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Epidemiology of glial and non-glial brain tumours in Europe

Published:January 09, 2012DOI:https://doi.org/10.1016/j.ejca.2011.12.013

      Abstract

      To the central nervous system (CNS) belong a heterogeneous group of glial and non glial rare cancers.
      The aim of the present study was to estimate the burden (incidence, prevalence, survival and proportion of cured) for the principal CNS cancers in Europe (EU27) and in European regions using population-based data from cancer registries participating in the RARECARE project.
      We analysed 44,947 rare CNS cancers diagnosed from 1995 to 2002 (with follow up at 31st December 2003): 86.0% astrocytic (24% low grade, 63% high grade and 13% glioma NOS), 6.4% oligodendroglial (74% low grade), 3.6% ependymal (85% low grade), 4.1% Embryonal tumours and 0.1% choroid plexus carcinoma. Incidence rates vary widely across European regions especially for astrocytic tumours ranging from 3/100,000 in Eastern Europe to 5/100,000 in United Kingdom and Ireland. Overall, about 27,700 new rare CNS cancers were estimated every year in EU27, for an annual incidence rate of 4.8 per 100,000 for astrocytic, 0.4 for oligodendroglial, 0.2 for ependymal and embryonal tumours and less than 0.1 for choroid plexus carcinoma.
      More than 154,000 persons with rare CNS were estimated alive (prevalent cases) in the EU at the beginning of 2008.
      Five-year relative survival was 14.5% for astrocytic tumours (42.6% for low grade, 4.9% for high grade and 17.5% for glioma NOS), 54.5% for oligodendroglial (64.9% high grade and 29.6% low grade), 74.2% for ependymal (80.4% low grade and 36.6% high grade), 62.8% for choroid plexus carcinomas and 56.8% for embryonal tumours. Survival rates for astrocytic tumours were relatively higher in Northern and Central Europe than in Eastern Europe and in UK and Ireland. The different availability of diagnostic imaging techniques and/or radiation therapy equipment across Europe may contribute to explain the reported survival differences.
      The estimated proportion of cured patients was 7.9% for the ‘glial’ group to which belong astrocytic tumours.
      Overall results are strongly influenced by astrocytic tumours that are the most common type.
      This is the first study to delineate the rare CNS cancer burden in Europe by age, sex and European region.

      Keywords

      1. Introduction

      Central Nervous System (CNS) cancers are a group of different tumour entities anatomically close to each other but diverse in terms of morphology, site, molecular biology and clinical behaviour and presumably aetiology.
      • Wrensch M.
      • Minn Y.
      • Chew T.
      • Bondy M.
      • Berger M.S.
      Epidemiology of primary brain tumors: current concepts and review of the literature.
      In Europe, the standardised (World) incidence of primary CNS cancers ranges from 4.5 to 11.2 cases per 100,000 men and from 1.6 to 8.5 per 100,000 women.

      Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.

      The two most common CNS cancers, high-grade glioma and brain metastasis occur more frequently during adulthood and especially among the elderly. In Europe, the peak of incidence is 18.5/100,000 in people aged ⩾65 years.

      Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.

      The relative frequency of CNS tumours is however highest during childhood, when they account for 23% of all the cancers diagnosed.
      • Kaatsch P.
      Epidemiology of childhood cancer.
      In adults the 5-year survival rate for the primary CNS cancers in Europe was 17% for males and 19% for females (1995–2002),
      • Sant M.
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      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      with differences across European regions.

      Sant M, Minicozzi P, Lagorio S, et al. Survival of European patients with central nervous system tumours. Int J Cancer 2011; doi:10.1002/ijc.26335. [Epub ahead of print].

      Survivorship is higher for young European patients – 63% – than for the elderly ones.
      • Gatta G.
      • Zigon G.
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      • et al.
      Survival of European children and young adults with cancer diagnosed 1995–2002.
      Statistics on CNS tumours are estimated by grouping all malignancies arising in all the CNS anatomic sites: meninges, brain, spinal cord, cranial nerves and other localisation of CNS (ICD-10 topography codes C70-C72).

      World Health Organization. International Classification of Diseases. 10th revision, Geneva; 1992.

      However, rare tumours are more appropriately defined as a combination of topographical and morphological characteristics, as defined by the International Classification of Diseases for Oncology (ICD-O).

      Percy C, Shanmugaratnam K, Whelan S, et al. International Classification of Diseases for Oncology (ICD-O), 3rd ed. Geneva, Switzerland: World Health Organization; 2000.

      The Surveillance of Rare Cancers in Europe (RARECARE; www.rarecare.eu) project, is a large collaboration of population-based cancer registries (CRs) across Europe which provides a list of rare cancers on the basis of topography and morphology. Clinical factors, such as difficulties in achieving diagnosis, in clinical decision making and in conducting clinical studies and the lack of standardised treatment mainly affected the definition of the type of cancers of the RARECARE list. Under the threshold proposed by the RARECARE project, incidence lower than 6 per 100,000 per year, CNS malignant tumours are included. However, despite the rarity of entities selected by using this cut-off, there are many sub-entities for each group (i.e. different histologies and WHO grade of glial tumours) with different prognosis and different treatment approaches that complicate the picture. This means that management of these rare brain tumour subgroups has to be considered hyper-specialistic, as well as treatment options centralised in large volumes hub centres with recognised expertise in this field. Furthermore, central pathology review in CNS tumours is particularly important. The experience of modern clinical trials (i.e. European Organisation for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) studies on grade III gliomas) showed very high (up to 50%) inter-observer variability among neuropathologists in the differential diagnosis between astrocytic and oligodendroglial tumours.
      • Kros J.M.
      • Gorlia T.
      • Kouwenhoven M.C.
      • et al.
      Panel review of anaplastic oligodendroglioma from European Organization For Research and Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome.
      The objective of this study was to establish a picture of incidence, prevalence and survival of rare CNS cancers in Europe based on the new RARECARE list of tumours.

