INCIDENCE AND SURVIVAL OF CENTRAL NERVOUS SYSTEM MALIGNANCIES ACCORDING TO HISTOLOGICAL SUBTYPES. RESULTS OF A POPULATION-BASED STUDY IN GIRONA (SPAIN) Marcos-Gragera R1; Vilardell L1; Perez-Bueno F2; Osca G1; Cano A1; Fuentes-Raspall R3 1 Girona Cancer Registry, Oncology Coordination Plan. Department of Health. Autonomous Government of Catalunya. Catalan Institute of Oncology, Girona, Spain. 2Pathology Service, Hospital Universitari de Girona “Dr.Josep Trueta”, Girona, Spain 3Radiation Oncology Service, Catalan Isntitute of Oncology, Girona, Spain. Posar una foto del congrès

INTRODUCTION Primary malignant brain tumors represent a heterogenous group of diseases. Risk Factors: Hereditary syndromes Tuberous sclerosis, neurofibromatosis, nevoid basal cell carcinoma syndrome, adenomatous polyposis syndromes, Li-Fraumeni cancer family syndrome Family history of brain tumours Ionizing radiation Epidemiological data of Central nervous systems (CNS) malignancies by morphological groups in Europe are not frequently reported.

Fuente: Atlas Municipal de Mortalidad por Cáncer en España. 1989-1998

Primary malignant brain tumors:survival Survival for these malignancies is generally low; During last few years, new developments in the management of this tumours using different combinations of surgery, radiation therapy and chemotherapy have been translated into better outcomes.

Multicenter phase 3 trial To compare: Radiotherapy alone vs Radiotherapy + Temozolomide (oral alkylating agent) Treatment 5-y OS Radiotherapy 1.9% Combined 9.8%

OBJECTIVE Estimate the population-based incidence and survival of primary brain tumours by Histological subtypes sex age at diagnosis Treatment (Temozolomide) in patients diagnosed by Glioblastoma.

Participants (period & person-years) Source: Girona Cancer Registry Population (2007): 706.185 Period 1994 2007 Person-years 7.973.367 Inclusion (ICD10) C71 (Brain) C72 (spinal cord, cranial nerves and other parts of the CNS) Exclusion Meningeal, soft tissue and spinal cord tumours were excluded, also primary CNS lymphoma

METHODS (2) All pathological records were revised in order to classify them according to the 2007 WHO Classification.

METHODS (3) Incidence Incidence rates were calculated as the average annual number of cases per 100.000 person-years. Age-standardised rates (ASRs) were calculated by the direct method using the world standard population. Incidence time-trends Overall incidence trends were evaluated using Poisson models adjusted by age, sex and the presence of change-points in the trends was assessed with a Joinpoint analysis. Survival Follow-up until 31-12-2010. Observed survival was calculated using Kaplan-Meier method and relative survival by Hakulinen method. DCO cases were excluded for survival analysis RETOCAR AMB LES DADES NOSTRES 11

Primary malignant brain tumors, Girona (Spain) 1994-2007 Primary malignant brain tumors, Girona (Spain) 1994-2007. Data quality indicators Death certificate only (DCO) 4.9% Microscopical verification (MV) 61.3% Completeness 98.7% Number of cases 658 RESULTS

Age-specific incidence rates (males and female) of primary brain tumours Mean (years) Median Rank ♂ 57.71 63 0-93 ♀ 59.02 64 1-92 ♂ ♀ 58.3 RESULTS

Incidence by hitological subtype and sex according to the WHO classification. Girona (Spain) 1994-2007 Histological subtype Both sexes N % CR ASRw CI 95% Astrocytic tumours 333 50.84 4.18 3.19 (2.81; 3.57) Diffuse astrocytoma (WHO grade II) 87 13.28 1.09 0.98 (0.74; 1.21) Anaplastic astrocytoma (WHO grade III) 31 4.73 0.39 0.30 (0.18; 0.41) Glioblastoma (WHO grade IV) 215 32.82 2.70 1.92 (1.64; 2.20) Oligodendroglial & oligoastrocytics 22 3.36 0.28 0.22 (0.13; 0.31) Ependymal tumors 18 2.75 0.23 0.26 (0.12; 0.40) Embryonal tumors 25 3.82 0.31 0.44 (0.25; 0.63) Choroid plexus tumors 1 0.15 - Without histological confirmation 256 39.08 3.21 1.58 (1.36; 1.80) TOTAL 658 100 8.21 5.72 (5.21; 6.23) RESULTS Men: 6.53 (95% CI: 5.77;7.30) Women: 4.96 (95% CI: 4.28;5.64). Sex ratio: 1.32

Temporal incidence in malignant neuroepithelial tumors Temporal incidence in malignant neuroepithelial tumors. Trends calculated using joinpoint analysis, Girona (Spain) 1994-2007 PCA: -1.02 (CI95% -3.68 ; 1.72) RESULTS

Temporal incidence trends in glioblastoma tumors Temporal incidence trends in glioblastoma tumors. Trends calculated using joinpoint analysis, Girona (Spain) 1994-2007 PCA: 0.99 (CI 95% -3.34 ; 5.53) RESULTS

Kaplan-Meier estimated of overall observed survival curves for patients diagnosed with a primary brain and central nervous system tumours, Girona (Spain) 1994-2007 All tumours 5-y OS Median: 0.4 yr 15.5 5-y RS 16.3 No. at Risk 658 218 151 127 96 81

