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TRAINING FOR THE HEALTH SECTOR [Date …Place …Event…Sponsor…Organizer]

TRAINING FOR THE HEALTH SECTOR [Date …Place …Event…Sponsor…Organizer]. CHILDREN AND CANCER. Children's Health and the Environment WHO Training Package for the Health Sector World Health Organization www.who.int/ceh. CHILDHOOD CANCER. OBJECTIVES To discuss childhood cancer

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TRAINING FOR THE HEALTH SECTOR [Date …Place …Event…Sponsor…Organizer]

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  1. TRAINING FOR THE HEALTH SECTOR [Date …Place …Event…Sponsor…Organizer] CHILDREN AND CANCER Children's Health and the Environment WHO Training Package for the Health Sector World Health Organization www.who.int/ceh

  2. CHILDHOOD CANCER OBJECTIVES • To discuss childhood cancer • To address the links between childhood environments and adult onset of cancer • To present current knowledge of causation and environmental risk factors • To discuss cancer clusters • To present educational and preventive measures

  3. OVERVIEW • INCIDENCE AND TYPES OF CHILDHOOD CANCER • CAUSES, RISK FACTORS AND HYPOTHESES • BIOLOGICAL PROCESSES LEADING TO CANCER DEVELOPMENT • EXPOSURE ASSESSMENT AND ITS CHALLENGES • INVESTIGATING POTENTIAL CANCER CLUSTERS • 6. QUESTIONS FROM PARENTS

  4. TEN LEADING CAUSES OF DEATH (Children aged under 15 years) U.S. 2006 * Rates are per 100,000 population and age adjusted to the 2000 US standard population. Based on US Mortality Data, 2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009

  5. INCIDENCE CHILDHOOD CANCER (Globally) • Childhood 14.9 per 100,000 < 15 years of age 16.4 per 100,000 < 20 years of age • Adult 470.1 per 100,000 • Childhood 160,000 new cases/year < 15 years of age 90,000 deaths/year < 15 years of age Ferlay J, IARC Cancer Base N°5, 2004 INCIDENCE CHILDHOOD CANCER (U.S. 2006) Ries LAG, SEER U.S. 2000-2004

  6. INCIDENCE CHILDHOOD CANCER (Children agedunder 15 years) Leukaemias Brain & other nervous system Non-Hodgkin's lymphomas Rate per 100000 person-years Hodgkin's disease All non-epithelial skin Based on Linet MS et al. J Natl Cancer Inst 1999;91(12):10520 Year

  7. Cancer Leukemia Nonleukemia Gross National Cancer Leukemia Nonleukemia Gross National Country incidence incidence incidence income Country incidence incidence incidence income * * Low-income 102 16 85 491 High-income 130 41 89 32872 countries (n = 9) countries (n=9)    Malawi 100.0 1.1 98.9 160    Finland 148.6 47.3 101.3 37460    Uganda 183.5 10.3 173.2 280    United Kingdom 118.2 38.6 79.6 37600    Zimbabwe 111.2 22.8 88.4 340    Japan 107.6 35.5 72.1 38980    Mali 77.4 4.0 73.4 380    Sweden 149.4 45.6 103.8 41060    Nigeria 71.2 8.6 62.6 560    USA 137.9 43.1 94.8 43740    Vietnam 108.4 33.4 75.0 620    Iceland 109.0 37.2 71.8 46320    Papua New Guinea 100.0 8.1 91.9 660    Denmark 149.3 47.2 102.1 47390    Pakistan 100.0 40.5 59.5 690    Switzerland 139.5 43.8 95.7 54930    India 64.4 19.2 45.2 730    Norway 143.2 44.0 99.2 59590 INCIDENCE CHILDHOOD CANCER Incidence data are from the International Agency for Research on Cancer.    Low-income country (LIC): the mean per capita annual income in 2005 is less than US $825; high-income country (HIC): the mean per capita annual income is more than $10,065. Annual per capita figures in US dollars. Gross national incomes were taken from the world development indicators database of the World Bank for 2005. Kaposi sarcoma accounted for 68.5 nonleukemia cancers per million per year in Uganda and 10.7 in Zimbabwe. Based on Scott CH, Cancer, 2007

  8. CAUSES OF CHILDHOOD CANCERS • Identified familial and genetic factors • (5-15%) • Known Environmental exposures & exogenous factors • (<5-10%) • UNKNOWN • 75-90%

  9. Gene pool Parental gametes Environmental exposures Parental grandmothers Parental preconceptional Gestational Postnatal Maternal Paternal eg. Hepatocellular carcinoma (hepatitis B virus) eg. Vaginal adenocarcinoma (DES) Transplacental Direct eg. Leukaemia (trisomy) eg. Leukaemia (X-ray) eg. Retinoblastoma MULTI-CAUSAL! - MULTI-GENERATIONAL? Based on Anderson LM, Environ Health Perspect, 2000, 108(suppl 3):573-594