      2. Materials and methods/cancer cases

      Rare cancers of the CNS presented in this paper are based on the new list of cancer types provided by RARECARE. The list is organised into three tiers. The bottom tier (tier 3) corresponds to the World Health Organisation (WHO) name of individual cancer entities [http://www.iarc.fr/en/publications/pdfs-online/pat-gen/] and their corresponding ICD-O-3 morphology and topography codes. Tier 3 entities were grouped into categories of cancers (tier 2) considered similar from the point of view of clinical management and research. These categories were further grouped into more general categories (tier 1), considered to involve the same clinical expertise and patient referral structure. Accordingly the following cancer entities were identified and will be described in this paper:
      • Glial tumours (tier 1 entity) which include astrocytic, oligodendroglial, oligoastrocytic and ependymal tumours with malignant behaviour only (tier 2 entities) and
      • Non glial tumours of CNS and pineal gland (tier 1 entity) which includes embryonal tumours and choroid plexus carcinomas (tier 2 entities).
      Glial tumours were also divided and analysed in low- and high-grade gliomas according to the WHO classification.
      • Louis D.N.
      • Ohgaki H.
      • Wiestler O.D.
      • et al.
      The 2007 WHO classification of tumours of the central nervous system.
      Low grade astrocytic included the ICD-O3 morphology (M) 9382, 9400, 9410, 9411, 9420, 9423 and M 9424; high grade astrocytic included the ICD-O3 M 9381, 9401, 9430, 9440-9442. Low grade oligodendroglial tumours were M9450 and M 9460; the high grade group included M 9451 only. Finally the low grade ependymal tumours included M9391 and M 9393; the high grade group was made by M 9392.
      Table 1 shows the morphology and topography codes of the tumours described in this article.
      Table 1Data quality indicators of rare central nervous system cancers diagnosed 1995–2002 and archived in 76 RARECARE cancer registries.
      TierEntityCases (N)Data quality indicatorICD-O3
      The following tumours are excluded: metastasis, unspecified malignant neoplasms (8000/3 and 8001/3), sarcomas, germ cell tumours, meningiomas, gliomas of optic nerve and pilocytic astrocytoma (grade WHO I).
      codes
      Death certificate only (%)Autopsy (%)Microscopic verification (%)Cases 1995–1998 censored before five years (%)TopographyMorphology
      Rare central nervous system (CNS) tumours
      1Glial tumour Of CNS43,1251.20.587.00.5C71, C72.0, C72.8-C72.99380-9384, 9391-9460
      2Astrocytic tumours of CNS38,6531.30.586.10.4C71, C72.0, C72.8-C72.99380-9382, 9384, 9400-9442
      2Oligodendroglial tumours of CNS28660.50.494.91.0C71, C72.0, C72.8-C72.99450-9451,9460
      2Ependymal tumours of CNS16060.40.795.21.6C71, C72.0, C72.8-C72.99383, 9391-9394
      1Non-glial tumour of CNS and pineal gland18720.40.296.82.0C71, C72.0, C75.39362, 9390, 9470-9474, 9490, 9500-9505, 9508
      2Embryonal tumours of CNS18220.30.297.02.0C71, C72.0, C75.39362, 9470-9474, 9490, 9500-9505, 9508
      2Choroid plexus carcinoma of CNS504.00.092.00.0C71, C72.0, C75.39390
      a The following tumours are excluded: metastasis, unspecified malignant neoplasms (8000/3 and 8001/3), sarcomas, germ cell tumours, meningiomas, gliomas of optic nerve and pilocytic astrocytoma (grade WHO I).
      It is worth stressing that pilocytic astrocytoma (grade WHO I), the most frequent brain tumour of children is excluded, following its downgrading to non-malignant behaviour in ICDO-3. Other primary and secondary tumour entities usually included in the CNS (metastasis, sarcomas, germ cell tumours, meningiomas, gliomas of optic nerve) are also excluded from this analysis because they are described in other dedicated papers. Unspecified malignant neoplasms (8000/3 and 8001/3) are also excluded from the analysis.
      RARECARE data were extracted from the EUROCARE-4 study dataset covering the period of diagnosis 1978–2002, with status information available up to 31st December 2003. For 11 countries CRs covered the entire national population (Austria, Iceland, Ireland, Malta, Norway, Slovakia, Slovenia, Sweden, Northern Ireland, Scotland and Wales). Other 10 countries were represented by regional CRs, covering variable proportions of their respective national populations. In the present paper, data from 76 CRs out of the 89 accepting to participate in the RARECARE project were considered. CRs which did not classify cancers according to the third edition of the ICD-O3 and also those which collected data on childhood cancers only were excluded from the analysis.
      The incidence analysis considered case incidents from 1995 to 2002 and excluded specialised registries. Thus, 64 CRs were included in the incidence analyses. Age-standardised incidence rates per 100,000 were computed using the European standard population.
      The prevalence per 100,000 was estimated at the index date of 1st January 2003. Only data from 22 CRs with data covering the period 1988–2002 were used for prevalence estimates. The counting method,
      • Capocaccia R.
      • Colonna M.
      • Corazziari I.
      • et al.
      Measuring cancer prevalence in Europe: the EUROPREVAL Project.
      based on CR incidence and follow-up data, was applied to CR data from 1988 to 2002. The completeness index method,
      • Capocaccia R.
      • De Angelis R.
      Estimating the completeness of prevalence based on cancer registry data.
      was used to estimate complete prevalence, and involved adding the estimated surviving cases diagnosed prior to 1988 to those counted in 1988–2002.
      The expected number of new cases per year and of prevalent cases in Europe (EU27) was estimated multiplying the crude incidence and prevalence estimates (obtained as described above) to the 2008 European population (EU27 = 497,455,033) provided by EUROSTAT (ec.europe.eu/eurostat). In providing glial and non glial tumours burden estimates, we assumed that the population covered by our CRs was representative of the population of the EU27 as a whole. We assumed that incidence, survival and the population for the period 2003–2008 did not change. A total of 4,302,067 cancer cases were used to produce the prevalence estimates.
      Period survival indicators for the years 2000–2002 were estimated using the Brenner algorithm.
      • Brenner H.
      • Söderman B.
      • Hakulinen T.
      Use of period analysis for providing more up-to-date estimates of long-term survival rates: empirical evaluation among 370,000 cancers patients in Finland.
      Period analysis provides more up-to-date survival experience by considering survival experience in 2000-2002 (survival data were collected from 46 European CRs participating in the RARECARE study). Survival has been computed as relative survival that is the ratio of absolute survival to expected age-specific and sex-specific survival of the general population. It is a measure of the excess mortality for patients with cancer compared with that for the general population. The proportion of cured patients for rare CNS tumours was estimated using a mixture or cure model.
      • Francisci S.
      • Capocaccia R.
      • Grande E.
      • et al.
      The cure of cancer: a European perspective.
      This type of survival model assumes that cured cases have the same mortality as the general population, while the complementary fraction (the fatal cases) has an excess death rate attributed to the CNS cancer.
      • Francisci S.
      • Capocaccia R.
      • Grande E.
      • et al.
      The cure of cancer: a European perspective.
      This analysis was carried out on 44,947 cases of rare CNS cancers diagnosed in 1995–2002.
      The main data quality indicators for the cancer diagnoses in 1995–2002 are presented in Table 1. Among glial tumours 1.2% of the cases were known from death certificate only (DCO); among non glial tumours DCO were 0.4% ranging from 0.3% (embryonal tumours) to 4.0% (choroids plexus carcinomas). About 87% of the glial tumour cases included in the analysis had histological documentation, although the proportion varied among cancer entities from 86.1% for astrocytic tumours to 95% to ependymal tumours. The 97.0% of non-glial tumours of CNS and pineal gland was microscopically verified. The proportion of cases known from autopsy was very low, with a maximum of 0.7% for ependymal tumours.
      Quality indicators for CNS tumours are computed on all participating CR (44,947 cases from 76 cancer registries) while incidence rates are reported for general CR only (44,842 cases from 64 cancer registries). The survival analysis was undertaken on 46 CR because only those had data available to perform period survival.

