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In 2014, the European Food Safety Authority (EFSA) started the PROMETHEUS (PROmoting METHods for Evidence Use in Scientific assessments) project to improve further and increase the consistency of the methods it uses in its scientific assessments. The project defined a set of principles for the scientific assessment process and a 4‐step approach (plan/carry out/verify/report) for their fulfilment, which was tested in ten case studies, one from each EFSA panel. The present report describes the benefits, issues, needs and solutions related to the implementation of the 4‐step approach in EFSA, identified in a dedicated workshop in October 2017. The key benefits of the approach, which was deemed applicable to all types of EFSA scientific assessment including assessments of regulated products, are: 1) increased ‘scientific value’ of EFSA outputs, i.e. the extent of impartiality, methodological rigour, transparency and engagement; 2) guarantee of fitness‐for‐purpose, as it implies tailoring the methods to the specificities of each assessment; 3) efficiency gain, since preparing a protocol for the assessment upfront helps more streamlined processes throughout the implementation phase; 4) innovation, as the approach promotes the pioneering practice of ‘planning before doing’ (well established in primary research) for broad scientific assessments in regulatory science; and 5) increased harmonisation and consistency of EFSA assessments. The 4‐step approach was also considered an effective system for detecting additional methodological and/or expertise needs and a useful basis for further defining a quality management system for EFSA's scientific processes. The identified issues and solutions related to the implementation of the approach are: a) lack of engagement and need for effective communication on benefits and added value; b) need for further advances especially in the field of problem formulation/protocol development, evidence appraisal and evidence integration; c) need for specialised expertise in the previous aspects; and specific needs for d) assessments of regulated products and e) outsourced projects.

Background The objective of the EUROCHIP project in Estonia was to describe the organized cervical cancer screening program started in 2006 (after pilot studies in 2003–2005), to compare its performance with opportunistic screening, and to define priorities for improvement of the program. Methods Population data was retrieved from Statistics Estonia, data about performed Pap-smear tests within the screening program from the Estonian Cancer Society and from clinics and labs participating in the program, data about Pap-smear tests outside the screening program from the Estonian Health Insurance Fund, and data about cancer incidence and mortality from the Estonian Cancer Registry database. Results During the first year after implementing the nationwide cervical cancer screening program in Estonia, the number of tests outside the organized program remained high. Within the organized program, the number of Pap-tests in different age groups increased with age except for the oldest age group while population coverage with Pap-tests outside the organized screening program decreased with age. The number of cervical cancer cases at early stages increased after implementation of organized screening. The time-frame does not permit to draw any definitive conclusions. Conclusions Implementation of organized cervical cancer screening did not decrease the volume of opportunistic screening. The factors influencing attendance in the organized cervical cancer screening program in different age groups should be studied further. Moreover, a central cancer screening registry without restrictive data protection legislation would improve data collection and enable to evaluate performance of the program on a regular basis.

International audience; The present study is aimed to compare survival and prognostic changes over time between elderly (70-84 years) and middle-aged cancer patients (55-69 years). We considered seven cancer sites (stomach, colon, breast, cervix and corpus uteri, ovary and prostate) and all cancers combined (but excluding prostate and non-melanoma skin cancers). Five-year relative survival was estimated for cohorts of patients diagnosed in 1988-1999 in a pool of 51 European populations covered by cancer registries. Furthermore, we applied the period-analysis method to more recent incidence data from 32 cancer registries to provide 1- and 5-year relative survival estimates for the period of follow-up 2000-2002. A significant survival improvement was observed from 1988 to 1999 for all cancers combined and for every cancer site, except cervical cancer. However, survival increased at a slower rate in the elderly, so that the gap between younger and older patients widened, particularly for prostate cancer in men and for all considered cancers except cervical cancer in women. For breast and prostate cancers, the increasing gap was likely attributable to a larger use of, respectively, mammographic screening and PSA test in middle-aged with respect to the elderly. In the period analysis of the most recent data, relative survival was much higher in middle-aged patients than in the elderly. The differences were higher for breast and gynaecological cancers, and for prostate cancer. Most of this age gap was due to a very large difference in survival after the 1st year following the diagnosis. Differences were much smaller for conditional 5-year relative survival among patients who had already survived the first year. The increase of survival in elderly men is encouraging but the lesser improvement in women and, in particular, the widening gap for breast cancer suggest that many barriers still delay access to care and that enhanced prevention and clinical management remain major issues.

