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 Department of Epidemiology


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 Welch Center for Prevention, Epidemiology, and Clinical Research


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Dose-response relationships between
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alcohol, nasopharyngeal cancer and

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          other endpoints

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                  Eliseo Guallar, MD, DrPH
                     eguallar@jhsph.edu

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                   Presenter’s Name




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http://basicpathology-histopathology.blogspot.com/2009/11/pharynx-anatomy-and-physiology.html
Nasopharyngeal carcinoma -
Pathology

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Nasopharyngeal cancer usually arise from the

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epithelial cells lining the nasopharynx

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3 histological types

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  Type 1: Keratinizing squamous cell carcinoma

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  (differentiated carcinoma)

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  Type 2: Non-keratinizing carcinoma

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  Type 3: Undifferentiated carcinoma


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Types 2 and 3 are:

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  The major forms in high-risk regions

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  Associated with high Epstein-Barr virus titers
Type 1 identified in 1/3 to 1/2 of cases in low-
risk areas
Nasopharyngeal carcinoma –
Epidemiology (I)

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Rare in most regions

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  Worldwide incidence <1 per 100,000 person-years


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  Incidence in US

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     White men: 0.5 per 100,000 person-years

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     White women: 0.2 per 100,000 person-years


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  23rd most common cancer
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High incidence rates in specific regions

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Populations at increased risk of
nasopharyngeal carcinoma

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Yu MC and Yuan J-M. Semin Cancer Biol 2002:12:421-9
China provinces with high incidence
of nasopharyngeal carcinoma

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Yu MC and Yuan J-M. Semin Cancer Biol 2002:12:421-9
Nasopharyngeal carcinoma –
Epidemiology (II)

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Male:Female ratio 2-3:1


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Age distribution

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  Low risk populations: monotonic with age

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  High risk populations: with age until 45-54

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  years of age, then with age at older ages


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  In some low to moderate risk populations: minor
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  peak in incidence between ages 15-24

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In high-risk areas, low socio-economic status

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is associated with incidence
     Time trends in incidence rates
     of nasopharyngeal carcinoma

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Age-standardized (world population) incidence rates per 100,000 person-years



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      Yu MC and Yuan J-M. Semin Cancer Biol 2002:12:421-9
Nasopharyngeal carcinoma -
Etiology

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Epstein-Barr virus infection

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Environmental factors

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   Cantonese-style salted fish


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   Preserved foods


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   Reduced intake of fresh fruits and vegetables


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   Smoking
   Occupational exposures (formaldehyde, wood dusts)


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Genetic factors

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   HLA alleles


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   Cytochrome P450


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   Glutathion S-transferase
   Polymeric immunoglobulin receptor
Family history
Causal model for endemic
(types 2 and 3) NPC

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Chang L and Adami H-O. Cancer Epidemiol Biomarkers Prev 2006;15:1765-77
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Chen L, et al. Nutr Cancer 2009;6:1-15
Search strategy


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 Electronic search of 14 non-Chinese databases,

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 including PubMed, Embase, and the Cochrane

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 Library

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 Electronic search of the Chinese Biomedical

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 Literature Database System (in Chinese)

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 Hand search of the references cited in the 1997


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          Presenter’s the
 WCRF report, in Name articles chosen for data
 abstraction, and in relevant review articles or meta-

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 analyses identified in the PubMed
 No language restrictions
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 3,225 potentially relevant unique articles published
 by April 2006 were identified
Chen L, et al. Nutr Cancer 2009;6:1-15
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Data extraction for alcohol
intake

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 We extracted data on total alcohol intake and
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 on beer, wine, spirits, and other alcohol drinks

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 We collected all quantitative information

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 reported on:

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      Alcohol intake


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           Presenter’s assessment
      Type of dose Name


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      Duration of alcohol drinking
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 Doses of alcohol converted to number of

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 drinks per week
      1 drink = 13.7 g of ethanol