  10. CHILDREN ARE NOT LITTLE ADULTS • Different and unique exposures • Dynamic developmental physiology • Longer life expectancy • Politically powerless Raphael, National Gallery of Art, Washington, DC

  11. OVERVIEW • INCIDENCE AND TYPES OF CHILDHOOD CANCER • CAUSES, RISK FACTORS AND HYPOTHESES • BIOLOGICAL PROCESSES LEADING TO CANCER DEVELOPMENT • EXPOSURE ASSESSMENT AND ITS CHALLENGES • INVESTIGATING POTENTIAL CANCER CLUSTERS • 6. QUESTIONS FROM PARENTS

  12. RISK FACTORS Definition : Specific agent statistically associated with a disease either positively or negatively Increasing levels of exposure   or  incidence of disease  causation more likely

  13. RISK FACTORS Carcinogenic Agents identified as Risk Factors • EXTERNAL AGENTS: • Physical carcinogens: • ionizing radiation (X-ray) • non-ionizing radiation (electromagnetic fields, UV) • Biological carcinogens: • infections from viruses (Epstein Barr virus: Burkitt's lymphoma and Hodgkin's disease; Hepatitis B: liver carcinoma; and HHV8 and HIV: Kaposi's sarcoma)

  14. Chemical carcinogens: • tobacco: mothers who smoke during pregnancy • pesticides, asbestos: parental occupation • aflatoxin, arsenic: food and drinking water contaminants • drugs and medication: pregnant women treatment (diethylstilboestrol: cell adenocarcinoma of the vagina or cervix ) • Dietary constituents • INTERNAL AGENTS: • Inherited factors • predisposition to particular familial diseases • genetically determined features

  15. RISK FACTORS • Weight of evidence may be • Known • Suggestive • Limited • according to extent to which evidence of causality supports a relationship between • a risk factor and a disease

  16. Associated with each type of Childhood Cancer RISK FACTORS • Known • Genetic/congenital disorders • Age peak • Ethnics • Gender • Environmental • Suggestive • Family history • Reproductive factors • Environmental • Limited • Family History • Environmental

  17. Known RISK FACTORS Genetic risks factors associated with childhood cancer Familial neoplastic syndromes Based on Stiller CA. Oncogene, 2004, 23:6429–6444

  18. RISK FACTORS • Known Based on Stiller CA. Oncogene, 2004, 23:6429–6444

  19. RISK FACTORS • Known Age peak • Age at onset: • Age-related exposures • Some prenatal exposures (see: e) Environmental exposures) • Hormonal influences of adolescence • Age peak: • infancy: sympathetic nervous system tumors, rhabdomyosarcoma, Wilm’s tumor •  adolescent: malignant bone tumors, soft tissue sarcomas, renal cell carcinoma

  20. Ethnical differences: • incidence in Blacks: sympathetic nervous system cancers, Ewing sarcoma, ALL • incidence in Asians: renal tumors • incidence in Arabs: bilateral retinoblastoma   RISK FACTORS • Known Ethnics Average annual rate per million White Black Am. Indian API Hispanic Ethnicity Based on Ries LAG et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Am. Indian = American Indian/Native American API = Asian/Pacific Islander Hispanic = Hispanic of any race and overlaps other categories

  21. RISK FACTORS • Known Gender • Gender: • Exposures differing by gender • Effects of hormonal influences • Gender related genetic differences • Male / female ratio: •  males: Hodgkin’s and Non-Hodgkin’s lymphomas, ALL, ependymomas, primitive neuroectodermal tumours •  females: thyroid carcinoma, malignant melanoma WHO

  22. RISK FACTORS • Known Environmental exposures • Ionizing radiation: • Diagnostic x-ray in utero acute lymphoblastic leukaemia • Chernobyl radiation fallout thyroid cancer • Radiation therapy malignant bone tumours, leukaemia • Immunosuppressive therapy: Non-Hodgkin’s lymphoma • Treatment with diethylstilboestrol: adenocarcinoma of vagina • Infections: • HIV/AIDS  Kaposi’s sarcoma • Malaria and Epstein Barr virus  Burkitt’s lymphoma

  23. RISK FACTORS • Suggestive Maternal reproductive factors • Fetal loss, first born and age > 35 years: acute lymphoblastic leukaemia • Diet (cured meats): brain tumours • Preterm birth: germ cell tumours • Alcohol, tobacco: sympathetic nervous system tumours

