IARC Handbooks of Cancer Prevention Volume 10 Cervix Cancer Screening International Agency For Research On Cancer The International Agency for Research on Cancer (IARC) was established in 1965 by the World Health Assembly, as an independently financed organization within the framework of the World Health Organization The headquarters of the Agency are in Lyon, France The Agency conducts a programme of research concentrating particularly on the epidemiology of cancer and the study of potential carcinogens in the human environment Its field studies are supplemented by biological and chemical research carried out in the Agency’s laboratories in Lyon and, through collaborative research agreements, in national research institutions in many countries The Agency also conducts a programme for the education and training of personnel for cancer research The publications of the Agency contribute to the dissemination of authoritative information on different aspects of cancer research Information about IARC publications, and how to order them, is available via the Internet at: http://www.iarc.fr/ This publication represents the views and opinions of an IARC Working Group on the Evaluation of Cancer Preventive Strategies which met in Lyon, France, Lyon, 20–27 April 2004 WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Handbooks of Cancer Prevention Volume 10 Cervix Cancer Screening IARCPress Lyon, 2005 Published by the International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372 Lyon Cedex 08, France © International Agency for Research on Cancer, 2005 Distributed by IARCPress For Europe and the World except US and Canada: Fax: +33 472 738 302; E-mail: press@iarc.fr; For the USA and Canada: Fax: +1 (202) 223 1782; E-mail: iarcpress@who.int) The World Health Organization, Marketing and Dissemination, CH-1211 Geneva 27 (fax: +41 227 914 857) and Oxford University Press, Walton Street, Oxford OX2 6DP, UK (fax: +44 1865 267782) Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol of the Universal Copyright Convention All rights reserved The designations used and the presentation of the material in this publication not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters The authors alone are responsible for the views expressed in this publication The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full Applications and enquiries should be addressed to the Communications Unit, International Agency for Research on Cancer, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available IARC Library Cataloguing in Publication Data Cervix cancer screening/IARC Working Group on the Evaluation of CancerPreventive Strategies (2004 : Lyon, France) (IARC Handbooks of Cancer Prevention ; 10) Cervix Neoplasms – diagnosis Cervix Neoplasms - prevention & control Mass Screening I IARC Working Group on the Evaluation of Cancer Prevention Strategies II Series ISBN 92 832 3010 ISSN 1027–5622 (NLM Classification: QZ39) Printed in France Contents List of participants ix Preface xi Cervical cancer and screening Cervical cancer incidence and mortality worldwide Pathology of cervical neoplasia Diagnosis and treatment of cervical preinvasive and invasive disease 18 The etiology of cervical cancer 26 Principles of screening 45 Natural history of cervical cancer 46 Considerations for screening programmes 57 Screening tests 59 Cervical cytology 59 Visual inspection 76 Colposcopy 85 Cervicography 90 HPV DNA testing 93 Combinations of different modalities 109 Effectiveness of screening in populations 201 Incidence and mortality trends in relation to screening 201 Issues in the implementation of screening 212 Hazards of screening programmes 214 Performance evaluation 217 Economic evaluation and cost-effectiveness of cervical cancer screening 223 Summary of data 227 Evaluation 237 Recommendations for public health implementation and further research 239 References 243 Glossary 293 Working procedures 299 Use of screening for cervical cancer 117 Delivery and uptake of screening 117 Behavioural considerations in screening 147 Efficacy of screening 163 Methodology and analytical issues in assessment of efficacy 163 Cytological screening 168 Visual inspection 183 Human papillomavirus testing 186 Other screening methods 191 Efficacy of screening among HIV-positive women 196 v Note to the Reader Anyone who is aware of published data that may influence any consideration in these Handbooks is encouraged to make the information available to the International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France Although all efforts are made to prepare the Handbooks as accurately as possible, mistakes may occur Readers are requested to communicate any errors to the IARC, so that corrections can be reported in future volumes Acknowledgements We are very grateful for generous support received from the Bill and Melinda Gates Foundation, through the Alliance for Cervical Cancer Prevention (ACCP), that made this publication possible vi List of participants A Anttila Finnish Cancer Registry Institute for Statistical and Epidemiology Cancer Research Liisankatu 21 B 00170 Helsinki Finland D Aoki Department of Obstetrics and Gynecology Keio University School of Medicine 35 Shinanomachi Shinjuku-ku Tokyo 160-8582 Japan M Arbyn Scientific Institute of Public Health European Network of Cervical Cancer Screening J Wytsmanstraat 14 1050 Brussels Belgium J Austoker Cancer Research UK Primary Care Education Research Group Division of Public Health University of Oxford Institute of Health Sciences Old Road, Headington, Oxford OX3 7LF United Kingdom X Bosch∗∗ Servei d’Epidemiologia Institut Català d’Oncologia Av Gran Via s/n, km 2.7 08907 L’Hospitalet del Llobregat Barcelona Spain Z.M Chirenje Department of Obstetrics and Gynaecology University of Zimbabwe PO Box A178 Avondale Harare Zimbabwe J Cuzick∗∗ Cancer Research UK Wolfson Institute of Preventive Medicine Department of Epidemiology Mathematics & Statistics Charterhouse Square London EC1M 6BQ United Kingdom N.E Day (Chairman) Institute of Public Health Strangeways Research Laboratory Wort’s Causeway Cambridge CB1 8RN United Kingdom L.A Denny Faculty of Health Sciences Obstetrics and Gynaecology Groote Schuur Hospital Observatory 7925 Cape Town, Western Cape South Africa S Fonn School of Public Health University of the Witwatersrand York Road - Parktown