This is a part II of chapter Cancer screening (Cancon work package 9) of the Guide. See part I of the chapter.
Cancer screening part I:
Governance of cancer screening
Integrated evaluation, part I
Continued from the previous part
Quality management must include both continuous monitoring of the quality indicators and programme improvement when indicated by monitoring or related evaluation projects. Quality assurance should be performed both at institutional and individual level, as appropriate. Linking indicators of quality with reimbursement of screening procedures provides a powerful tool for quality assurance and can initiate mechanisms to provide training and education to professionals failing to reach the minimum quality requirements and to exclude from participation in the screening programme any institutions and individual specialists repeatedly failing to reach agreed benchmarks of quality.
Monitoring and evaluation reports must be published regularly to inform the public and decisionmakers and to permit timely modification of programme policy, if necessary (5). Because of the importance of acceptance of the programme by society, the results have to be communicated to the public on a regular basis. Collaboration between countries in monitoring and evaluating routine programmes will ensure better comparability of results and may encourage higher standards in all aspects of quality assurance. Countries with federated screening programmes need central collection of monitoring data for calculation and analysis of performance indicators and their publication and dissemination. An example of such a monitoring organization is provided by the Osservatorio Nazionale Screening (National Centre for Screening Monitoring) in Italy (56). An important advantage of population-based screening programmes is that they can contribute to improve equity by comparison with other preventive health service modalities such as case finding or opportunistic testing (3). This is achieved by improved access to services through the personalized invitations to all individuals in the target population and adoption of comprehensive quality assurance of services throughout the programme span (57,58).
However, social inequalities in access to cancer screening can still be observed within population-based programmes, evident as lower participation in cancer screening programmes by lower socioeconomic status, within minority ethnic groups or in deprived areas (59–68). Participation in and performance and outcome of population-based screening varies remarkably also between countries (23,35–37,54,69), indicating large inequalities throughout Europe. According to a recent report on breast cancer screening, only about half of the EU Member States monitor access to screening by socioeconomic level, educational level and/or ethnicity/nationality (70). There is also some evidence on the association between cancer burden and human development index, a composite indicator of life expectancy, education and gross domestic product using aggregated data (71–73). Increases in the unemployment rates during the recent economic recession have also been associated with rises in cancer mortality (74).
Evaluation and regular monitoring of screening performance by demographic and socioeconomic groups,, and in regions by their development index, is essential to verify whether screening reduces social inequalities in cancer and improves equity in health. Information on socioeconomic and ethnic or language groups, and on issues such as education level can be generated through linkages with appropriate population registries and census records. Evaluation research with experimental designs – also with qualitative components – is needed when social inequalities in cancer have been revealed (68). When attempting to correct social inequalities in cancer screening, it would be very useful to have partners from different countries and programmes with earlier experiences on the relevant interventions. Collaboration and investments in translational research are needed to develop research activities in the local, specific programme settings (e.g. in the case of poor attendance or poor adherence to quality assurance guidelines) on reasons and on how to optimize attendance and to develop balanced, appropriate information for the programme. The Council of the European Union’s recommendation (5) already covers most aspects of monitoring content and aims. However, explicit address of social inequalities as an essential part and specific aim for monitoring is added here.
Whenever relevant, evaluation and regular monitoring of cancer screening should also detect social inequalities and trigger research and interventions on improved equity in health. Research collaboration has an added value to develop interventions and solutions in the local settings where social barriers and social inequalities in cancer have prevailed.
The current criteria for new cancer screening programmes (for primary sites other than breast, cervix and colorectum) or for programmes utilizing completely new screening methods that are not understood as modifications to the current method include synthesis of the evidence of effectiveness: benefits, harms and their balance. The overall benefits should outweigh the expected side-effects and the harm, and the potential programme should satisfy the requirements of cost-effectiveness, based on evaluations from appropriate RCTs (3–5).