In international comparisons of cancer registry based survival it is common practice to restrict the analysis to first primary tumours and exclude multiple cancers. The probability of correctly detecting subsequent cancers depends on the registry's running time, which results in different proportions of excluded patients and may lead to biased comparisons. We evaluated the impact on the age-standardised relative survival estimates of also including multiple primary tumours. Data from 2,919,023 malignant cancers from 69 European cancer registries participating in the EUROCARE-4 collaborative study were used. A total of 183,683 multiple primary tumours were found, with an overall proportion of 6.3% over all the considered cancers, ranging from 0.4% (Naples, Italy) to 12.9% (Iceland). The proportion of multiple tumours varied greatly by type of tumour, being higher for those with high incidence and long survival (breast, prostate and colon-rectum). Five-year relative survival was lower when including patients with multiple cancers. For all cancers combined the average difference was -0.4 percentage points in women and -0.7 percentage points in men, and was greater for older registries. Inclusion of multiple tumours led to lower survival in 44 out of 45 cancer sites analysed, with the greatest differences found for larynx (-1.9%), oropharynx (-1.5%), and penis (-1.3%). Including multiple primary tumours in survival estimates for international comparison is advisable because it reduces the bias due to different observation periods, age, registration quality and completeness of registration. The general effect of inclusion is to reduce survival estimates by a variable amount depending on the proportion of multiple primaries and cancer site. (C) 2008 Elsevier Ltd. All rights reserved.

Colorectal cancer survival has increased in recent years, however, the impact of these cancers and their treatment on long-term survivors has not been extensively investigated at the population level. This pilot study assessed the prevalence of late outcomes in long-term colorectal cancer survivors registered by two European population-based cancer registries (CRs) to determine the feasibility of using the approach on a wider basis in Europe. Long-term survivors diagnosed in 1990 and in 1997 in Cote d’Or (France) and Varese (Italy) CRs were surveyed. Questionnaires to general practitioners (GPs) and survivors investigated a wide range of outcomes. Information on stage at diagnosis, primary treatment, stoma inserted during main surgery, and vital status was available from a previous study. Logistic regression was used to identify associations of late outcomes with sex, age at survey, country, year of diagnosis, and site. Participation was 51.8% (45.2% of French and 56.6% of Italian cases identified). Of the 256 survivors available for analysis, 10% had bowel incontinence, about 70% had other bowel, gastrointestinal, or urination problems, 10% had second primary cancer, 4% had colorectal recurrence, and 10% had stoma. The proportion with stoma reduced by 65% in survivors diagnosed between 1990 and 1997, but no other outcomes reduced in prevalence with time. Most (67%) had optimal GP-assessed ECOG performance status. Around 80% were followed-up with liver imaging or colonoscopy. We identified non-trivial rates of bowel and bladder problems after colorectal treatment, but overall good levels of functioning. High-resolution studies of this kind must be population-based to provide data useful for public health provision. This pilot study encountered difficulties in contacting GPs and suffered from low compliance. However, it is the first to investigate late outcome trends after treatment for colorectal cancer.