      3. Results

      3.1 Incidence

      Table 2 shows crude, sex and age-specific incidence rates recorded in Europe during the period 1995–2002.
      Table 2Observed cases with crude incidence (rate per 100,000/year) and standard errors (SE) in Europe. Rates and SE by sex and age, with estimated incident cases in Europe (EU27). Cases diagnosed 1995–2002 in 64 European cancer registries (CRs).
      Rare central nervous system (CNS) cancersEU overallSexAgeEstimated cases in EU27 per year
      MaleFemale0–1920–3940–5960+
      Observed Cases 1995-2002RateSERateSERateSERateSERateSERateSERateSEN
      Glial tumour of CNS and pineal gland43,0375.4<0.16.3<0.14.5<0.11.2<0.12.5<0.17.0<0.112.10.126,610
      Astrocytic tumours of CNS38,5884.8<0.15.7<0.14.0<0.10.9<0.12.0<0.16.2<0.111.60.123,859
      Oligodendroglial tumours of CNS2,8450.4<0.10.4<0.10.3<0.10.1<0.10.3<0.10.6<0.10.4<0.11759
      Ependymal tumours of CNS16040.2<0.10.2<0.10.2<0.10.2<0.10.2<0.10.2<0.10.2<0.1992
      Non-glial tumour of CNS and pineal gland18050.2<0.10.3<0.10.2<0.10.6<0.10.2<0.10.1<0.1<0.1<0.11116
      Embryonal tumours of CNS17550.2<0.10.3<0.10.2<0.10.6<0.10.2<0.10.1<0.1<0.1<0.11085
      Choroid plexus carcinoma of CNS50<0.1<0.1<0.1<0.1<0.1<0.1<0.1<0.10.0<0.10.0<0.10.0<0.131
      Among CNS cancers, astrocytic tumours were the most common tumours, with a standardised incidence rate of 4.8 (3.0 high grade, 1.2 low grade and 0.6 glioma NOS) per 100,000 per year in Europe, followed by oligodendroglial tumours (0.4 overall; 0.3 low and 0.1 high grade), embryonal (0.2) and ependymal tumours (0.2 overall; 0.17 low grade and 0.03 high grade). The incidence rate of choroid plexus carcinomas was under 0.1 per 100,000/year.
      Rare CNS tumours were slightly more common in men than in women. The male to female crude rates ratio ranged between 1.5 (embryonal), to 1.4 (astrocytic) and to 1.3 (oligodendroglial), Table 2.
      As regards age-specific incidence rate (per 100,000), incidence rates for glial tumours overall (11.9/100,000/year) and for astrocytic tumours (11.6/100,000/year) were highest in the oldest age group (60 years and more). Incidence peaked in the age group 40–59 years for oligodendroglial tumours (0.6). The incidence of ependymal tumours was quite stable across the age-groups while embryonal tumours had their highest incidence among younger patients (0–19 years; 0.6/100,000/year) and then incidence fell throughout the age range.
      Table 2 shows the number of new cases of CNS tumours estimated in the European Union (EU27) per year. There are about 27,700 new diagnosis of CNS cancers per year of which, 26,610 are ‘glial tumours of CNS’ (23,859 astrocytic tumours with unspecified gliomas; 1,759 oligodendroglial tumours and 992 ependymal tumours) and 1,116 are ‘non glial tumours of CNS and pineal gland’ (99% of which are embryonal tumours).
      Fig. 1 shows incidence trend for the period 1995–2002 for glioma, as overall and for age-classes. The overall trend is flat and the same is true for all the analysed age-groups with the exception of the oldest one (60+ years) that shows an increasing-incidence trend.
      Table 3 describes the standardised incidence rates (1995–2002) for EU in the whole and each European Region. For the purposes of the analyses five regions were identified as follow: Northern Europe (Iceland, Norway, Sweden), United Kingdom and Ireland (England, Scotland, Wales, Northern Ireland, Republic of Ireland), Central Europe (Belgium, Austria, France, Germany, The Netherlands, Switzerland), Eastern Europe (Poland, Slovakia) and Southern Europe (Italy, Malta, Portugal, Slovenia, Spain).
      Table 3Age-standardised incidence rates (per 100,000) for central nervous system (CNS) tumours in 1995–2002, with standard errors (SE) by European region.
      Rare central nervous system (CNS) cancersRegion
      Northern Europe (Iceland, Norway, Sweden), Central Europe (Austria, Belgium, France, Germany, the Netherlands, Switzerland), Eastern Europe (Poland, Slovakia), Southern Europe (Italy, Malta, Slovenia, Portugal, Spain).
      EU overall
      Northern EuropeCentral EuropeEastern EuropeSouthern EuropeUnited kingdom and Ireland
      Adj. rateSEAdj. rateSEAdj. rateSEAdj. rateSEAdj. rateSEAdj. rateSE
      Glial tumour of CNS and pineal gland5.30.14.80.13.50.14.40.15.7<0.15.0<0.1
      Astrocytic tumours of CNS4.60.14.20.13.10.13.80.15.1<0.14.4<0.1
      Oligodendroglial tumours of CNS0.4<0.10.3<0.10.3<0.10.3<0.10.4<0.10.4<0.1
      Ependymal tumours of CNS0.3<0.10.2<0.10.2<0.10.2<0.10.2<0.10.2<0.1
      Non-glial tumour of CNS and pineal gland0.3<0.10.3<0.10.2<0.10.3<0.10.2<0.10.3<0.1
      Embryonal tumours of CNS0.3<0.10.3<0.10.2<0.10.3<0.10.2<0.10.3<0.1
      Choroid plexus carcinoma of CNS<0.1<0.1<0.1<0.1<0.1<0.1<0.1<0.1<0.1<0.1<0.1<0.1
      a Northern Europe (Iceland, Norway, Sweden), Central Europe (Austria, Belgium, France, Germany, the Netherlands, Switzerland), Eastern Europe (Poland, Slovakia), Southern Europe (Italy, Malta, Slovenia, Portugal, Spain).
      There was marked geographical variation in incidence for astrocytic tumours, with the highest rate in UK and Ireland (5.1 cases per 100.000) and the lowest (3.1) in eastern Europe. The differences in geographical rates for all the other types of rare CNS tumours were negligible, Table 3.