Braamfontein (PO Box 1038) Johannesburg South Africa E Franco∗∗ Division of Cancer Epidemiology McGill University 546 Pine Avenue West Montreal QC, H2W 1S6 Canada S J Goldie* Department of Health Policy and Management Harvard School of Public Health 718 Huntington Avenue, 2nd Floor Boston MA 02115-5924 USA T Iftner∗∗ Sektion Experimentelle Virology Universitätsklinikum Tübingen Elfriede-Aulhorn Strasse 72076 Tübingen Germany A Kricker Cancer Genes, Environment & Behaviour Program School of Public Health University of Sydney Medical Foundation Building K25 92 Parramatta Road Camperdown NSW Australia H Lawson Division of Cancer Prevention and Control National Center for Chronic Disease Prevention 4770 Buford Highway N.E MS-K57 Atlanta, GA 30341-3717 United States of America ∗ Unable to attend **Invited specialist vii IARC Handbooks of Cancer Prevention Volume 10: Cervix Cancer Screening E Lynge University of Copenhagen Institute of Public health Blegdamsvej 2200 Copenhagen N Denmark L.D Marrett Division of Preventive Oncology Cancer Care Ontario 620 University Avenue Toronto, Ontario M5G 2L7 Canada E McGoogan∗∗ University Medical School Department of Pathology Royal Infirmary of Edinburgh 51 Little France Crescent Edinburgh EH164 United Kingdom C.J Meijer Department of Pathology Vrije Universiteit Medical Center De Boelalaan 1117 POB 7057 1007 MB Amsterdam The Netherlands A.B Miller (Vice-Chairman) Department of Public Health Sciences University of Toronto Box 992 272 King Street Niagara on the Lake Ontario LOS 1JO Canada J Patnick NHS Cancer Screening Programme The Manor House 260 Ecclesall Road South S11 9PS Sheffield United Kingdom ∗∗ Invited viii specialist S.C Robles Pan American Health Organization Program on Non-Communicable Diseases 525 23rd Street, N.W Washington, D.C 20037 United States of America G Ronco∗∗ Centro per la Prevenzione Oncol Piemonte Azienda Sanitaria Ospedaliero S G Battista Via S Francesco da Paola 31 10123 Turin Italy M.H Schiffman Hormonal and Reproductive Epidemiology Branch National Institutes of Health Executive Plaza South Room 7066 6120 Executive Blvd Rockville, MD 20892 United States of America J.W Sellors∗∗ Program for Appropriate Technology in Health 1455 NW Leary Way Seattle WA 98107-5136 United States of America A Singer∗∗ Whittington Hospital NHS Trust Department of Women’s & Children’s Health Highgate Hill Jenner Building London N19 SNF United Kingdom E.J Suba Kaiser Permanente Medical Center 1200 E1 Camino Real South San Francisco, CA 904080 United States of America T.C Wright** Department of Pathology College of Physicians and Surgeons Columbia University Room 16-404, P&S Bldg 630 West 168th Street New York, NY 10032 United States of America Observers N Broutet P Claeys K Shapiro A Ullrich WHO,Geneva, Switzerland Secretariat S Arrossi F Bianchini (Co-responsible officer) F Bray J Cheney (Editor) V Cogliano G Clifford S Franceschi M Hakama (Responsible officer) A Kreimer A Loos C Mahé D.M Parkin P Pisani R Sankaranarayanan A Sasco B Secretan K Straif M Tommasino H Vainio (Head of Programme) S Vaccarella Post-meeting scientific assistance F Bianchini M Hakama Technical assistance J Mitchell A Rivoire J Thévenoux Preface Why a Handbook on Cervix Cancer Screening ? Cervix cancer is an important public health problem It is the third cancer in frequency in women worldwide and the most or second most common cancer among women in developing countries The conventional screening modality for cervical squamous intraepithelial lesions is the cytological test, or Pap smear This was introduced as a routine screening modality in much of Europe, North America and Oceania without formal evidence on efficacy from randomized trials However, data on time trends in countries with centrally organized programmes that started in the 1960s and 1970s have provided convincing evidence that cervical cytology screening, by the identification and treatment of preinvasive lesions, can prevent a large proportion of invasive cervical cancers In 1985, the IARC, in collaboration with the UICC, published a monograph on cervical cancer screening, which included a detailed analysis of the effectiveness of different screening policies, including the frequency of screening and the age at which it should start That volume has been widely used, particularly in Europe, to define national screening policy Since 1985, there have been two notable advances The most important is the identification of certain oncogenic types of human papillomavirus (HPV) as the major cause of cervical cancer; indeed it may be that the disease does not occur in the absence of HPV infection With the development of vaccines against these oncogenic HPV types, it is becoming possible to envisage the primary prevention of most cases of cervical cancer It will be several decades, however, before most women in the relevant age groups will benefit from such vaccines, since they will already have been at risk of exposure to the virus Of more immediate potential benefit is the role of hightechnology HPV testing in screening, either as an adjunct to cervical cytology or as the primary screening modality The second advance has been the development of low-cost, low-technology cervical screening modalities These may be appropriate as alternatives to cytology in many developing countries that have a high incidence of cervical cancer and limited infrastructure and health-care resources, as well as other competing health priorities Furthermore, in the 20 years since the earlier monograph, the pattern of cervical cancer and its precursor lesions has changed in many countries, with rapidly increasing incidence in younger age groups and some evidence that the natural history may be age-dependent Such age-dependence could have implications for screening policies The purpose of this Handbook is to consider the implications for cervical cancer screening of the advances that have been made over the past 20 years, and of the changing patterns of cervical cancer incidence In particular, it gives an evidence-based critical evaluation of the efficacy and effectiveness of the modalities currently available for cervical cancer screening, and of their rela- tive appropriateness depending on the resources available and competing priorities Further aims are to provide recommendations for the public health