Background: Population based colorectal cancer survival among patients diagnosed in 1985–89 was lower in Europe than in the USA (45% v 59% five year relative survival). Aims: To explain this difference in survival using a new analytic approach for patients diagnosed between 1990 and 1991. Subjects: A total of 2492 European and 11 191 US colorectal adenocarcinoma patients registered by 10 European and nine US cancer registries. Methods: We obtained clinical information on disease stage, number of lymph nodes examined, and surgical treatment. We analysed three year relative survival, calculating relative excess risks of death (RERs, referent category US patients) adjusted for age, sex, site, surgery, stage, and number of nodes examined, using a new multivariable approach. Results: We found that 85% of European patients and 92% of US patients underwent surgical resection. Three year relative survival was 69% for US patients and 57% for European patients. After adjustment for age, sex, and site, the RER was significantly high in all 10 European populations, ranging from 1.07 (95% confidence interval 0.86–1.32) (Modena, Italy) to 2.22 (1.79–2.76) (Thames, UK). After further adjustment for stage, surgical resection, and number of nodes examined (a determinant of stage), RERs ranged from 0.77 (0.62–0.96) to 1.59 (1.28–1.97). For some European registries the excess risk was small and not statistically significant. Conclusions: US-Europe survival differences in colorectal cancer are large but seem to be mostly attributable to differences in stage at diagnosis. There are wide variations in diagnostic and surgical practice between Europe and the USA.

Background Animal experiments should be appropriately designed, correctly analysed and transparently reported to increase their scientific validity and maximise the knowledge gained from each experiment. This systematic review of animal experiments investigating statins evaluates their quality of reporting and methodological aspects as well as their implications for the conduction of meta-analyses. Methods We searched medline and embase for studies reporting research on statins in mice, rats and rabbits. We collected detailed information about the characteristics of studies, animals and experimental methods. Results We retrieved 161 studies. A little over half did not report randomisation (55%) and most did not describe blinding (88%). All studies reported details on the experimental procedure, although many omitted information about animal gender, age or weight. Four percent did not report the number of animals used. None reported the sample size. Fixed- and random-effects models gave different results (ratio of effect size increased by five folds). Heterogeneity was consistently substantial within animal models, for which accounting for covariates had minimal impact. Publication bias is highly suspected across studies. Conclusions Although statins showed efficacy in animal models, preclinical studies highlighted fundamental problems in the way in which such research is conducted and reported. Results were often difficult to interpret and reproduce. Different meta-analytic approaches were highly inconsistent: a reliable approach to estimate the true parameter was imperceptible. Policies that address these issues are required from investigators, editors and institutions that care about the quality standards and ethics of animal research.

Survival for ovarian cancer is the poorest of all gynaecological cancer sites. Our aim was to present the most up-to-date survival estimate for ovarian cancer by age and morphology and to answer the question whether survival for ovarian cancer improved in Europe during the 1990s.This analysis was performed with data from the EUROCARE database. We considered all adult women diagnosed with ovarian cancer between 1995 and 2002 and life status followed up until the end of 2003. A total of 97 691 cases were contributed by 72 European cancer registries in 24 countries. We estimated the most up-to-date relative survival for a mean of 23 661 patients followed up in 2000-2003 using the period hybrid approach and described the relative survival trends from the beginning of 1990s.Overall, the European age-standardised one-year, five-year and five-year conditional on surviving one-year relative survival were 67.2% (95% CI 66.6-67.8), 36.1% (95% CI 35.4-36.8) and 53.7% (95% CI 52.8-54.7), respectively. Five-year relative survival was 58.6% (95% CI 57.4-59.8), 37.1% (95% CI 36.1-38.1) and 20.5% (95% CI 19.1-21.9) in women aged 15-54, 55-74 and 75-99 years, respectively. The age-standardised five-year relative survival was 38.1% (95% CI 36.9-39.3) for serous tumours and 51.9% (95% CI 49.0-54.9) for mucinous cancers and the crude five-year relative survival was 85.6% (95% CI 81.2-90.0) for germ cell cancers. Overall, the age-standardised five-year relative survival increased from 32.4% (95% CI 31.7-33.2) in 1991-1993 to 36.3% (95% CI 35.5-37.0) in 2000-2003. There is a need to better understand the reasons for the wide variation in survival of ovarian cancer in Europe. Actions aiming to harmonise the protocols for therapy should contribute to narrowing the wide gap in survival and research on screening and early detection of ovarian cancer should be enforced.