To gather the required evidence, the Council of the European Union has also recommended that such trials need to be actively run and has proposed also pooling of relevant trials from representative settings in order to help with evidence assessments. Once evidence exists to support these criteria, implementation research in each country is needed to assess the feasibility of fulfilling the national requirements in practice (Fig. 4.1). So far, evidence on the above aspects has not been considered adequate in the EU to recommend screening for cancers other than breast, cervix and colorectum. Yet only a few such trials and/ or pooling exercises have been carried out. The potential to gain further improvement in cancer control through new cancer screening programmes is vast. This section deals with current information from trials on potential new cancer screening programmes for four cancer sites (prostate, lung, stomach and ovaries). These are used as examples to highlight key policy-making aspects. There are also other primary sites potentially relevant for screening and prevention interventions for which no or few trials are available.
Based on criteria for screening of WHO and others (1,3,4), it can be concluded that there are three key criteria for deciding whether a screening programme should be adopted: (i) is there evidence for the effectiveness of screening; (ii) is there evidence that the benefits of screening outweigh the harms; and (iii) is screening cost-effective (4). These three steps will be described in more detail below. The remaining criteria are relevant for the subsequent process of implementation, monitoring, evaluation, affordability and sustainability of the programme. In addition to evidence criteria, other aspects affect policy-making, such as prioritization because of the burden of disease, feasibility, affordability and availability of resources to organize the programme adequately. These are important in the national decision-making context, but are not discussed further here.
Step 1: effectiveness
The first step is to determine whether screening is effective, that is, does it reduce mortality from the target disease. This can only be done by means of RCTs with disease-specific mortality as the primary end-point. Observational studies (case-control studies or cohort studies) should be interpreted with caution since they are prone to selection bias: because individuals participating in screening are almost invariably healthier than those who do not, they are likely to have better outcomes, even in the absence of screening. Studies comparing survival rates between screendetected and clinically detected cases are hardly informative, since in addition to selection bias they are prone to two other forms of bias: lead-time bias and length bias.
As a result, screening seems to prolong survival even if it does not extend life. Because cancer is just one cause of death and because of the inherent time lag between a screening intervention and its effect on mortality, RCTs evaluating screening have to be large and follow-up has to be long. As a result, screening trials are relatively expensive. Still, it is important to realize that they are indispensable. No alternatives (e.g. by using proxy end-points and/or simulation) are acceptable as primary evidence on the effectiveness of a new screening programme (83,84).
Step 2: benefit-harm ratio
The second step is to determine whether the benefits of screening outweigh the harms. A frequently used method to value the health effects of screening is by using utility weights. These weights correct the time spent in a certain disease state for the quality of life experienced in that state. The valued effects can be summed up as the number of QALYs gained. Possible benefits of a screening programme are a reduction in disease-specific mortality or all-cause mortality, a reduction of advanced disease and aggressive treatment, and QALYs gained. Possible harms of screening are pain and stress of the screen test and diagnosis, false-positive tests results, more life living with the knowledge of the disease, false reassurance, overdiagnosis, overtreatment and treatment-related adverse events (4,83,84).
Step 3: economic evaluation
Health care expenditure per capita varied from €400 to €5500 (87). The national choices for the threshold values for cost-effectiveness vary as a result of variation in the resources available for health care. There is no common threshold value proposed for the EU. The health care resources should be taken into account in the healtheconomical and inequity analyses and when preparing European-level recommendations.
1) Variation by the gross domestic product per capita ranged in 2014 from US$ 7800 (Bulgaria) to US$ 56 100 (Denmark) and US$ 111 700 USD (Luxembourg), with the average in the EU approximately US$ 35 000 (87).
The current evidence is that the European Randomized Study of Screening for Prostate Cancer has showed that screening using levels of prostate-specific antigen (PSA) results in a 21% prostate cancer mortality reduction in an intention-to-treat analysis (88–90). The trial efficacy point estimates varied between participating countries because of differences in length of follow-up, underlying test and referral rates and contamination for PSA in the control arm. No mortality difference was found after a median follow-up of 11 years in a trial in the United States, failure to do so likely attributable to heavy contamination of the control arm (91,92).
Although there are particularly concerns on the harms of overdiagnosis and overtreatment resulting from screening (93,94), it has been shown, based on the European trial results, that the benefits still outweigh the harms (95). Based on assessment utilizing the European Study results on cause-specific mortality, the cost-effectiveness of a screening programme with three screens at age 55–59 years with a two-year interval is at US$ 45 600 and with four screens at age 55–67 years with a four-year interval at US$ 92 000 (96). Cost-effectiveness with a single screen at age 55 years was estimated at US$ 31 500.