      3.2 Prevalence

      Table 4 shows the observed prevalence proportions at 2, 5, 15-year and the estimated complete prevalence in Europe (index date 1st January 2003).
      Table 4Observed prevalence per 100,000 (Prev) with standard errors (SE) by time (2, 5 and 15 years) from diagnosis, with estimated complete prevalence per 100,000 and estimated total prevalent cases in EU27 of central nervous system (CNS) tumours. Index date 31 December 2003.
      Rare central nervous system (CNS) cancersObserved prevalenceEstimated prevalence
      2 years after diagnosis5 years after diagnosis15 years after diagnosisCompleteEU27
      Prev.SEPrev.SEPrev.SEPrev.SENo. of cases
      Glial tumour of CNS and pineal gland5.00.18.30.114.50.226.30.4130,764
      Astrocytic tumours of CNS4.10.16.30.110.90.120.40.4101,593
      Oligodendroglial tumours of CNS0.6<0.11.2<0.12.00.12.70.113,187
      Ependymal tumours of CNS0.3<0.10.8<0.11.70.13.80.119,125
      Non-glial tumour of CNS and pineal gland0.4<0.10.8<0.11.60.14.70.223,569
      Embryonal tumours of CNS0.4<0.10.7<0.11.5<0.14.30.221,470
      Choroid plexus carcinoma of CNS<0.1<0.1<0.1<0.10.1<0.10.30.11735
      More than 154,000 persons were alive in EU at the beginning of the year 2008 with a past diagnosis of rare CNS cancers, of whom 130,000 had had in their past clinical history a ‘glial tumour of CNS’ and about 23,000 a ‘non glial tumour of CNS and pineal gland’.
      As regards ‘glial tumours of the CNS’, 19% and 32% were diagnosed within 2 and 5 years before the prevalence date, respectively. The difference (13%) between these two proportions represents the proportion of cases in the 3rd–5th years after diagnosis, presumably still undergoing clinical follow-up. The remaining fraction of 68% represents long-term survivors (surviving more than 5 years), and 47,000 of these (47% of the total) were those surviving more than 15 years after diagnosis. Therefore, the majority of patients alive with a diagnosis of glial tumours of the CNS are cases diagnosed several years before (long survivors). A possible explanation for this is the high frequency of low grade tumours which have a good prognosis.
      As regards ‘Non-glial tumours of the CNS and pineal gland’, 9%, 17% and 34% of the prevalent cases were diagnosed within 2, 5 and 15 years before the prevalence date, respectively. The very long term survivors, those who survived more than 15 years after diagnosis, represented the majority of these cases (66% of the total, about 15,500 subjects).
      Astrocytic tumours were the most common among prevalent rare CNS cancers (about 100,000 cases), followed by embryonal tumours (about 21,000), ependymal tumours (about 19,000), oligodendroglial tumours (about 13,000) and choroid plexus carcinomas (1,700). Choroid plexus carcinomas, embryonal and astrocytic tumours were those with the highest proportion of very long term (more than 15 years) survivors (67%, 63% and 47%, respectively), Table 4.