implementation of screening, including the frequency of screening and the age groups that should constitute the target population, and to identify areas for further research Public health authorities in middleand low-income countries are following closely the debate on the role of new screening technologies Vaccination against HPV infection for primary prevention of cervical cancer opens a new avenue for control of cervix cancer Between the fear of increased healthcare costs associated with the adoption of new technologies or boosting available efforts on the one hand and the promising results coming from the research front on HPV vaccines on the other, it is tempting to take a wait-andsee attitude concerning cervical cancer prevention This posture could lead to decreased funding for cervical cancer screening in the false hope that HPV vaccines will be available soon to 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Hakama, M., Lynge, E., Schouten, L.J & Parkin, D.M., eds, Evaluation and Monitoring of Screening Programmes, Brussels, Luxembourg, Europe Against Cancer Programme, pp 99–118 Zehbe, I., Wilander, E., Delius, H & Tommasino, M (1998a) Human papillomavirus 16 E6 variants are more prevalent in invasive cervical carcinoma than the prototype Cancer Res., 58, 829–833 Zehbe, I., Voglino, G., Delius, H., Wilander, E & Tommasino, M (1998b) Risk of cervical cancer and geographical variations of human papillomavirus 16 E6 polymorphisms Lancet, 352, 1441–1442 Zeisler, H., Mayerhoffer, K., Joura, E.A., Sator, M & Kainz, C.(1997) Psychological burden of women with mild cervical intraepithelial neoplasia Oncol Rep., 4, 1063–1065 Zelen, M & Feinleib, M (1969) On the theory of screening for chronic diseases Biometrika, 56, 601–614 Zhang, Z.F., Parkin, D.M., Yu, S.Z., Estève, J., Yang, X.Z & Day, N.E (1989) Cervical screening attendance and its effectiveness in a rural population in China Cancer Detect Prev., 13, 337–342 Zhou, C., Gilks, C.B., Hayes, M & Clement, P.B (1998) Papillary serous carcinoma of the uterine cervix: a clinicopathologic study of 17 cases Am J Surg Pathol., 22, 113–120 Zielinski, G.D., Snijders, P.J., Rozendaal, L., Voorhorst, F.J., van der Linden, H.C., Runsink, A.P., de Schipper, F.A & Meijer, C.J (2001a) HPV presence precedes abnormal cytology in women developing cervical cancer and signals false negative smears Br J Cancer, 85, 398–404 Zielinski, G.D., Snijders, P.J., Rozendaal, L., Voorhorst, F.J., Runsink, A.P., de Schipper, F.A & Meijer, C.J (2001b) High-risk HPV testing in women with borderline and mild dyskaryosis: long-term follow-up data and clinical relevance J Pathol., 195, 300–306 References Zielinski, G.D., Snijders, P.J., Rozendaal, L., Daalmeijer, N.F., Risse, E.K., Voorhorst, F.J., Jiwa, N.M., van der Linden, H.C., de Schipper, F.A., Runsink, A.P & Meijer, C.J (2003) The presence of high-risk HPV combined with specific p53 and p16INK4a expression patterns points to high-risk HPV as the main causative agent for adenocarcinoma in situ and adenocarcinoma of the cervix J Pathol., 201, 535–543 Zielinski, G.D., Bais, A.G., Helmerhorst,T.J., Verheijen, R.H., de Schipper, F.A., Snijders, P.J., Voorhorst, F.J., van Kemenade, F.J., Rozendaal, L., Meijer, C.J (2004) HPV testing and monitoring of women after treatment of CIN 3: Review of the literature and meta-analysis Obstet Gynaecol Surv., 59, 543–553 Zunzunegui, M.V., King, M.C., Coria, C.F & Charlet, J (1986) Male influences on cervical cancer risk Am J Epidemiol., 123, 302–307 zur Hausen, H (1976) Condylomata acuminata and human genital cancer Cancer Res., 36, 794 specific human papillomavirus types Curr Top Microbiol Immunol., 186, 131–156 zur Hausen, H (2000) Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis J Natl Cancer Inst., 92, 690–698 zur Hausen, H (2002) Papillomaviruses and cancer: from basic studies to clinical application Nat Rev Cancer, 2, 342–350 zur Hausen, H (1994) Molecular pathogenesis of cancer of the cervix and its causation by 291 Glossary Atypical squamous cell Cells that are considered suggestive but not diagnostic of a squamous intraepithelial lesion, at cytology Background cervical cancer incidence rate The cervical cancer incidence rate expected in the absence of screening It is not directly observable but estimated from the incidence in the target population before screening started (and adjusted for trend) or incidence at about the same time in an unscreened referent population, or in unscreened controls in the case of a randomized trial Biopsy Tissue specimen for morphological or immunohistochemical diagnosis Cancer registry System of ongoing reporting of cancer patients in a defined population More broadly a research institute that utilizes a cancer register and other information for epidemiological research Cervical cancer incidence rate The rate at which new cases of cervical cancer occur in a population The numerator is the number of newly diagnosed cases of cervical cancer that occur in a defined period The denominator is the population at risk of a diagnosis of cervical cancer during this defined period multiplied by the length of this period, sometimes expressed as person-time Cervical cancer mortality rate The rate at which deaths from cervical cancer occur in a population The numerator is the number of cervical cancer deaths that occur in a defined time period The denominator is the population at risk of dying from cervical cancer during this defined period multiplied by the length of the period, sometimes expressed as person-time Cervical cancer register Recording of information on all new cases of and deaths from cervical cancer occurring in a defined population Cervicography Photography of the cervix taken after the application of 5% acetic acid, using a camera with a fixed focal length and internal light source The images are projected on a screen at a fixed distance to simulate magnification and are interpreted as to grade of neoplasia by a specially trained evaluator Cohort effect Effect of an etiological exposure or medical or societal intervention that affects differently persons born in successive birth cohorts Colposcopy Magnified visual examination of the cervix using a low-power stereoscopic binocular field microscope with a powerful light source 293 IARC Handbooks of Cancer Prevention Volume 10: Cervix Cancer Screening