These cost-effectiveness ratios apply to health care costs as incurred in the United States and may be lower in European settings. For the Netherlands, cost-effectiveness has been estimated at €19 000 per QALY (H. de Koning, personal communication). In future, further improvements are expected because of more use of active surveillance and improved discrimination between indolent and significant disease through use of new biomarkers and magnetic resonance imaging (97–99). Hence, in some wealthy settings with a considerably high threshold value, the cost-effectiveness criteria for some policy options may already be satisfied based on current knowledge. In less affluent countries with less available money for health care, affordability issues and the prioritization of several potentially cost-effective health care interventions certainly need more deliberation before decisions can be made.
Most EU countries are planning, piloting or implementing population-based screening programmes for breast, cervical and colorectal cancers. However, there are deficiencies and barriers in many of these programmes, as indicated in a recent implementation report (6), for example in access to screening and in systematic quality assurance throughout the screening chain. Challenges in screening implementation are related in early phases to issues in planning and gradual well-controlled introduction of currently recommended programmes in regions or settings where effective and cost-effective programmes do not yet exist; in later phases challenges relate to modifying and reorganizing currently running programmes with new tests, treatments, policies or working models (Fig. 4.1).
Developing key strategic tools on evaluations needed for policy-making on possible new cancer screening programmes (other than for breast, cervical or colorectal cancer) is also essential. Considerable deficiencies in the governance structures of population-based screening were identified during the development of this chapter (Fig. 4.3), which may severely impede the full implementation of effective population-based cancer screening programmes in Europe. Key functions of screening governance are to secure political and professional commitment to an agreed screening policy with common targets; adequate legal, financial and organizational frameworks and resources to coordinate, evaluate and continuously improve the programme; and a transparent and well-informed decision mechanism for starting, modifying or stopping population-based screening (Recommendations 1–3).
Coordination of a multifaceted screening programme with a number of stakeholders by a competent management team needs to be established immediately following the decision to implement. The management is responsible for the planning and organizing of feasibility studies, piloting, roll-out, training of staff, development of information technology systems capable of population-based invitation and monitoring, comprehensive quality assurance functions and manuals in collaboration with the clinical specialties (Recommendations 4.4 and 4.5). This work starts in the preplanning phase of programme implementation and continues through to the continuous quality improvement of the established programme (Fig. 4.2).
Recognition of the human and financial resources needed for this activity is important at the point a decision is made to start a programme. Routine monitoring and evaluation of the performance and outcomes of screening can be considered an ethical imperative of population-based screening, and allow its maintenance and gradual quality improvement (Recommendations 4.6 and 4.10). The ability to individually link screening and cancer records is required. In addition to continuous quality assurance, essential parts of population-based screening are periodic evaluation of the effectiveness, benefit-harm ratio and health economy of screening; prospective evaluation of new screening methods; and dissemination of the results (Recommendation 4.8).
There is a continuing need to develop further research and interventions to ensure equal access to quality screening, irrespective of socioeconomic status, ethnic background or domicile (Recommendation 4.7). There is untapped potential for cancer prevention through extending population-based screening to new cancer sites beyond breast, cervix and colorectum. However, solid evidence on the effectiveness of new programmes from randomized trials is needed. These trials are necessarily large, time-consuming and, therefore, relatively costly; hence financing mechanisms through pan-European cooperation are recommended (Recommendations 4.11 and 4.12).
Such cooperation is particularly relevant since cost-effectiveness can vary between disparate regions of Europe and cannot always be directly transferred across different economic, epidemiological and organizational settings. At present, evidence on the effectiveness of prostate cancer screening is available; evidence on lung cancer screening is expected in the near future, but acquisition of evidence is still in its infancy for other cancer sites. All new potential cancer screening programmes require investment in research on optimal strategies for acceptable benefit-harm ratios and costeffectiveness in different settings (Recommendation 4.9). Cost-effective screening programmes need good governance, monitoring with standard key indicators throughout the screening chain and evaluation of outcome. Establishing sustainable models for funding is still in focus in many Member States. The wide variation in resources for health care between Member States should be taken into account when planning for Europe-wide recommendations and research strategies. Cancer control plans provide an essential mechanism where these issues can be elaborated and integrated into the planning and development of the health service.
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