The observational clinical registry (cohort design) of the European Reference Network on Rare Adult Solid Cancers: The protocol for the rare head and neck cancers

Care for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374). Study design Registry-based cohort study including only people with rare head and neck cancers. Objectives 1.To help describe the natural history of rare head and neck cancers; 2.To evaluate factors that influence prognosis; 3.To assess treatment effectiveness; 4.To measure indicators of quality of care. Methods Settings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won t select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients and cancers variables and indicators describing the quality of care. Multivariable Cox s proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/ confounders and confounding by indication (selective prescribing) will be present. Results The registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed

Survival for haematological malignancies in Europe between 1997 and 2008 by region and age: Results of EUROCARE-5, a population-based study

BACKGROUND: More effective treatments have become available for haematological malignancies from the early 2000s, but few large-scale population-based studies have investigated their effect on survival. Using EUROCARE data, and HAEMACARE morphological groupings, we aimed to estimate time trends in population-based survival for 11 lymphoid and myeloid malignancies in 20 European countries, by region and age. METHODS: In this retrospective observational study, we included patients (aged 15 years and older) diagnosed with haematological malignancies, diagnosed up to Dec 31, 2007, and followed up to Dec 31, 2008. We used data from the 30 cancer registries (across 20 countries) that provided continuous incidence and good quality data from 1992 to 2007. We used a hybrid approach to estimate age-standardised and age-specific 5-year relative survival, for each malignancy, overall and for five regions (UK, and northern, central, southern, and eastern Europe), and four 3-year periods (1997-99, 2000-02, 2003-05, 2006-08). For each malignancy, we also estimated the relative excess risk of death during the 5 years after diagnosis, by period, age, and region. FINDINGS: We analysed 560 444 cases. From 1997-99 to 2006-08 survival increased for most malignancies: the largest increases were for diffuse large B-cell lymphoma (42·0% [95% CI 40·7-43·4] to 55·4% [54·6-56·2], p<0·0001), follicular lymphoma (58·9% [57·3-60·6] to 74·3% [72·9-75·5], p<0·0001), chronic myeloid leukaemia (32·3% [30·6-33·9] to 54·4% [52·5-56·2], p<0·0001), and acute promyelocytic leukaemia (50·1% [43·7-56·2] to 61·9% [57·0-66·4], p=0·0038, estimate not age-standardised). Other survival increases were seen for Hodgkin's lymphoma (75·1% [74·1-76·0] to 79·3% [78·4-80·1], p<0·0001), chronic lymphocytic leukaemia/small lymphocytic lymphoma (66·1% [65·1-67·1] to 69·0% [68·1-69·8], p<0·0001), multiple myeloma/plasmacytoma (29·8% [29·0-30·6] to 39·6% [38·8-40·3], p<0·0001), precursor lymphoblastic leukaemia/lymphoma (29·8% [27·7-32·0] to 41·1% [39·0-43·1], p<0·0001), acute myeloid leukaemia (excluding acute promyelocytic leukaemia, 12·6% [11·9-13·3] to 14·8% [14·2-15·4], p<0·0001), and other myeloproliferative neoplasms (excluding chronic myeloid leukaemia, 70·3% [68·7-71·8] to 74·9% [73·8-75·9], p<0·0001). Survival increased slightly in southern Europe, more in the UK, and conspicuously in northern, central, and eastern Europe. However, eastern European survival was lower than that for other regions. Survival decreased with advancing age, and increased with time only slightly in patients aged 75 years or older, although a 10% increase in survival occurred in elderly patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic myeloid leukaemia. INTERPRETATION: These trends are encouraging. Widespread use of new and more effective treatment probably explains much of the increased survival. However, the persistent differences in survival across Europe suggest variations in the quality of care and availability of the new treatments. High-resolution studies that collect data about stage at diagnosis and treatments for representative samples of cases could provide further evidence of treatment effectiveness and explain geographic variations in survival. FUNDING: Compagnia di San Paolo, Fondazione Cariplo, European Commission, and Italian Ministry of Health

Survival of 86,690 patients with thyroid cancer: A population-based study in 29 European countries from EUROCARE-5

Background Incidence rates of thyroid cancer (TC) increased in several countries during the last 30 years, while mortality rates remained unchanged, raising important questions for treatment and follow-up of TC patients. This study updates population-based estimates of relative survival (RS) after TC diagnosis in Europe by sex, country, age, period&nbsp;and histology. Methods Data from 87 cancer registries in 29 countries were extracted from the EUROCARE-5 dataset. One- and 5-year RS were estimated using the cohort approach for 86,690 adult TC patients diagnosed in 2000–2007 and followed-up to 12/31/2008. RS trends in 1999–2007 and 10-year RS in 2005–2007 were estimated using the period approach. Results In Europe 2000–2007, 5-year RS after TC was 88% in women and 81% in men. Survival rates varied by country and were strongly correlated (Pearson ρ&nbsp;=&nbsp;75%) with country-specific incidence rates. Five-year RS decreased with age (in women from &gt;95% at age 15–54 to 57% at age 75+), from 98% in women and 94% in men with papillary TC to 14% in women and 12% in men with anaplastic TC. Proportion of papillary TC&nbsp;varied by country and increased over time, while survival rates were similar across areas and periods. In 1999–2007, 5-year RS increased by five percentage points for all TCs&nbsp;but only by two for papillary&nbsp;and by four for follicular TC. Ten-year RS in 2005–2007 was 89% in women and 79% in men. Conclusions The reported increasing TC survival trend and differences by area are mainly explained by the varying histological case-mix of cases