      3.3 Survival

      Table 5 shows 1 and 5-year survival of first and second tier entities of rare CNS tumours. Survival was better for ‘non glial tumours of CNS and pineal gland’ (601 cases analysed), than for ‘glial tumours of CNS’ (13,667 cases). One- and five year survival were 81.0% and 43.8%, and 56.9% and 19.6%, respectively.
      Table 5One-year and 5-year relative survival (%) for central nervous system (CNS) tumours with standard errors (SE) by European region for 2000–2002.
      Rare central nervous system (CNS) cancersEU overallRegion
      Northern Europe (Iceland, Norway, Sweden), Central Europe (Austria, Belgium, France, Germany, the Netherlands, Switzerland), Eastern Europe (Poland, Slovakia), Southern Europe (Italy, Malta, Slovenia, Portugal, Spain).
      EUEUNorthernCentralEasternSouthernUK and Ireland
      1 year5 years1 year5 years1 year5 years1 year5 years1 year5 years1 year5 years
      (SE)(SE)(SE)(SE)(SE)(SE)(SE)(SE)(SE)(SE)(SE)(SE) 
      Glial tumour of CNS and pineal gland442051234623461751193617
      (0.5)(0.4)(1.1)(0.9)(0.9)(0.8)(1.7)(1.2)(1.2)(0.9)(0.7)(0.6)
      Ependymal tumours of CNS907494798969826689759178
      (1.4)(2.1)(2.5)(4.2)(2.7)(4.2)(6.9)(8.3)(3.7)(5.1)(2.7)(4.1)
      Oligodendroglial tumours of CNS835587638260693486548151
      (1.4)(1.8)(2.7)(0.4)(2.9)(3.6)(6.6)(5.8)(3.2)(4.3)(2.3)(3.2)
      Astrocytic tumours of CNS391546164217431446133112
      (0.5)(0.3)(1.2)(0.9)(1.0)(0.8)(1.8)(1.2)(1.3)(0.9)(0.7)(0.6)
      Non-glial tumour of CNS and pineal gland815780488768785079557956
      (1.7)(2.2)(3.7)(4.7)(2.8)(3.8)(6.3)(7.9)(4.5)(5.5)(3.3)(4.4)
      Choroid plexus carcinoma of CNS78631005086
      Statistic could not be calculated.
      50501001005738
      (8.7)(10.7)(25.1)(13.2)(35.4)(35.4)(18.2)(20.0)
      Embryonal tumours of CNS815779488767794978548056
      (1.7)(2.2)(3.8)(4.8)(2.9)(3.8)(6.3)(8.2)(4.6)(5.5)(3.3)(4.5)
      Statistic could not be calculated.
      a Northern Europe (Iceland, Norway, Sweden), Central Europe (Austria, Belgium, France, Germany, the Netherlands, Switzerland), Eastern Europe (Poland, Slovakia), Southern Europe (Italy, Malta, Slovenia, Portugal, Spain).
      Within glial CNS tumours, ependymal tumours had the best 5-year prognosis (74% overall, 80% low grade and 37% high grade). Intermediate prognosis was reported for oligodendroglial tumours (55% overall; 65% low grade and 30% high grade) and low survival was estimated for astrocytic tumours (15%). Astrocytic tumours include aggressive-phenotype tumours as glioblastoma (ICD-O 9440) but also lower grade astrocytomas (ICD-O 9400) and gliomas with a relatively good prognosis. According, the 5-year survival varied from 4.9% for high grade to 43% for low grade tumours.
      Within ‘non glial tumours’, a good prognosis was estimated for choroid plexus carcinomas (63%) and an intermediate survival was observed for embryonal tumours (57%).
      For glial tumours five-year survival was slightly higher for women (20.7%; 95% confidence interval 19.6–21.9) than for men (18.7%; 95% CI 17.8–19.7) (data not shown). Overall, 5-year survival was quite good for children and adolescents (0–19 years; 58.1%), and for young adults (20–39 years; 52.8.0%), and decreased steadily for adults (40–59 years; 19.1%), and especially for older subjects (60+ years; 4.4%) (data not shown). The decreasing survival with increasing age was a common pattern for all rare CNS types with the exception of ependymal tumours for which the decrease was less pronounced than for other tumours.
      The overall EU 5-year survival for glial tumours was 19.6%, with the highest values in northern (22.8%) and central Europe (22.6%), intermediate value in southern Europe (19.2%) and the lowest survival rates in eastern Europe (17.2%) and in UK and Ireland (16.6%). The overall geographical difference was mainly driven by differences for astrocytic tumours with less evident gradient for the other rare CNS types.
      There was geographic variation in 1-year survival from astrocytic tumours, ranging from 31% in UK and Ireland, to 46% in northern and southern Europe (data not shown).

      3.4 Estimated proportion of cured patients

      The proportion of patients that did not show an excess mortality compared with that for the general population (‘cured patients’) varied widely among the different groups of rare CNS tumours. The highest proportion of cured, 40.8%, was reported for ‘non glial tumour of CNS and pineal gland’; the lowest (7.9%) for ‘glial tumours of the CNS’, mainly due to the very poor survival of astrocytic tumours that are the most common glial tumours (and with high grade astrocytic which represent 62% of all astrocytic tumours).

      4. Discussion

      The present study shows that rare CNS cancers represent a vast array of tumours with different biological characteristics and different epidemiological features. Although all rare CNS tumours belong to rare tumours according to their relative frequency (overall < 6/100,000), astrocytic tumours represent the majority of them accounting for about 86% of all the 27,726 CNS tumours annually estimated in EU and for about 90% of the 23,859 ‘glial tumours of CNS’. Therefore, the overall epidemiological figures of rare CNS tumours in Europe are greatly influenced by astrocytic tumours,
      • Schwartzbaum J.A.
      • Fisher J.L.
      • Aldape K.D.
      • Wrensch M.
      Epidemiology and molecular pathology of glioma.
      especially by high grade astrocytic that are the most frequent (62% of astrocytic tumours) and have the worse survival. Astrocytic tumours influence also the overall prevalence of rare CNS tumours. In fact, due to the poor survival of astrocytic (high grade) tumours, their relevance is slightly lower for complete prevalence than for incidence. Astrocytic tumours represent 78% of the 154,000 EU complete prevalent cases, and ‘glial tumours’ in total represent 85%.
      Incidence of astrocytic tumours is higher among men than women. The 1.4 male excess observed in Europe has also been documented in the US, both in the SEER

      Altekruse SF, Kosary CL, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975–2007, Bethesda, MD: National Cancer Institute. Available from: http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010.

      and in the Central Brain Tumour Registry of the United States (http://www.cbtrus.org/).
      Overall, the median age estimated at diagnosis for CNS tumours is 56 (55 for males and 57 for females) years in the United States

      Altekruse SF, Kosary CL, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975–2007, Bethesda, MD: National Cancer Institute. Available from: http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010.

      and 53 (53 for males and 54 for females) years in Europe.
      The overall incidence increases with age with the highest values among subjects of 60+ years. This overall result is mainly driven by astrocytic tumours, while embryonal tumours have the highest incidence rate in the age-group 0–19, oligodendroglial tumours in the age-group 40–59 and ependymal tumours have stable rates. This confirms that, although rare CNS incidence increases with age, some of the CNS tumours are more common in younger adults. During childhood CNS tumours are the most common type of solid tumour accounting for one-fifth to one-fourth of all the cancers.
      • Kaatsch P.
      Epidemiology of childhood cancer.
      The incidence of CNS cancers varies widely across the world with the highest rates in developed Western (Europe and North America) and Western-type (Australia/New Zealand) countries.

      Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.

      Also across Europe there is certain variability in age-standardised incidence rates—the highest values were evidenced in UK, Ireland and northern Europe and the lowest ones in Eastern Europe. The geographical differences worldwide may be due, at least in part, to the availability of highly advanced imaging technology,
      • Parkin D.M.
      • Bray F.
      • Ferlay J.
      • Pisani P.
      Global Cancer Statistics, 2002. CA Cancer.
      and this may be true, to some extent, also across Europe. The use of magnetic resonance imaging (MRI) may also lead to the diagnosis of unexpected lesions. In a recent systematic review and meta-analysis of 16 studies, the prevalence of neoplastic incidental brain findings was 0.70%.
      • Morris Z.
      • Whiteley W.N.
      • Longstreth Jr, W.T.
      • et al.
      Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis.
      The prevalence of neoplastic lesions significantly increased with age and it was more likely using high resolution MRI sequences than standard resolution sequences.
      • Morris Z.
      • Whiteley W.N.
      • Longstreth Jr, W.T.
      • et al.
      Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis.
      However, survival data do not support a relevant amount of indolent lesions to explain the differences in Europe, and especially the high incidence rates in UK and Ireland.
      • Sant M.
      • Allemanni C.
      • Santaquilani M.
      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      As regards incidence of CNS tumours although the aetiology of such tumours is largely unknown there is a major concern for the possible role of cellular phone. The studies published up to the beginning of 2011 provided conflicting results thus are not useful to interpret geographical differences in incidence of CNS across EU regions. Several studies, including the recent Interphone study, did not demonstrate an increased risk within approximately 10 years of ‘reasonable’ use of phones for any tumour of the brain or any other head tumour.
      • Ahlbom A.
      • Feychting M.
      • Green A.
      • et al.
      Standing committee on epidemiology. epidemiologic evidence on mobile phones and tumor risk. A review.

      INTERPHONE Study Group. Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case-control study.Int J Epidemiol 2010;39:675–94.

      However, other studies suggested higher risk for malignant brain tumours in people with ipsilateral mobile phone use and >10 years latency period.
      • Khurana V.G.
      • Teo C.
      • Kundi M.
      • Hardell L.
      • Carlberg M.
      Cell phones and brain tumors: a review including the long-term epidemiologic data.
      The issue has been recently addressed by a working group coordinated by the International Agency for Research on Cancer specifically aimed at a IARC Monograph on the potential carcinogenic hazards from the exposure to radiofrequency electromagnetic fields frequency (range 30kHz-300GHz). According to the critical revision of the available evidences IARC classified radiofrequency electromagnetic fields as possibly carcinogenic to humans (Group 2B). The Monograph is in press,

      IARC. IARC monograph on the evaluation of carcinogenic risks to humans. In: Non-Ionizing radiation, radiofrequency electromagnetic fields, vol. 102. Lyon: International Agency for Research on cancer, in press.

      a concise summary with the main conclusions has been recently published.
      • Baana R.
      • Grosse Y.
      • Lauby-Secretan B.
      • et al.
      Carcinogenicity of radiofrequency electromagnetic fields.
      As regards time trends, data from the present study show stable (or even decreasing) incidence trends in all the age-classes analysed with the exception of the age-group 60+ years which shows an increasing trend.
      The increased use of technology imaging devices, such as computed tomography (CT) and MRI, may have contributed to the more precise diagnosis of such tumours. Trends for CNS with and without microscopic confirmation showed an increase in incidence for microscopic verified cases especially among the elderly. The improved ability to diagnose brain tumours by stereotactic and frameless biopsy procedures may have contributed to the increase in microscopically verified cases.

      Dammers R, Schouten JW, Haitsma IK, et al. Towards improving the safety and diagnostic yield of stereotactic biopsy in a single centre. Acta Neurochir . doi: 10.1007/s00701-010-0752-0.

      • Hoffman S.
      • Propp J.M.
      • McCarthy B.J.
      Temporal trends in incidence of primary brain tumors in the United States, 1985–1991.
      The present study showed very different survival results for different rare CNS tumours with the worst prognosis for astrocytic tumours (14.5% survival at 5-years, 5% for high grade astrocytic tumours), moderately good values for embryonal (56.8%), oligodendroglial (54.5%) and choroid plexus carcinomas (42.6%) and the best survival for ependymal tumours (74.2%). The overall CNS value is strongly influenced by the frequency of astrocytic tumours. Recent European estimates – that included all the CNS histologies – showed an overall 5-year survival of 19.7% for brain tumours.
      • Sant M.
      • Allemanni C.
      • Santaquilani M.
      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      This datum was quite similar across Europe with values higher than the European average for Finland (26.8%), Portugal (24.5%) UK-Wales (23.8%) and Norway (23.5%) and values below the average for UK-England (17.6%) and UK-Northern Ireland (15.3%).
      • Sant M.
      • Allemanni C.
      • Santaquilani M.
      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      Low survival values were measured in UK and Ireland also in the present study. In a recent paper, the survival differences between European regions were mainly attributed to the case-mix (morphological type of tumours). However, also after the adjustment for age and morphology there were an excess risk of death of 10% in Southern Europe, 20% in Central Europe, 30% in Eastern Europe and 40% in UK and Ireland in comparison with Northern Countries.

      Sant M, Minicozzi P, Lagorio S, et al. Survival of European patients with central nervous system tumours. Int J Cancer 2011; doi:10.1002/ijc.26335. [Epub ahead of print].