Cost-effectiveness An analysis of the costs relative to the effectiveness of a procedure or activity, or comparisons of similar activities to determine the relative degree they will achieve similar effectiveness Coverage Number of women invited as a proportion of target population Also the number of women who have a screening test within the recommended interval as a proportion of all women who are eligible to attend for screening In the second meaning, this term is equivalent to attendance or participation rate Delay time The time between when a lesion destined to became cancer could be detected by screening and when it is actually detected by screening Not directly observable Cf lead time Demonstration project A health-care project with built-in provision for measuring cost, performance and outcome of a model service Detectable preclinical phase (DPCP) The time between that at which a tumour could be found by screening and that at which it would become clinically recognized (not directly observable) Length of DPCP is sojourn time and it is composed of delay time and lead time Detection method for sensitivity To estimate sensitivity by detection rate and interval cancer incidence Detection rate Proportion of cancers (preinvasive lesions) confirmed during the screening episode among those screened or in the target population Direct-to-vial Where liquid-based cytology is used and cells exfoliated from the cervix are placed directly and completely in the vial of preservative liquid Down-staging Screening with identification of invasive disease in asymptomatic women at an earlier clinical stage than those detected clinically Effect The result of screening Effect measures are changes in incidence of and/or mortality from cervical cancer Effectiveness The reduction in incidence of and/or mortality from invasive cervical cancer due to screening practice, under real conditions and among those in the target population Efficacy The reduction in incidence of and/or mortality from invasive cervical cancer under ideal conditions (in randomized trials), and among those screened compared to the incidence or mortality in those randomized not to be screened but compliant if invited to be screened Efficiency The effects or end results achieved in relation to the effort expended in terms of money, resources and time Episode The period from the time of test (taking the smear) to the end of time of further assessment, i.e., the time of decision to intervene or not 294 Glossary False (change) gain in sensitivity When a second, adjunct test is added to a conventional, primary test and positive results by the second test are used to supplement the positivity of the primary test, the estimate of sensitivity will always be greater than that of the first test used alone, even if the second test were totally random with respect to the disease or to the first test The increased combined sensitivity may or may not be greater than that contributed by an unrelated adjunct test in the same screening setting Ideally, studies should consider sensitivity gains of combined testing only after taking into account this chance increase in sensitivity Further assessment Additional diagnostic steps (either non-invasive or invasive) performed to clarify the nature of an abnormality detected by the screening test, either at the time of screening or on recall or as a result of referral Gold standard A diagnostic method that is considered to have the best sensitivity and specificity among all methods available Incidence method for sensitivity To estimate sensitivity as – ratio of interval cancer incidence rate between two screens to that expected if there was no screening Incidence (annual) of preinvasive lesions Detection rate of the lesion at given subsequent screen divided by the screening interval Alternatively, the number of new cases of preinvasive lesions divided by the person time, which equals number of women screened multiplied by screening interval Informed choice Decision about whether or not to participate, based on the provision of information about the benefits and limitations of screening Informed consent Voluntary consent given by a subject for participation, after being informed about the purpose, procedures, benefits and risks Infrastructure Material and human resources and their interrelationships Interval cancer An invasive cervical cancer diagnosed in an attender, after a negative screen, either: • before the next invitation to screening was due or • within a period equal to a screening interval for a woman who has reached the upper age limit for screening Interval cancer (incidence) rate Interval cancers divided by person years in the period the cancers are derived from The rate is different for test, episode and programme Lead time Period between when a lesion destined to become cancer is found by screening and when it would have been clinically recognized if no screening took place (cf delay time) Length bias The bias towards detection by screening of cancers with longer sojourn times and therefore better prognosis 295 IARC Handbooks of Cancer Prevention Volume 10: Cervix Cancer Screening Loop electrosurgical excision procedure (LEEP) LEEP uses a thin wire loop electrode attached to an electrosurgical generator as a precise and rapid surgical tool The generator transmits a painless electrical current that quickly cuts away affected cervical tissue in the immediate area of the loop wire Microinvasive cancer Cancers that have invaded no more than mm deep and mm wide into the underlying cervical stroma Organized screening Screening programmes organized at national or regional level, with an explicit policy, that includes several essential elements from target population to treatment Opportunistic screening Screening outside an organized or population-based screening programme, as a result of, for example, a recommendation made during a routine medical consultation for the woman, consultation for an unrelated condition, on the basis of a possibly increased risk for developing cervical cancer or by self-referral Outcome Event related to objective of screening (death from cervical cancer), sometimes also to the performance of screening Overcall Recall or referral with poor specificity Overdiagnosis Detection of cervical cancers or preinvasive lesions that would never have progressed