Background: Head and neck cancers are a heterogeneous group of malignancies, affecting various sites and subsites, with differing prognoses. The aim of this study was to analyse survival for European head and neck cancer patients in populations covered by population-based cancer registries (CRs), in relation to tumour subsite as prognostic factor. Patients and methods: We analysed 51 912 adult head and neck cancer cases (36 322 mouth-pharynx and 15 590 larynx) diagnosed from 1995 to 1999 and archived by 45 CRs in 20 countries participating in EUROCARE-4. Five-year age-standardised relative survival was estimated for mouth-pharynx and larynx sites by sex and country. Relative survival was modelled to provide estimates of relative excess risks (RERs) of death by country, adjusted for confounding factors. Results: A large but site-variable proportion of tumours were incompletely specified. Five-year age-standardised relative survival was low in Slovakia and high in The Netherlands. Adjustment for subsite reduced RERs of death for most countries; 5-year relative survival increased from 1990-1994 to 1995-1999 for all subsites, while between country differences in survival narrowed. Conclusion: Differences in subsite distribution explain a considerable part of the survival differences for head and neck cancers, however, incomplete/inaccurate subsite reporting complicate interpretation, peer-reviewed

Objective The present descriptive study summarizes the historical activity on cervical cancer screening in Latvia, assesses the current screening situation, and defines the existing and expected obstacles and problems for the implementation of a proper organized population-based cervical cancer screening program in Latvia. Material and methods Available data on cervical cancer burden were collected from Latvian cancer registry. Availability of trained medical staff and laboratory systems were obtained through the Latvian Association of Cytologists and the Health Compulsory Insurance State Agency of Latvia (HCISA). Results Cervical cancer incidence in Latvia is increasing since 1989 when the compulsory preventive gynecologic examinations were stopped. Cervical opportunistic screening program in Latvia should be performed by GPs. But only 30 out of 1470 GPs provide gynecological care for their patients while, out of 484 certified gynecology practitioners, 35 had direct contractual relationship with the HCISA while 398 had only an indirect contractual relationship with the Agency. Moreover, in Latvia, there are about 29 laboratory specialists employed with cytological testing with an average age of 57 years: 13 of them have already passed the retirement limit. Conclusions Traditionally in Latvia, most women request gynecological services for preventive and health promotion reasons or in the case of having a gynecological disease. So the overloaded general practitioners and the lack of involvement of gynecologists are one of the main obstacles to solve for implementing an organized screening program in Latvia. Moreover insufficient availability of quality-assured services and resources for cytology testing and other services of the program, and for monitoring and evaluating the whole program, must be considered in the implementation of a comprehensive screening plan.

International audience; Adenoid cystic carcinoma (ACC) of salivary gland origin is rare. The EUROCARE data provide a good opportunity to study the survival of this uncommon cancer in a large population. A total of 2611 cases, aged 15 to 99 years, diagnosed between 1983 and 1994 with primary salivary gland ACC were analyzed. Thirty-two population based cancer registries from seventeen countries participating in EUROCARE contributed the data. Relative survival by sex, age, period of diagnosis, region, site and stage, and the adjusted relative excess risk (RER) of death were estimated. Survival since diagnosis was 94%, 78% and 65% at 1, 5 and ten years, respectively. Ten-year survival was best (69%) in patients of the youngest age group (15-54 years) and from Northern Europe (69%). In the UK was higher (65%) than in Western (62%) and Eastern (56%) Europe. ACCs in nasal cavity (RER 2.6), pharynx (RER 3.5) and larynx and bronchus (RER 3.9) had a worse prognosis compared to those of oral cavity. A strong effect of stage at diagnosis on RERs and some worsening of survival at five years over time (80% in 1983-1985, 76% in 1992-1994) were also evident. The findings of the present study, as those from clinical studies, confirm the important impact of primary site and stage at diagnosis on survival. Furthermore, we could demonstrate that survival for ACC did not improve over time and that cases from Eastern countries had a significant worse prognosis. Improvements in the disease detection in its early stage and international collaborative research should be encouraged.