Chen L, et al. Nutr Cancer 2009;6:1-15
Studies selected


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 14 studies were included in the meta-analysis

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      11 studies had data on total alcohol intake and


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      NPC risk


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 Geographic location

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      8 studies conducted among Chinese in Asian

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      countries or regions (3 mainland China, 2 Taiwan,


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            Presenter’s Singapore)
      2 Malaysia, 1 Name


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      5 studies conducted in the US
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      1 study conducted among Thai in Thailand


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 All studies used a case-control design
      9 pouplation-based controls
      5 hospital-based controls
Chen L, et al. Nutr Cancer 2009;6:1-15
Measurement of alcohol intake


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 6 studies measured alcohol as a
 dichotomous variable (yes/no)
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 6 studies measured reported alcohol

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 consumption in 3 or more categories

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 2 studies reported duration of alcohol intake

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 in yearsPresenter’s Name

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 1 study reported lifetime cumulative alcohol

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 consumption (g·yr)

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Chen L, et al. Nutr Cancer 2009;6:1-15
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Chen L, et al. Nutr Cancer 2009;6:1-15
Meta-regression analysis


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 Studies controlling for smoking
      Yes:
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      No:             OR = 1.47 (95% CI = 1.02–2.12)


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 Study population

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      Chinese: OR = 1.21 (95% CI = 0.98–1.62)


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                  OR = 1.50 (95% CI = 1.08–2.10)
      US: Presenter’s Name


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 NumberDate categories of reported alcohol
        of

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 intake

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      2:              OR = 1.15 (95% CI = 0.82–1.62)
      ≥3:             OR = 1.45 (95% CI = 1.12–1.87)

Chen L, et al. Nutr Cancer 2009;6:1-15
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Chen L, et al. Nutr Cancer 2009;6:1-15
Quadratic dose-response trend


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 Present in the 6 studies reporting dose-

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 response data

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 P value for quadratic term = 0.005

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 The risk of nasopharyngeal carcinoma

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 decreased up to 15 drinks/week and

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         Presenter’s Name
 increased at higher intakes

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      OR comparing 15 to 0 drinks/week = 0.82

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      OR comparing 30 to 0 drinks/week = 1.12

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Chen L, et al. Nutr Cancer 2009;6:1-15
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Chen L, et al. Nutr Cancer 2009;6:1-15
Limitations of meta-analysis


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 Case-control design of included studies
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 Limited quality of included studies
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 Limited adjusting for major potential

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 confounders

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      Epstein Barr virus infection, salted fish, smoking


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 Limitation in collecting alcohol intake

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 Publication bias

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      4 studies reporting non-significant associations

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      but without quantitative information were
      excluded

Chen L, et al. Nutr Cancer 2009;6:1-15
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Risk of NPG by alcohol consumption
– Singapore Chinese Health Study
1993 – 2005

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Friborg JT, et al. Cancer 2007;109:1183-91
Dose-response meta-analysis for
15 alcohol-related conditions

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 Corrao G, et al. Prev Med 2004;38:613-9
Dose-response meta-analysis for
alcohol and coronary heart disease

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   Corrao G, et al. Prev Med 2004;38:613-9
Biological plausibility for an
risk of cancer with alcohol

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Acetaldehyde

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  Oxidation product of ethanol


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  Toxic, carcinogenic, mutagenic

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  Interferes DNA synthesis and repair

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Induction of cytochrome P450 (CYP2E1)

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activity in mucosal cells

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SolventDate penetration of other carcinogens
Production of ROS and RNS
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Vitamin and trace element deficiencies
  Folate, iron, zinc, vitamin A
Genetic susceptibility factors
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Biological plausibility for a
risk of cancer with alcohol

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Conclusion


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Possible J-shaped dose response

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relationship between alcohol and NPC

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Large, high-quality studies needed to

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confirm the relationship

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Mechanism for inverse association at low

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alcohol doses unclear

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