional aggregation over different periods of time is recommended, particularly over the full screening interval of a given screening programme (3 or 5 years), and is required for some of the performance parameters. Wherever possible, longer and shorter evaluation periods should also be considered.

For calculations for a given period of time, such as the recommended screening interval (3 or 5 years), the dates on which the period starts and ends and the procedure for determining the target population should be recorded. For calculations on the basis of the size of the target population, use the average over the given time period.

Note that parameters 6 (Incidence of invasive cancer in unscreened women), 14 (Cancer incidence after normal cytology) and 19 (Incidence of invasive cancer after abnormal cytology) require linkage with cancer registry data. The follow-up periods recommended for calculation of cervical cancer incidence are 6 months longer than the recommended screening interval of the respective programme (3.5 or 5.5 years). The purpose of adding one-half year to the screening interval is to include screen-detected cancer at the next screening episode. Calculations on the basis of longer follow-up periods are also recommended.

References

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