Quality analysis of population-based information on cancer stage at diagnosis across Europe, with presentation of stage-specific cancer survival estimates: A EUROCARE-5 study

Background Cancer registries (CRs) are fundamental for estimating cancer burden, evaluating screening and monitoring health service performance. Stage at diagnosis—an essential information item collected by CRs—has been made available, for the first time, by CRs participating in EUROCARE-5. We analysed the quality of this information and estimated stage-specific survival across Europe for CRs with good data quality. Data and methods Sixty-two CRs sent stage (as TNM, condensed TNM or extent of disease) for 15 cancers diagnosed in 2000–2007. We assessed the quality, partly by comparing stage according to the three systems. We also developed procedures to reconstruct stage (categories: local, regional, metastatic and unknown) using information from all three systems, thus minimising the amount of missing information. Results Moderate-to-excellent stage concordance was found for practically all 24 CRs, for which it was possible to compare at least two staging systems. However, since stage was often incorrectly assigned, and information on the presence/absence of metastases was often lacking, data on only 7/15 cancers from 34/62 CRs (15 countries) were of sufficient quality for further analysis. Cases diagnosed ≥70 years had more advanced (or lacking) stage– and worse stage-specific survival than those &lt;70 years. Conclusions Many European CRs collect and record reasonably accurate stage information. Others have difficulties. Both the completeness of primary data and the accuracy of stage coding need to be improved in order for CRs to fulfil their expanding roles in cancer control. We propose our stage reconstruction/checking procedures as a means of fully exploiting the stage information provided by EUROCARE CRs. More advanced (or lacking) stage at diagnosis plus poorer stage-specific survival in the elderly are worrying

Survival of male genital cancers (prostate, testis and penis) in Europe 1999-2007: Results from the EUROCARE-5 study

Background We provide updated estimates of survival and survival trends of male genital tumours (prostate, testicular and penis cancers), in Europe and across European areas. Methods The complete approach was used to obtain relative survival estimates for patients diagnosed in 2000-2007, and followed up through 2008 in 29 countries. Data came from 87 cancer registries (CRs) for prostate tumours and from 86 CRs for testis and penis tumours. Relative survival time trends in 1999-2007 were estimated by the period approach. Data came from 49 CRs in 25 countries. Results We analysed 1,021,275 male genital cancer cases. Five-year relative survival was high and decreased with increasing age for all tumours considered. We found limited variation in survival between European regions with Eastern Europe countries having lower survival than the others. Survival for penile cancer patients did not improve from 1999 to 2007. Survival for testicular cancer patients remained stable at high levels since 1999. Survival for prostate cancer patients increased over time. Conclusions Treatment standardisation and centralisation for very rare diseases such as penile cancers or advanced testicular tumours should be supported. The high survival of testicular cancer makes long-term monitoring of testicular cancer survivors necessary and CRs can be an important resource. Prostate cancer patients' survival must be interpreted considering incidence and mortality data. The follow-up of the European Randomised Study of Screening for Prostate Cancer should continue to clarify the impact of screening on prostate cancer mortality together with population based studies including information on stage and treatments

Reasons for low cervical cancer survival in new accession European Union countries: a EUROCARE-5 study

Purpose: With better access to early diagnosis and appropriate treatment, cervical cancer (CC) burden decreased in several European countries. In Eastern European (EE) countries, which accessed European Union in 2004, CC survival was worse than in the rest of Europe. The present study investigates CC survival differences across five European regions, considering stage at diagnosis (local, regional and metastatic), morphology (mainly squamous versus glandular tumours) and patients’ age. Methods: We analysed 101,714 CC women diagnosed in 2000–2007 and followed-up to December 2008. Age-standardised 5-year relative survival (RS) and the excess risks of cancer death in the 5&nbsp;years after diagnosis were computed. Results: EE women were older and less commonly diagnosed with glandular tumours. Proportions of local stage cancers were similar across Europe, while morphology- and stage-specific RS (especially for non-metastatic disease) were lower in Eastern Europe. Adjusting for age and morphology, excess risk of local stage CC death for EE patients remained higher than that for other European women. Conclusion: Stage, age and morphology alone do not explain worse survival in Eastern Europe: less effective care may play a role, probably partly due to fewer or inadequate resources being allocated to health care in this area, compared to the rest of Europe