      The overall geographical difference was mainly driven by differences for astrocytic tumours with less evident gradient for the other rare CNS types. Astrocytic tumours include aggressive-phenotype tumours as glioblastoma but also tumours with a relatively good prognosis. In our series glioblastomas were less frequent in Eastern (38%) than in the other European regions (around 50%). This suggests that other prognostic factors than case mix of the neoplasm contributed to the survival variation across Europe.
      Similar geographical variation in survival was found for adults with any type of brain tumour in EUROCARE-4.
      • Sant M.
      • Allemanni C.
      • Santaquilani M.
      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      Survival was quite similar across Europe for children and young adults, though with lower values in UK.
      • Gatta G.
      • Zigon G.
      • Capocaccia R.
      • et al.
      Survival of European children and young adults with cancer diagnosed 1995–2002.
      Survival was slightly better for women than for men, as elsewhere documented

      Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.

      • Micheli A.
      • Ciampichini R.
      • Oberaigner W.
      • et al.
      The advantage of women in cancer survival: An analysis of EUROCARE-4 data.
      and the strong tendency for survival rates to worsen with age observed in the present study is consistent with previous findings from survival time-trend analyses in Nordic countries.

      Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.

      The geographical differences in 1-year survival may be due to a variation in the timeliness of diagnosis and therapy which may exert its effect in the short term. Brain cancer 1-year survival in 23 European countries ranged between 34.2% and 48.3%, with high survival estimates in Switzerland, France, Sweden, Belgium and Italy and lower estimates in Poland, Czech Republic, Ireland, Denmark and United Kingdom–Northern Ireland.
      • Sant M.
      • Allemanni C.
      • Santaquilani M.
      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      Five-year survival conditional on having survived the first year after diagnosis varied less between countries.
      • Sant M.
      • Allemanni C.
      • Santaquilani M.
      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      Also in the present study there were values lower than the EU average for UK and Ireland for 1-year survival for astrocytic tumours.
      In the treatment of brain cancer, radiotherapy is widely used. Therefore, the access to radiotherapy might influence the treatment outcome and consequently survival of CNS tumours. The number of linear accelerators per million population is far lower in UK and Ireland, as well as in Eastern Europe compared to Nordic and Central-Europe countries. ESTRO QUARTS project has analysed the ratio of actual number of megavoltage therapy units to the evidence-based required numbers in 13 European countries.
      • Bentzen S.M.
      • Heeren G.
      • Cottier B.
      • et al.
      Towards evidence-based guidelines for radiotherapy infrastructure and staffing needs in Europe: the ESTRO QUARTS project.
      The largest gap was seen for Eastern-European countries (Slovenia and Poland) followed by the Czech Republic and UK. In contrast, in Northern and Central European countries (Sweden, France and Belgium), the availability of megavoltage therapy units exceeded 90% of the QUARTS estimate.
      The lower survival rates reported in this study for some EU regions could be explained by less accessibility to Magnetic Resonance Imaging (MRI). EUROSTAT data on medical technology (http://epp.eurostat.ec.europa.eu/) showed for the year 2000 a huge variability of the number of MRI units among EU countries: from 0.0 per 100,000 persons in Lithuania and 0.1 in Slovakia to 0.8 in Italy. Different availability of surgical, radio-therapeutical and chemotherapeutical facilities across Europe can also contribute to explain the lower survival observed in some countries. Further data from EUROSTAT showed that in the year 2000, the number of operations on the nervous system (not only for cancer) varied from 69 in Bulgaria and 74 in Romania to 1268 per 100,000 inhabitants in Belgium. Evidence based medicine is, by definition, weaker in rare tumours: this results, in CNS tumours, in a reduced utilisation of more aggressive, still not of high-evidence levels, treatments such as total resection in low grade gliomas achievable by more modern techniques (i.e. awake surgery) or less intense chemotherapeutic approaches in malignant tumours, such as adjuvant temozolomide longer than the 6 conventional cycles, more than one salvage treatment or the use of Gliadel wafer at recurrence.
      • Brem H.
      • Piantadosi S.
      • et al.
      Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group..
      • Mason W.P.
      • Maestro R.D.
      • Eisenstat D.
      • et al.
      Canadian recommendations for the treatment of glioblastoma multiforme.
      In the present study pilocytic astrocytoma were excluded from the analyses. We do not know whether these tumours are represented in the same proportions in the glioma NOS and astrocytoma NOS tiers across Countries. This is especially important for the younger age groups. In EUROCARE-4, pilocytic astrocytoma accounted for 49% of all astrocytomas in children aged 0–14 and 24% of astrocytomas in adolescents and young adults aged 15–24 years; inclusion of pilocytic astrocytoma increased the 5-year period survival estimates for astrocytoma from 63% to 78% in children and from 56% to 64% in adolescents and young adults.
      • Sant M.
      • Allemanni C.
      • Santaquilani M.
      • et al.
      EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary.
      Prevalence estimates are a useful tool for public health strategies and evaluations, as they measure the burden on the health care system.
      • Porter K.R.
      • McCarthy B.J.
      • Freels S.
      • Kim Y.
      • Davis F.G.
      Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology.
      Prevalence of CNS tumours was about 30 per 100,000, below the threshold of the European definition for rare diseases (50 per 100,000) therefore these tumours are rare according also to the European definition on rare diseases

      European Parliament and Council of the European Communities (1999). Decision No 1295/1999/EC of the European Parliament and of the Council of 29 April 1999 adopting a programme of Community action on rare diseases within the framework for action in the field of public health (1999 to 2003).

      and may profit to the EU Directive on orphan drugs. Prevalence estimates showed that there are about 154,000 citizens living with rare CNS tumours in EU, 27,000 of them diagnosed within 2 years and therefore in a period with very intensive follow-up. As with most cancers, mortality is highest for CNS tumours in the short term. The ratio between complete prevalence and estimated annual number of diagnosed cases is around 4 for astrocytic tumours, 8 for olygodendroglial tumours, 20 for ependymal and embryonal tumours and almost 60 for choroid plexus carcinomas.
      Rare CNS tumours represent a heterogeneous group with great differences in terms of frequency, prognosis and treatment approaches. Despite remarkable improvement in the ability to diagnose and treat brain tumours, the prognosis for most of rare CNS cancer patients remains poor. The varying availability of highly advanced imaging technology and of radiotherapy equipment as well as the lack of evidence based protocols reduces the possibility of getting timely diagnosis and treatment. This means that management of these rare brain tumours has to be considered hyper-specialistic, and the treatment has to be centralised in large volumes hub centres with recognised expertise in this field.