The aim of this study was to report on malignant digestive endocrine tumours (MDET) prognosis in several European countries. We analysed survival data from 19 cancer registries in 12 European countries on 3,715 MDET diagnosed between 1985 and 1994. The overall 5-year survival rate was 47.5%. It was 58.1% for differentiated MDET and 8.1% for small-cell MDET (p < 0.001), 55.9% for patients under 65 and 37.0% for older patients. Survival rates for small intestinal and colorectal were higher than for the other sites. The 5-year relative survival rates were 60.3% in Northern Europe, 53.6% in Western Continental Europe, 42.5% in the UK, 37.6% in Eastern Europe (p < 0.001). Among well-differentiated pancreatic tumours, 5-year relative survival was 55.6% for insulinoma, 48.4% for gastrinoma, 33.4% for glucagonoma, 28.8% for carcinoid tumours and 49.9% for non-functioning tumours. The relative excess risk of death was significantly lower in Western Continental Europe and Northern Europe and significantly higher in Easter European compared to the UK. MDET differentiation, site, geographic area, age and sex, were independent prognostic factors. Overall, in Europe approximately half of the patients with MDET survive 5 years after the initial diagnosis. Prognosis varies with tumour differentiation, anatomic site and histological type. There are significant differences in survival from MDET among European countries, independently of other prognostic factors.

International audience; OBJECTIVE: To estimate survival in patients in whom uveal melanoma was diagnosed between January 1, 1983, and December 31, 1994, in Europe. METHODS: Survival analysis of data from 32 cancer registries in 16 European countries adhering to the European Cancer Registry for 5788 patients with uveal melanoma diagnosed between January 1, 1983, and December 31, 1994, with follow-up to 1999. RESULTS: Five-year relative survival was 68.9% overall and remained stable with the period of diagnosis. Relative excess risk of death was 2.45 (95% confidence interval [CI], 2.10-2.86) in patients aged 75 years or older compared with patients aged 54 years or younger and was slightly higher in male patients (relative excess risk, 1.10; 95% CI, 1.02-1.19) than in female patients. Survival was similar in Nordic countries (relative excess risk, 1.03; 95% CI, 0.87-1.21) compared with the United Kingdom (reference country) and was lower in eastern and western European countries (1.26; 1.05-1.52, and 1.25; 0.90-1.60, respectively) compared with the reference country. CONCLUSIONS: In this large series of patients with uveal melanoma, 5-year relative survival remained stable with the introduction of conservative treatment in individuals in whom uveal melanoma was diagnosed between 1983 and 1994. We found differences in survival between sexes and in European areas that should be investigated in studies that consider tumor characteristics at the individual level.

A previous study has shown a lower survival for colorectal cancer in Europe than in the United States of America (USA). It is of interest to examine the extent to which anatomical location and morphological type influence this difference in colorectal cancer survival. We analysed survival for 151,244 European and 53,884 US patients diagnosed with colorectal cancer aged 15-99 years during the period of 1985-1989, obtained from 40 cancer registries that contribute to the EUROCARE study from 17 countries, and nine Surveillance, Epidemiology and End-Results (SEER) registries in the USA. Cases included in the analysis were first primary malignant tumours (ICD-O behaviour code 3 or higher). Relative survival was estimated to correct for competing causes of mortality. The Hakulinen-Tenkanen multiple regression approach was used to examine the prognostic impact of sub-site and ICD-O histology codes. Relative excess risks (RERs) derived from this approach estimate the extent to which the hazard of death differs from that in a reference region after adjustment for mortality in the general population. In order to explore geographical variation, we defined three groups of European registries within which survival rates were known to be broadly similar. The proportion of cases with unspecified sub-site was higher in Europe than the USA (10% versus 2%), but sub-site distributions were broadly similar in the two populations. With the exception of appendix, 5-year survival was 13-22% higher in the USA than in Europe for each anatomical sub-site. The proportion of non-microscopically-verified cases was higher in Europe than the USA (16 versus 3%). Adenocarcinomas arising in a polyp (ICD-O-2 8210, 8261, 8263) were more frequent in the USA than Europe (13 versus 2%). Five-year survival was higher in the USA than Europe for each morphological group, with the exception of non-microscopically-verified cases. When age, gender and sub-site were considered, RERs ranged from 1.52 to 2.40 for the European populations (with the USA as a reference). After inclusion of morphology codes, the range of RERs fell to between 1.28 and 1.86, mainly because of the high frequency of adenocarcinoma in polyps in the USA. This analysis suggests that the large survival advantage for colorectal cancer patients in the USA can only marginally be explained by differences in the distribution of sub-site and morphology. The main explanatory difference is the proportion of adenocarcinoma in polyps.