  24. RISK FACTORS • Suggestive Environmental exposures • Parental smoking:neuroblastoma, acute lymphoblastic leukaemia, acute myeloid leukaemia • Residential pesticides: • Prenatal maternal & paternal exposures  brain, bone, kidney tumours, acute myeloid leukaemia, Hodgkin’s disease • Postnatal exposures  brain, bone, kidney tumours, acute myeloid leukaemia, Hodgkin’s disease WHO

  25. RISK FACTORS • Suggestive • Parental occupational exposures: • Agriculture  brain, CNS, renal tumours • Paint, solvents germ cell tumours, hepatic tumours, brain and CNS tumours, acute lymphoblastic leukaemia • Welder renal tumours, retinoblastoma • Petroleum  acute lymphoblastic leukaemia, brain and CNS tumours, hepatic tumours • Paper or pulp millbrain tumours • High fluoride exposure  osteosarcoma WHO

  26. Example: Acute Lymphoblastic Leukaemia RISK FACTORS Known • Genetic/congenital disorders: ataxia telangiectasia, Fanconi syndrome, Bloom syndrome, neurofibromatosis • Age peak: 2-4 years • Age-adjusted incidence: 26.3 per million • Race: W:B = 2.0 • Gender: M:F = 1.3 • Environmental: Ionizing Radiation (diagnostic-in utero, therapeutic-postnatal)

  27. Example: Acute Lymphoblastic Leukaemia RISK FACTORS • Suggestive • Reproductive factors: maternal fetal loss, mother older than 35 years at pregnancy, first born • Limited • Environmental: Paternal smoking before conception • Parental occupational exposures (hydrocarbons, paints, motor vehicle exhaust) • 60-Hz magnetic fields >0.4ųT • Postnatal chloramphenicol use • Other: Decreased risk associated with breastfeeding

  28. RISK FACTORS • Limited:Infection (hypothesis) • Areas of rapid population growth • Areas of increased population commuting • Influences of population war, disasters, tourism • Maternal infection in pregnancy • Immunization  or  risks • 6. Exposure to infection in infancy or early childhood - child care, spacing of siblings

  29. OVERVIEW • INCIDENCE AND TYPES OF CHILDHOOD CANCER • CAUSES, RISK FACTORS AND HYPOTHESES • BIOLOGICAL PROCESSES LEADING TO CANCER DEVELOPMENT • EXPOSURE ASSESSMENT AND ITS CHALLENGES • INVESTIGATING POTENTIAL CANCER CLUSTERS • 6. QUESTIONS FROM PARENTS

  30. BIOLOGIC PROCESS: CARCINOGENESIS INITIATION PROMOTION PROGRESSION Cytotoxic/mutagenic DNA damage induction in some cells DNA damage is fixed as a mutation Mutated cell transforms Clonal expansion leads to cancer DNA repair or cell death mechanisms (eliminate damaged cells) Based on James MA and Travis LB. Nature Reviews Cancer, 2005, 5:943-955

  31. BIOLOGIC PROCESS: DNA DAMAGE (mutation: change coding sequence) Chemicals Viruses Heredity Radiation (double stranded DNA breaks) Based on National Cancer Institute pictures

  32. when activated: transforms normal to cancer cells when inactivated: disregulation of normal cells CANCER GENES Based on National Cancer Institute pictures

  33. BIOMARKERS AND OTHER MARKERS • Biomarkers: indicators that measure a physiological, biochemical, or pharmacological event. • Diagnostic (screening) biomarker:for diagnosis and classification • i.e. Bence–Jones protein in urine  indicator of multiple myeloma • Prognostic biomarker:forrefining staging • Stratification (predictive) biomarker:forpredicting or monitoring response to treatment • Circulatingtumour markers for cancer testing and noninvasive prenatal diagnosis: • nucleic acids : detection of gene mutations, chromosomal rearrangements, microsatellite alterations, viral sequences, gene promoter hypermethylation and changes in microarray-generated profiles (genetic signatures) • hormones, enzymes, glycoproteins, oncofoetal antigens and receptors

  34. Proteomics: promising for the analysis of biological fluids and biomarker identification. • Fetal-derived epigenetic markers in maternal plasma: differences between the maternal and the fetal DNA. • Ideal factors for a serological tumour biomarker: • Produced by the tumour cells and can also enter the circulation • Present at low levels in the serum of healthy individuals and those with benign disease but increases substantially in cancer (preferably in one cancer type only) • Easily quantifiable with an inexpensive assay • Present in detectable (or higher than normal) quantities at early or preclinical stages • Quantitative levels of the tumour marker reflect the tumour burden • High diagnostic sensitivity (few false negatives) and specificity (few false positives)

  35. Selected candidate biomarkers identified by DNA microarray analysis Cancer biomarkers that are currently in clinical use Based on Kulasingam V. Nature Clinical Practice Oncology, 2008,5:588-599 Based on Pollack JR. Am J Pathol, 2007, 171:375–385 D, diagnosis; P, prognosis. FISH, fluorescence in situ hybridization; Q-RT-PCR, quantitative RT-PCR; RISH, RNA in situ hybridization.