Kaplan-Meier estimated of overall observed survival curves for patients diagnosed with a primary brain and central nervous system tumours by sex. Girona (Spain) 1994-2007 Sig. Log Rank (Mantel-Cox) 0.392 SEX 5-y OS 5-y RS Men 16.1 17.2 Women 14.9 15.3 Men Women No. At Risc Men 364 125 84 71 51 45 Woman 294 93 67 56 36

Kaplan-Meier survival estimates of overall survival by histological groups according to WHO classification groups. Girona (Spain) 1994-2007 Sig. Log Rank (Mantel-Cox) < 0.001 Histological type 5-y OS 5-y RS Astrocytic tumours 15.5 15.9 Oligodendroglial & oligoastrocytics 54.5 55.3 Ependymal tumours 48.5 49.4 Embryonal tumours 36.0 36.1 Without histological confirmation 7.7 8.7 Faltaria afegir una taula amb les medianes de supervivencia

Kaplan-Meier estimates of overall survival of astrocytic tumours according to WHO grades (Girona, Spain, 1994-2007) Glioblastoma Anaplastic astrocytoma Diffuse astrocytoma Years Sig. Log Rank (Mantel-Cox) < 0.001 Histological type 5-y OS 5-y RS Diffuse astrocytoma (WHO grade II) 42.5 43.4 Anaplastic astrocytoma (WHO grade III) 4.8 5.0 Glioblastoma (WHO grade IV) 5.8 6.1 No. at Risk Diffuse astrocytoma 87 54 41 39 33 31 Anaplastic astrocytoma 14 6 4 2 1 Glioblastoma 215 60 29 20 12 9

Most Common Brain and CNS Tumors by Age Age (years) Most Common Histology Second Most Common Histology < 15 Diffuse astrocytoma CNS without histological confirmation 15-44 Glioblastoma 45-64 65-74 > 75 Gliomatosis cerebri

Kaplan-Meier estimates of overall survival for patients diagnosed of a primary brain and central nervous system tumours by age groups. Girona (Spain) 1994-2007 < 15 years 15-44 years 65-74 years 45-64 years >75 years Sig. Log Rank (Mantel-Cox) <0.001 Age group 5-y OS 5-y RS <15 years 43.9 15-44 years 45.8 46.1 45-64 years 15.3 15.7 65-74 years 2.9 3.6 > 75 years 3.3 4.6 No. at Risk   <15 31 11 8 3 15-44 113 44 17 2 45-64 196 20 9 65-74 168 4 >75 150

Kaplan-Meier estimated of overall observed survival curves for patients diagnosed of a primary brain and central nervous system tumours by period of diagnosis. Girona (Spain) 1994-2007 Sig. Log Rank (Mantel-Cox) 0.282 Period 5-y OS 5-y RS 1994-2003 10.9 11.5 2004-2007 14.9 16.1 2004-2007 1994 - 2003 Crec que aquesta gràfica no es correspon amb el total de casos No. at Risk 1994-2003 441 145 97 79 68 62 2004-2007 217 73 54 48 28 19

Kaplan-Meier estimates of overall survival by treatment group Kaplan-Meier estimates of overall survival by treatment group. Glioblastoma. Treatment 5-y OS 5-y RS Combined (n=42) 7.1 7.4 Radiotherapy (n=146) 2.6 2.7

NB: Patients older than 15 yrs Hazard ratios (HRs) and 95% confidence intervals (CIs) for Glioblastomas (ICD-O3: 9440/3).   Cases, n HR CI (95%) Sex Male 103 1 Female 85 1.086 (0.81 – 1.45) Age (years) 15-44 20 45-64 77 2.90 (1.67 – 5.02) 65-74 71 2.71 (1.55 – 4.72) >75 19 3.58 (1.80 – 7.11) Period 1994-2004 113 2005-2007 75 0.83 (0.61 – 1.11) Temozolomide Si 42 No 146 2.29 (1.60 – 3.27) NB: Patients older than 15 yrs

Astrocytic tumours constituted over 50% of CNS tumours. MAIN RESULTS 2007 WHO classification characterize homogeneous subgroups in brain tumours. Astrocytic tumours constituted over 50% of CNS tumours. Glioblastoma (WHO grade IV) constituted over 30% of malignant CNS tumours Better diagnosis imaging is most probably the cause of an increasing number of patients without histological verification.

MAIN RESULTS Survival of CNS tumours patients is strongly depenent on histological typing and grading. Survival for ependymal and oligodendroglial tumours was more favourable in comparison to other tumours types. Glioblastoma and anaplastic astrocytoma had worst survival. Oligodendroglial & oligoastrocytics had relative good survival

MAIN RESULTS Slightly better survival for men than women. Age is a predictive factor. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a statiscally significant survival

Thank you Gracias Gràcies Merci Mulţumiri Grazie Obrigado

Kaplan-Meier estimates of overall survival by age groups (children vs adults). Girona (Spain) 1994-2007 Sig. Log Rank (Mantel-Cox) < 0001 Age group 5-y OS 5-y RS ≤ 14 years 43.9 46.9 > 14 years 14.6 15.4 Afegir la supervivencia observada, relativa als 5 anys i les medianes de supervivencia segons els grups d’edat.