Paediatric brain tumours: a challenge for epidemiologists

1. Paediatric brain tumours:a challenge for epidemiologists Joachim Schüz Head, Section of Environment and Radiation International Agency for Research on Cancer Lyon, France I4C Meeting, Lyon, November 2012

2. Paediatric brain tumors ICCC-3

3. Age distribution 0-14 years in Europe,1988-1997 by diagnostic group. Source ACCIS Peris-Bonet et al., Eur J Cancer, 2006

4. Time trends in incidence rates Peris-Bonet et al., Eur J Cancer, 2006

5. Time trends in incidence rates Raaschou-Nielsen et al., Br J Cancer, 2006

6. Time trends in incidence rates Schmidt et al., Pediatr Blood Cancer, 2011

7. Regional variation Kaatsch et al., Cancer, 2001

8. Aetiology ? Environmental factors? Genetic Predisposition?

9. Pitfalls in epidemiological studies • Rare tumour (sample size & statistical power) • Histological heterogeneity (dilution by lumping?) • Changes in classification systems over time • Histological classification difficult (subjective) • Date of diagnosis (doctor’s and patient’s delay) • Investigation of rare exposures • Questionnaire-based case-control studies- selection / participation bias- recall bias • Comparability across countries

10. Genetic syndromes

11. Familial aggregation • Parents: • 2 studies on the risk of CNS tumours, one significant association • Risk of non-CNS cancer was found to be significantly increased in 3 of 4 studies, but not the same cancers • Siblings: • No general excess of cancer • Of 6 studies 2 found a significant risk of CNS tumours (SIR 2.27 ;SIR 8.8) • 2 out of 4 studies found a significantly increased risk of childhood CNS tumours (SIR 3.6; 3.28) • Relatives: • Inconclusive information about cancer occurrence • No excess of CNS tumours in most studies • Detected associations often with wide confidence intervals Dearlove et al., J Pediatr Hematol Oncol, 2008

12. Ionizing radiation: Environmental Per 10^3 Bq/m^3-years Raaschou-Nielsen et al., Epidemiology, 2008

13. Ionizing radiation:Diagnostic • Diagnostic X ray: strong associations in studies from the 60s – 80sPreston-Martin et al.: 2.5-fold with full mouth X – rayHowe et al.: 6-8-fold with X ray of the scull • Modest or no associationsin later case-control studies • Radiation exposure from CT examinations in children Linet et al., Pediatr Radiol, 2009 Pearce et al., Lancet, 2012

14. Non-Ionizing radiation: ELF 1.14 (0.61, 2.13) Kheifets et al., Am J Epidemiol, 2010

15. Non-Ionizing radiation: RF CEFALO study – cumulative mobile phone use:(7-19 year olds) OR Aydin et al., J Natl Cancer Inst, 2012

16. Smoking • Meta analyses on 6566 patients <20 years: RR 1.05 (0.9-1.21)(maternal smoking during pregnancy) • Swedish cohort study on 480 cases: RR 1.24 (95% CI 1.01-1.53) Huncharek et al., J Neurooncol, 2002

17. Diet • N-nitroso compounds (NOC) are:- neurocarcinogenic in experimental animals- found in food containing nitrite or exposed to nitrogen oxides, particularly cured meat • are formed in the stomach of the mother • could cross the placenta US California CC (1982) 2.3 (p for trend < 1% across categories) US California CC (1996) 2.1 (1.3-3.2) US New York (1996) 1.3 (1.0-1.8) US and Canada PNET 1.1 (0.6-2.0) Glioma 1.7 (1.0-2.9) US Delaware Valley 2.0 (p for trend = 4%) US Denver 1.0 (bacon) to 2.3 (hot dogs) Australia 2.5 (1.1-5.7; ajdusted for vitamins) Israel 1.1 (0.8-1.6, p=0.5) France 1.0 (ham), 0.6 (sausage), 0.6 (salami) Consistency with time trends in incidence?

18. Birth weight 3443 cases and ~16000 controls adjusted for GA Schmidt et al., Cancer Epidemiol Biomarkers Prev, 2010

19. Other birth characteristics Fetal growth Schmidt et al., Cancer Epidemiol Biomarkers Prev, 2010

20. Other birth characteristics Apgar score at 5 min. <7 • Heart rate • Respiratory effort • Muscle tone • Reflex irritability • Colour CNS tumours and lowApgar score at 1 min. (Fear Cancer CausesControl 2001 OR 2.7 (1.0-7.4) (Linet Cancer CausesControl 1996 OR 1.4(0.9-2.2) (McKinney Br J Cancer 1999 OR 0.66 (0.22-1.96) Schmidt et al., Cancer Epidemiol Biomarkers Prev, 2010

21. Infections Childcare attendance Schmidt et al., Br J Cancer, 2010

22. Comparison withUS Five States Study Birth order: Maternal age: N US: 3561 Nordic:3572 <20 20-24 25-29 30-34 35-39 40+ Johnson et al., Br J Cancer, 2011

23. Pesticides • Neurotoxic properties of pesticides – biological plausible hypothesis • Methods • Very little precision with regard to exposure classification • Majority of studies are based on paternal occupational exposure • Results • The majority of studies report a positive association (Review 1998 by Zahm and Ward) • No increased risk in the offspring of male pesticides applicators in Sweden or Canada (Heacook 2000, Flower 2004) • Cohort study paternal occupational exposure RR 3.65 (95% CI 1.27-4.39) (Feychting 2001)

24. Other factors • No association with air pollution but few studies • Few data on atopic disease, although consistent relationship with glioma in adults • Some positive findings for head injuries, but self-reported data • Positive association with epilepsy, but might be an early symptom of the tumour • Occupational exposure of fathers: lack of consistency(motor-vehicle industry, chemical industry, painters) • Nitrite in drinking water: lack of data

25. I4C Challenge of numbers of expected cases for a rare & heterogeneous disease Perinatal factors: potential of mutual adjustment Environmental factors: identification of high exposure groups? Child‘s development?