to be clinically recognized during a woman's life Overtreatment Treatment of lesions that would never have progressed to be clinically recognized during a woman's life Participation rate Proportion of those screened among those invited according to the scheduled policy (organized screening) In a programme not based on invitations, participation has the same meaning as coverage Performance Quality of screening activities mainly related to the laboratory, sometimes to all the screening process rather than outcome Performance indicators Quantitative measures of the process of screening Generally, targets are set of the quantity which is required for good quality process Period effect Effect of an etiological exposure or medical or societal intervention that affects differently in time Pilot study A demonstration project that provides information on performance but not on outcome and is based on a limited population Population access Proportion of the national population of eligible women who have access to a screening programme (cf coverage) Positive predictive value Proportion of diagnoses of cancer in all positive results of the screening test A process measure Positivity rate of test Proportion of diagnoses of cancer in all positive results of the screening test A process measure 296 Glossary Primary screening Detection of cases of cervical cancer or of its precursor lesions among asymptomatic women without a referral diagnosis, i.e., as true population screening, either opportunistic or systematic Quality assurance Maintenance of minimum standards and continual striving for excellence Quality control The supervision and control of all operations involved in a process, usually involving sampling and inspection, in order to detect and correct systematic or excessively random variations in quality Recall Clarification of a perceived abnormality detected at screening, by performance of an additional procedure Recall rate The number of women recalled for further assessment as a proportion of all women who were screened (test positivity rate) Referral Physical referral of women to a clinical facility as a consequence of the screening test for diagnostic confirmation, e.g., by histology Reflex HPV testing A protocol for routine triage of equivocal cervical cytological interpretations, by HPV testing either the residual liquid cytology specimen or an additional specimen collected at the same time as the original sample Relative sensitivity Ratio of detection rate of malignancy after test A to the detection rate of malignancy after test B Also sensitivity of test A relative to histology See verification bias Relative survival Survival if cervical cancer were the only cause of death among cervical cancer patients Screen and treat A procedure where testing, confirmation and treatment take place during the same episode Screening interval Fixed interval between routine screenings decided upon in each programme, depending on screening policy Screening policy Specific policy of a screening programme which dictates the targeted age group, the geographical area, the screening interval, etc Opportunistic systems may also have policies Screening test Test applied to all women in a programme that results in discrimination between those who test positive from those who test negative (e.g., Pap smear) Those who test positive will be recalled or referred for further assessment or diagnostic confirmation See and treat A procedure where the cervix is treated at first attendance for colposcopy and no histology information is available 297 IARC Handbooks of Cancer Prevention Volume 10: Cervix Cancer Screening Sensitivity Capacity of screening to identify unrecognized disease, i.e., future invasive cervix cancer in a population or disease in the DPCP • sensitivity of test is the proportion of those with a positive test among those with disease in the DPCP • sensitivity of the episode is the proportion of those with disease detected by screening among those with the disease in the DPCP among those screened • programme sensitivity is the proportion of those with disease detected by the screening organization among those with disease in the DPCP among total target population • sensitivity by incidence method is estimated with interval cancers and background incidence Sojourn time Detectable preclinical phase; time between that at which a tumour could be found by screening and that at which it would be clinically recognized if the woman was not screened (not directly observable) Specificity Capacity of screening to identify those who remain healthy in a population Split sample Sample of the exfoliated cervical cells where liquid-based cytology sample is split between preparation of a conventional Pap smear and the balance of cells being deposited in a vial of liquid preservative Target population The population eligible for screening, i.e., all women recommended to undergo screening according to the policy adpoted Triage Detection of cases of cervical cancer or of its precursor lesions among women who were initially found to have an abnormal screening test that requires further evaluation Undercall Recall or referral with poor sensitivity Verification bias A bias in the relative sensitivity and specificity estimates that occurs if the probability of disease verification via the gold standard (e.g., colposcopy and biopsy) is dependent on the screening test result It may also occur when there are two screening tests whose results the investigator uses to decide who will be referred for the gold standard In that case, bias will ensue if the positivity of the second test is evaluated conditionally on the positivity of the first test 298 Working Procedures Prevention of cancer is one of the key objectives of IARC Secondary prevention by early diagnosis and screening is a fundamental component of any cancer control programme The aim of secondary prevention is to reduce mortality and suffering from the disease When screening is planned as part of a cancer control programme, only strategies proved to be effective should be proposed to the general population Screening usually requires repeated interactions between ‘healthy’ individuals and health care providers, which can be inconvenient and costly Furthermore, screening requires an ongoing commitment between the public and health care providers