      Funding

      This research was supported by the European Commission through the Executive Agency for Health and Consumers (Grant No. 2006113), and the Programma Italia-USA Malattie Rare (Grant No. 526D/42).

      Conflict of interest statement

      None declared.

      Appendix A. The RARECARE Working Group for this paper consists of:

      Austria: N. Zielonk (Austrian National Cancer Registry); Belgium: E. Van Eycken (Belgian Cancer Registry), H. Sundseth, (European Cancer Patient Coalition), S. Marreaud (European Organisation for Research and Treatment of Cancer), R. Audisio (European Society of Surgical Oncology); France: G. Hedelin, (Bas-Rhin Cancer Registry); G. Launoy (Calvados Digestive Cancer Registry); A.V. Guizard (Calvados General Cancer Registry); A.M. Bouvier (Côte d’Or Digestive Cancer Registry); A.S. Woronoff (Doubs Cancer Registry); A. Buemi (Haut-Rhin Cancer Registry); B. Tretarre (Hérault Cancer Registry); M. Colonna (Isère Cancer Registry); S. Bara (Manche Cancer Registry); O. Ganry (Somme Cancer Registry); P. Grosclaude (Tarn Cancer Registry); Germany: B. Holleczek (Saarland Cancer Registry); J. Geissler (C.M.L. Advocates Network; Iceland: L. Tryggvadottir (Icelandic Cancer Registry); Ireland: H. Comber (National Cancer Registry of Ireland); Italy: F. Bellù (Alto Adige Cancer Registry); S. Ferretti (Ferrara Cancer Registry); D. Serraino (Friuli Venezia Giulia Cancer Registry); M. Vercelli (Liguria Cancer Registry c/o IST/UNIGE, Genoa); S. Vitarelli (Macerata Province Cancer Registry); M. Federico (Modena Cancer Registry); M. Fusco (Napoli Cancer Registry); A. Traina (Palermo Breast Cancer Registry); M. Michiara (Parma Cancer Registry); A. Giacomin (Piedmont Cancer Registry, Province of Biella); R. Tumino (Cancer Registry and Histopathology Unit, “M.P. Arezzo” Civic Hospital, Ragusa); L. Mangone (Department of Research Azienda Ospedaliera Arcispedale Santa Maria Nuova – IRCCS, Reggio Emilia); F. Falcini (Romagna Cancer Registry); A. Iannelli (Salerno Cancer Registry); M. Budroni (Sassari Cancer Registry); S. Piffer (Trento Cancer Registry); T. Intrieri (Tuscan Cancer Registry); F. La Rosa (Umbria Cancer Registry); P. Contiero (Varese Cancer Registry); P. Zambon (Veneto Cancer Registry); P.G. Casali, G. Gatta, A. Gronchi, L. Licitra, M. Ruzza, S. Sowe, (Fondazione IRCCS Istituto Nazionale dei Tumori); R. Capocaccia, R. De Angelis, S. Mallone, A. Tavilla (Centro Nazionale di Epidemiologia, Istituto Superiore di Sanità); A.P. Dei Tos (Local Health Unit No. 9, Region of Veneto); A.A. Brandes (Medical Oncology Department, Local Health Unit, Bologna); Malta: K. England (Malta National Cancer Registry); Norway: G. Ursin (Cancer Registry of Norway); Netherlands: O. Visser, R. Otter, S. Siesling, J.M. van der Zwan (Comprehensive Cancer Centre the Netherlands); J.W.W. Coebergh (Eindhoven Cancer Registry), H. Schouten (University of Maastricht); Poland: J. Rachtan (Cracow Cancer Registry); S. Gozdz (Kielce Cancer Registry); M. Zwierko (Warsaw Cancer Registry); M. Bielska-Lasota (National Institute of Public Health – National Institute of Hygiene, Warsaw); J. Slowinski (Department of Neurosurgery in Sosnowiec, Medical University of Silesia); Portugal: A. Miranda (Southern Portugal Cancer Registry); Slovakia: Ch. Safaei Diba (National Cancer Registry of Slovakia); Slovenia: M. Primic-Zakelj (Cancer Registry of Slovenia); Spain: A. Mateos (Albacete Cancer Registry); I. Izarzugaza (Basque Country Cancer Registry); A. Torrella-Ramos (Castillon Cancer Registry); R. Marcos-Gragera (Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Department of Health and Catalan Institute of Oncology, Girona, Spain); M.J. Sánchez (Granada Cancer Registry); C. Navarro (Department of Epidemiology, Murcia Regional Health Authority, Murcia, CIBER Epidemiología y Salud Pública (CIBERESP)); Eva Ardanaz (Navarra Cancer Registry); J. Galceran (Tarragona Cancer Registry); C. Martinez-Garcia, J.M. Melchor (Escuela Andaluza de Salud Pública); Sweden: J. Adolfsson (Stockholm-Gotland Cancer Registry); M. Lambe (Uppsala Regional Cancer Registry), T.R. Möller (Lund University Hospital); U. Ringborg (Karolinska Institute); Switzerland: G. Jundt (Basel Cancer Registry); M. Usel (Geneva Cancer Registry); S.M. Ess (St. Gallen Cancer Registry); A. Bordoni (Ticino Cancer Registry); I. Konzelmann (Valais Cancer Registry); J.M. Lutz (National Institute for Cancer Epidemiology and Registration); UK-England: D.C. Greenberg (Eastern Cancer Registration and Information Centre); J. Wilkinson (Northern and Yorkshire Cancer Registry); M. Roche (Oxford Cancer Intelligence Unit); J. Verne (South-West Public Health Observatory); D. Meechan (Trent Cancer Registry); G. Lawrence (West-Midlands Cancer Intelligence Unit); M.P. Coleman (London School of Hygiene and Tropical Medicine), J. Mackay (University College of London); UK-Northern Ireland: A. Gavin (Northern Ireland Cancer Registry); UK-Scotland: D.H. Brewster (Scottish Cancer Registry); I. Kunkler (University of Edinburgh); UK-Wales: J. Steward (Welsh Cancer Intelligence & Surveillance Unit).

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