  36. BIOMARKERS • exposure • early effects • mechanisms Human biological fluids: a source for biomarker discovery Biomarkers help link environmental exposures to disease outcomes: Based on Kulasingam V. Nature Clinical Practice Oncology, 2008,5:588-599 ENVIRONMENTAL EXPOSURES: chemicals radiations viruses DISEASE OUTCOMES Cancer (Leukaemia)

  37. OVERVIEW • INCIDENCE AND TYPES OF CHILDHOOD CANCER • CAUSES, RISK FACTORS AND HYPOTHESES • BIOLOGICAL PROCESSES LEADING TO CANCER DEVELOPMENT • EXPOSURE ASSESSMENT AND ITS CHALLENGES • INVESTIGATING POTENTIAL CANCER CLUSTERS • 6. QUESTIONS FROM PARENTS

  38. EXPOSURE ASSESSMENT Objective: obtaining measurements  quantifying effects • Environmental • Occupational • Biological

  39. EXPOSURE ASSESSMENT Approaches • Questionnaire data • Laboratory measurement • Environmental • Biological • Molecular genetic evidence

  40. EXPOSURE ASSESSMENT Challenges • Relevant past exposures • Recall variation in affected vs. healthy • Varying levels of exposures • Relation with growth, development, behaviour

  41. OVERVIEW • INCIDENCE AND TYPES OF CHILDHOOD CANCER • CAUSES, RISK FACTORS AND HYPOTHESES • BIOLOGICAL PROCESSES LEADING TO CANCER DEVELOPMENT • EXPOSURE ASSESSMENT AND ITS CHALLENGES • INVESTIGATING POTENTIAL CANCER CLUSTERS • 6. QUESTIONS FROM PARENTS

  42. CHILDHOOD CANCER CLUSTERS • Cluster definition: notable aggregations of cases in • Geographic proximity • Similar temporal onset seemingly statistically higher incidence than expected

  43. CHILDHOOD CANCER CLUSTERS • Residential/school proximity • Manufacturing facilities/waste sites • Underground storage tanks • Environmental/industrial accidents

  44. CHILDHOOD CANCER CLUSTERS Analysis of clusters • Define the minimum number of cases (rare disease small number of cases) • Type of cluster: • Transient: occurring in given period and disappearing • Prolonged: persisting, new cases developing • Define: • Homogeneous/heterogeneous types of cancer • Designate temporal and geographic boundaries (latency periods may be long)

  45. CHILDHOOD CANCER CLUSTERS Reporting cancer clusters • Logical time sequence (i.e. cause preceded effect) • Specificity of effect (i.e. same type of cancer) • Dose-response relationship • Biologic plausibility • Consistency with other observations • Exclusion of concomitant variables • 7. Disappearance of effect when cause removed

  46. Chernobyl childhood thyroid cluster CHILDHOOD CANCER CLUSTERS April 26, 1986 - nuclear reactor 4 releases1311 • Incidence thyroid cancer in Belarus (0-15 yrs age) • Total numbers reported • Mainly papillary thyroid cancer (aggressive)

  47. OVERVIEW • INCIDENCE AND TYPES OF CHILDHOOD CANCER • CAUSES, RISK FACTORS AND HYPOTHESES • BIOLOGICAL PROCESSES LEADING TO CANCER DEVELOPMENT • EXPOSURE ASSESSMENT AND ITS CHALLENGES • INVESTIGATING POTENTIAL CANCER CLUSTERS • 6. QUESTIONS FROM PARENTS

  48. PREVENTION • 1. Avoid smoking/SHTS, chewing tobacco • 2. Sun protection • Diet •  fibre  fat •  salt / smoke, cured food •  carotenoids •  aflatoxins • 4. Test for radon, asbestos (mitigate risks)

  49. EARLY CHILDHOOD EXPOSURES Predisposing to adult cancer • Ionising radiation breast cancer, ALL, thyroid cancer • Radiotherapy for Hodgkin’s disease  osteosarcoma, leukaemia, skin cancer, breast cancer, soft tissue sarcoma • UV sunlight  melanoma, basal and squamous cell carcinomas • Tobacco • Asbestos • Diet - fats and aflatoxins  cancer colon, breast, and Liver

  50. We hold our future in our handsand it is our children. Poster Contest by HRIDAY with support from WHO SEARO

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