Scope Cochrane (1972) first discussed the concepts of efficacy and effectiveness in the context of health interventions Efficacy was later defined by Last (1995) as "the extent to which a specific intervention, procedure or service produces a beneficial result under ideal circumstances" In contrast, the related term "effectiveness" is defined by the same author as " a measure of the extent to which a specific intervention, procedure, regimen or service, when deployed in the field in routine circumstances, does what it is intended to for a specific population." The distinction between efficacy as measured in experimental studies and the effectiveness of a mass population intervention is a crucial one for public health decision-making In particular, the fact that the effectiveness of a screening procedure may be different in different populations is often over- looked A mass programme of screening must satisfy certain minimal requirements (e.g acceptability, availability of relevant personnel, facilities for screening and access to pertinent health services) if it is to achieve the results that have been documented in epidemiological studies The acceptance and use of screening services may vary from one population to another, implying that a given screening procedure is not universally effective Even when a screening procedure is effective as a mass intervention, other outcomes such as harm and costs and the potential for other interventions to achieve equivalent benefits must be considered Efficacy is a necessary but not a sufficient basis for recommending screening The efficacy of a screening procedure can be inferred if effectiveness can be proven Screening has sometimes been implemented by a given procedure on the assumption that ‘earlier is better’, even when no evidence of efficacy was available If such interventions result in a significant reduction in mortality that cannot otherwise be explained, it can be inferred that the procedure is effective However, uncontrolled interventions in which individuals are exposed to unknown risks and benefits should be avoided Objectives The objectives of the Working Group are: (1) to evaluate the strength of the evidence for the efficacy of a screening procedure; (2) to assess the effectiveness of defined screening interventions in defined populations; (3) to assess the balance of benefit and harm in target populations; and (4) to formulate recommendations for further research and for public health action The conclusions of the Working Group are published as a volume in the series of the IARC Handbooks of Cancer Prevention Working groups An international working group of experts is convened by the IARC The tasks of the group are: (1) to ascertain that all appropriate data have been retrieved; (2) to select the data relevant for evaluation on the basis of scientific merit; (3) to prepare accurate reviews of data to allow the reader to follow the reasoning of the working group; (4) to evaluate the efficacy and effectiveness of the screening procedure; (5) to summarize the potential adverse consequences of screening; (6) to prepare recommendations for research and for public health action; and (7) to prepare an overall evaluation of the screening procedure at the population level Approximately 13 months before a working group meets, the topics of the Handbook are announced, and prospective participants are selected by IARC staff in consultation with other experts Working group participants who contributed to the considerations and evaluations within a particular handbook are listed, with their 299 IARC Handbooks of Cancer Prevention Volume 10: Cervix Cancer Screening addresses, at the beginning of each publication Each participant serves as an independent scientist and not as a representative of any organization, government or industry They are expected to put aside any stake they may have in a particular outcome and to evaluate the evidence objectively and with scientific rigour All participants are required to complete a form before the meeting on which they declare any potential conflict of interest, due for example to recent links with commercial or industrial bodies that have a stake in the outcome of the meeting Participants who declare any such potential conflict of interest are excluded from chairing the meeting or any of its subgroups, from drafting evaluations and from any voting that may be involved in reaching the final conclusions They may otherwise participate fully in the meeting, and are designated in the list of participants (pages vii-viii) as ‘invited experts’ Scientists nominated by national and international agencies, industrial associations and consumer and/or environmental organizations may be invited as observers IARC staff members involved in the preparation of the handbook are listed as secretariat Subsequently, relevant data are collected by the IARC from all available sources of published information About eight months before the meeting, the material collected is sent to meeting participants who are asked to prepare sections for the first drafts of the handbook These drafts are then compiled by IARC staff and sent, before the meeting, to all participants of the working group for review Data for handbooks The handbooks not necessarily cite all of the literature on the agent or strategy being evaluated Only those data considered by the working group to be relevant to making the evaluation are included Meeting abstracts and 300 other reports that not provide sufficient detail upon which to base an assessment of their quality are generally not considered With regard to reports of basic scientific research, epidemiological studies and clinical trials, only those that have been published or accepted for publication in the openly available scientific literature are reviewed by the working group In certain instances, government agency reports that have undergone peer review and are widely available are considered Exceptions may be made ad hoc to include unpublished reports that are in their final form and publicly available, if their inclusion is considered pertinent to making a final evaluation The available studies are summarized by the working group In general, numerical findings are indicated as they appear in the original report; units are converted when necessary for easier comparison The