Results on general and cause-specific mortality in a retrospective cohort of intravenous drug users in the Emilia Romagna Region (Italy) are presented. Four thousand two hundred and sixty subjects (3324 males, 936 females) in public treatment centres in Piacenza, Modena and Ferrara provinces have been observed for up to 20 years in the period 1975-95. AIDS age-adjusted death rates dramatically increased all during the period, while overdose and other causes (mostly accidental) increase up to the early nineties and then tend to decrease. This last pattern has not been described in other Italian cohorts, and could be related with changes in therapeutic strategies. General mortality is very high in this cohort, as in other studies (males: SMR 16.7, LC 15.3-18.2; females: SMR 33.4, LC 27.9-39.9). Survival probability after 15 years of observation is 65% in males and females combined. Apart from overdose and AIDS, other relevant excesses are observed for accidental deaths (especially car accidents), cirrhosis, infective causes and cancer in males; in females, accidental deaths (among which homicides) and digestive tract diseases. A higher death risk is observed for males who began drug use before age 20, who contacted treatment centres in the nineties and at an older age, and who came in contact with the law.

1045 Citation: European Journal of Cancer Supplements; Vol. 1, No. 5, September 2003, page S312 Rare tumour survival in adult European patients G. Gatta, L. Ciccolallo, P. Casali Istituto Nazionale per lo Studio e la Cura dei Tum, Epidemiology Unit, Milan, Italy Background: Most rare tumours present major clinical problems. Their rarity renders in depth study of natural history and identification of optimum treatment guidelines problematic, and early and accurate diagnosis sometimes difficult. Publications on these tumours typically derive from centres of excellence, which do not reflect the situation at the population level. The EUROCARE database presents a unique opportunity to investigate rare cancers in Europe at the population level. The aim of this communication is to describe survival of adult European patients with some rare tumours according to major demographic and clinical variables. Survival time trends and, depending of the number of cases, survival variations in different regions and countries will also be presented. Material and methods: The European survival figures for the period of diagnosis 1983-94 were derived from the EUROCARE database. The data were contributed by about 65 registries in 21 countries. The rare tumour chosen was on the basis the criteria reported above: very low incidence, treatment problems, follow-up difficulties, geographic variation, lack of literature. The rare cancer sites selected were: angiosarcoma of liver, mesothelioma, adenocarcinoma of cervix, sarcoma of uterus, anal squamous carcinoma, testis cancer in old men, soft tissue sarcoma of limb. Results: Five-year relative survival for these rare cancers diagnosed between 1983-94 will be analysed and will be described by sex, age, period of diagnosis and large regions. When available stage and therapy will be introduced in the analysis. Conclusions: The EUROCARE project provides a unique opportunity to study uncommon cancer survival at the population level. Topography with morphological codes will be considered in order to identify rare diagnostic categories of interest. For most rare cancers in the EUROCARE database, the proportion of microscopically confirmed cases is high, indicating good quality data and also the existence of detailed information on morphology.