Age and case mix-standardised survival for all cancer patients in Europe 1999-2007: Results of EUROCARE-5, a population-based study

Background Overall survival after cancer is frequently used when assessing a health care service's performance as a whole. It is mainly used by the public, politicians and the media, and is often dismissed by clinicians because of the heterogeneous mix of different cancers, risk factors and treatment modalities. Here we give survival details for all cancers combined in Europe, correlating it with economic variables to suggest reasons for differences. Methods We computed age and cancer site case-mix standardised relative survival for all cancers combined (ACRS) for 29 countries participating in the EUROCARE-5 project with data on more than 7.5 million cancer cases from 87 population-based cancer registries, using complete and period approach. Results Denmark, United Kingdom (UK) and Eastern European countries had lower survival than neighbouring countries. Five-year ACRS has been increasing throughout Europe, and substantial increases, between 1999-2001 and 2005-2007, have been achieved in countries where survival was lower in the past. Five-year ACRS for men and women are positively correlated with macro-economic variables like the Gross Domestic Product (GDP) and Total National Expenditure on Health (TNEH) (R 2 about 70%). Countries with recent larger increases in GDP and TNEH had greater increases in cancer survival. Conclusions ACRS serves to compare all cancer survival in Europe taking account of the geographical variability in case-mixes. The EUROCARE-5 data on ACRS confirm previous EUROCARE findings. Survival appears to correlate with macro-economic determinants, particularly with investments in the health care system

Quality analysis of population-based information on cancer stage at diagnosis across Europe, with presentation of stage-specific cancer survival estimates: A\uc2\ua0EUROCARE-5 study

BACKGROUND: Cancer registries (CRs) are fundamental for estimating cancer burden, evaluating screening and monitoring health service performance. Stage at diagnosis-an essential information item collected by CRs-has been made available, for the first time, by CRs participating in EUROCARE-5. We analysed the quality of this information and estimated stage-specific survival across Europe for CRs with good data quality. DATA AND METHODS: Sixty-two CRs sent stage (as TNM, condensed TNM or extent of disease) for 15 cancers diagnosed in 2000-2007. We assessed the quality, partly by comparing stage according to the three systems. We also developed procedures to reconstruct stage (categories: local, regional, metastatic and unknown) using information from all three systems, thus minimising the amount of missing information. RESULTS: Moderate-to-excellent stage concordance was found for practically all 24 CRs, for which it was possible to compare at least two staging systems. However, since stage was often incorrectly assigned, and information on the presence/absence of metastases was often lacking, data on only 7/15 cancers from 34/62 CRs (15 countries) were of sufficient quality for further analysis. Cases diagnosed 6570 years had more advanced (or lacking) stage- and worse stage-specific survival than those <70 years. CONCLUSIONS: Many European CRs collect and record reasonably accurate stage information. Others have difficulties. Both the completeness of primary data and the accuracy of stage coding need to be improved in order for CRs to fulfil their expanding roles in cancer control. We propose our stage reconstruction/checking procedures as a means of fully exploiting the stage information provided by EUROCARE CRs. More advanced (or lacking) stage at diagnosis plus poorer stage-specific survival in the elderly are worrying

Geographical variability in survival of European children with central nervous system tumours

Survival for childhood central nervous system (CNS) tumours varies across Europe, partly because of the difficulty of distinguishing malignant from non-malignant disease. This study examines bias in CNS tumours survival analysis to obtain the reliable and comparable survival figures. We analysed survival data for about 15,000 children (age &lt;15) diagnosed with CNS between 2000 and 2007, from 71 population-based cancer registries in 27 countries. We selected high-quality data based on registry-specific data quality indicators and recorded observed 1-year and 5-year survival by countries and CNS entity. We provided age-adjusted survival and used a Cox model to calculate the hazard ratios (HRs) of death, adjusting by age, site and grading by country. Recording of non-malignant lesions, use of appropriate morphology codes and completeness of life status follow-up differed among registries. Five-year survival by countries varied less when non-malignant tumours were included, with rates between 79.5% and 42.8%. The HRs of dying, for registries with good data, adjusting by age and grading, were between 0.7 and 1.2; differences were similar when site (supra- and infra-tentorial) was included. Several sources of bias affect the correct definition of CNS tumours, the completeness of incidence series and the goodness of follow-up. The European Network of Cancer Registries needs to improve childhood cancer registration and stress the need to update the International Classification for Cancer. Since survival differences persisted even when restricting the analysis to registries with satisfactory data, and since diagnosis of CNS tumours is difficult and treatment complex, national plans must aim for the revision of the diagnosis and the coordination of care, with adequate national and international networks

Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study

Cancer survival is a key measure of the effectiveness of health-care systems. EUROCARE-the largest cooperative study of population-based cancer survival in Europe-has shown persistent differences between countries for cancer survival, although in general, cancer survival is improving. Major changes in cancer diagnosis, treatment, and rehabilitation occurred in the early 2000s. EUROCARE-5 assesses their effect on cancer survival in 29 European countries