working group may conduct additional analyses of the published data and use them in their assessment of the evidence These analyses are described in the handbook Important aspects of a study, directly impinging on its interpretation, are brought to the attention of the reader Evaluation of screening The framework of a handbook on screening includes the following eight chapters: Chapter Disease characteristics, global burden and rationale for screening Descriptive epidemiology The purpose of this section is to document the importance of the disease in the context of the general health status of different populations The worldwide burden of the cancer is described (mortality, incidence, prevalence and survival rates) and integrated with measures of the occurrence of cancers at other sites, of mortality from all causes and life expectancy Expected trends in the absence of screening are a relevant component of this section Natural history of the disease as relevant to screening In this section, the natural history of the disease of interest and the relevance and potential of screening for early detection and for reducing mortality are described Evolving concepts and principles pertinent to screening are also discussed There is now a wealth of evidence (both direct and indirect) to support the principle that screening and detection of certain cancers in appropriate target populations are associated with a lower probability of dying from the disease.The scheme (on the next page) illustrates the temporal framework commonly subscribed to in modern screening models It should be noted that early diagnosis, due to greater awareness and improved access to appropriate medical services, has resulted in many countries in a reduction in diagnostic delay, probably reducing mortality As a consequence, symptomatic cancers are frequently diagnosed and treated early after the onset of symptoms in many developed nations In such instances, screening for the disease will improve outcomes (for example, reducing mortality) only if treatment of the disease at an even earlier phase in its development provides additional benefit The rapid evolution of molecular or genetic markers of pre-malignant conditions or individuals at high risk has modified the concepts of ‘disease onset’ and ‘lead time’ Hence, the model outlined above may require adaptation or development to allow for detection of pre-clinical conditions of undetermined significance (including serological and molecular markers and genetic predisposition), if they are relevant for screening for the cancer in question Chapter Screening tests It is important to distinguish between References Lead time Onset Pre-clinical detectable phase Symptoms Death Screening screening tests and screening procedures, i.e the test itself and the way in which it is administered The two merit separate, detailed evaluation Each of the screening tests to be considered is described The ability of each test to detect cancer and to distinguish cancer from non-cancer conditions will be assessed as: • the validity of the test, expressed as its sensitivity and specificity under various conditions; • all known or potential side-effects; and • the cost of the test when implemented in mass screening programmes Chapter Delivery and uptake of screening Information on how screening is delivered in different countries is reviewed in this section, with emphasis on the following aspects: • infrastructure for diagnosis and treatment: the nature of standard diagnostic procedures and treatment regimens and their availability to the target population; • extent of population coverage and participation rates; • equity, as defined by the extent to which access to the procedure (including diagnostic investigation and treatment) is ensured for all eligible individuals, irrespective of any personal characteristics; • informed decision and informed consent: the extent to which individual values are respected when information on potential benefit and harm is conveyed; and • behavioural and demographic considerations that affect participation in screening Chapter Efficacy of screening tests In this section, evidence from epidemiological studies is reviewed, and aspects of study design and analysis are critically discussed The handbooks are not intended to summarize all published studies The working group considers the following aspects: (1) the relevance of the study; (2) the appropriateness of the design and analysis to the question being asked; (3) the adequacy and completeness of the presentation of the data; and (4) the degree to which chance, bias and confounding may have affected the results Studies that are judged to be inadequate or irrelevant to the evaluation are generally omitted They may be mentioned briefly (i) when the information is considered to be a useful supplement to that in other reports, (ii) if they provide the only data available or (iii) in exceptional cases, if they have been widely perceived as being pertinent but are deemed otherwise by the working group Their inclusion does not imply acceptance of the adequacy of the study design nor of the analysis and interpretation of the results, and their limitations are outlined The appropriate outcomes) (mortality or incidence) of a given procedure, e.g the detectable phases) of the natural history of the disease, are also defined Aspects that are particularly important in evaluating experimental studies are: the selection of participants, the nature and adequacy of the randomization procedure, evidence that randomization achieved an adequate balance between the groups, the exclusion criteria used before and after randomization, compliance with the intervention in the screened group and ‘contamination’ with the intervention in the control group Other considerations are the means by which the end-point was determined and validated (either by screening or by other means of detection of the disease), the length and completeness of follow-up of the groups and the adequacy of the analysis Whenever possible, similar criteria should be used to evaluate non-experimental comparative studies In the Working Group's analysis of the efficacy of the screening procedure, a meta-analysis may be used, when applicable In evaluating case–control and cohort studies, particular attention is paid to the definition of cases, controls and exposure and, for cohort studies, the length and completeness of followup Potential bias, especially selection bias, is carefully examined in all observational studies Chapter Effectiveness of population-based screening The impact of the screening procedure when implemented in defined populations is examined in this section Indicators used to monitor effectiveness, such as positive and negative predictive values, detection rate, rates of interval cancers and the number of tests performed, are reported Time trends before and after implementation of screening as well as geographical comparisons of the occurrence of the disease and death from the disease in populations exposed and not exposed to screening are reviewed and interpreted In doing this, the Working Group takes into account differences in 301 IARC Handbooks of Cancer Prevention Volume 10: Cervix Cancer Screening screening procedures (e.g frequency and the age of the target population) and of participation rates An integral component of this section is an evaluation of the benefits and harms of the screening procedure to the population Reductions in mortality and/or incidence of invasive disease are fundamental measures of benefit An additional benefit is that more cases can be treated by less aggressive, less invasive procedures, thus improving the quality of life The spectrum of health care is dynamic, and a screening procedure should not be viewed in isolation Greater awareness of the disease, brought about by publicity about screening that may result in early diagnosis, could be regarded as another benefit of a screening programme This section should also consider the possibility that there might have been a change in treatment of the cancer, which even in the absence of screening would have resulted in a substantial decrease in mortality As far as possible, an evaluation should be made of the extent to which improved treatment has been responsible for any changes seen in mortality from the specific disease Estimates of the rates of false-positive and false-negative findings in screened individuals and their consequences (false sense of security with false-negatives and false alarm with false-positives) are an integral part of this section The rates of short- and long-term side-effects and the possibility of unnecessary treatment of borderline or indolent cases detected at screening are discussed Management procedures for lesions detected at screening are reviewed Psychological factors, such as anxiety induced by undergoing the test procedure, are also considered Finally, the cost-effectiveness of various modalities of test administration in various settings is considered The discussion takes into account the costs per case detected and per death prevented 302 Chapter Summary of data In this section, the relevant data are summarized Inadequate studies identified in the preceding text are generally not included Chapter Evaluation Evaluation of the efficacy of the screening procedure An evaluation of the degree of evidence for the efficacy of a screening procedure is formulated according to the following definitions: Sufficient evidence of the efficacy of cancer-preventive activity will apply when screening interventions by a defined procedure are consistently associated with a reduction in mortality from the cancer and/or a reduction in the incidence of invasive cancer, and chance and bias can be ruled out with reasonable confidence Limited evidence of the efficacy of cancer-preventive activity will apply when screening interventions by a defined procedure are associated with a reduction in mortality from the cancer and/or a reduction in the incidence of invasive cancer or a reduction in the incidence of clinically advanced cancer, but bias or confounding cannot be ruled out with reasonable confidence as alternative explanations for these associations Inadequate evidence of the efficacy of cancer-preventive activity will apply when data are lacking or when the available information is insufficient or too heterogeneous to allow an evaluation Sufficient evidence that the screening procedure is not efficacious in cancer prevention will apply when any of the following cases hold: • the test does not result in earlier diagnosis than with standard tests already in use; • the survival of cases detected at screening is no better than that of • cases diagnosed routinely; the screening interventions are consistently associated with no reduction in mortality from or incidence of invasive cancer, and bias can be ruled out with reasonable confidence In the case of limited or inadequate evidence, the Working Group should highlight those aspects of the procedure for which information is lacking and which led to the uncertainty in evaluation This will provide indications of research priorities Overall evaluation Finally, the body of evidence is considered as a whole, and summary statements are made about the cancer-preventive effects of the screening intervention in humans and other beneficial or adverse effects, as appropriate The overall evaluation is usually in the form of a narrative The data on the effectiveness of the screening intervention are summarized, including the factors that determine its success and failure under routine conditions Finally, the balance between expected benefit and harm is described Chapter Recommendations After its review of the data and its deliberations, the working group formulates recommendations, where applicable, for: • further research and • public health action References Cochrane, A.L (1972) Effectiveness and Efficiency: Random Reflections on Health Services, Oxford: Nuffield Provincial Hospitals Trust Last, J.M (1995) A Dictionary of Epidemiology, Oxford: Oxford University Press .. .IARC Handbooks of Cancer Prevention Volume 10 Cervix Cancer Screening International Agency For Research On Cancer The International Agency for Research on Cancer (IARC) was established... training of personnel for cancer research The publications of the Agency contribute to the dissemination of authoritative information on different aspects of cancer research Information about IARC. .. AGENCY FOR RESEARCH ON CANCER IARC Handbooks of Cancer Prevention Volume 10 Cervix Cancer Screening IARCPress Lyon, 2005 Published by the International Agency for Research on Cancer, 150 cours Albert