Patricia A. McKinney

Diet and upper-aerodigestive tract cancer in Europe: The ARCAGE study

There is suggestive, but inconclusive, evidence that dietary factors may affect risk of cancers of the upper aerodigestive tract (UADT). In the context of the alcohol‐related cancers and genetic susceptibility in Europe study, we have examined the association of dietary factors with UADT cancer risk. We have analyzed data from 2,304 patients with UADT cancer and 2,227 control subjects recruited in 14 centers in 10 European countries. Dietary data were collected through a semi‐quantitative food frequency questionnaire that also assessed preferred temperature of hot beverages. Statistical analyses were conducted through multiple logistic regression controlling for potential confounding variables, including alcohol intake and smoking habits. Consumption of red meat (OR per increasing tertile = 1.14, 95% CI: 1.05–1.25), but not poultry, was significantly associated with increased UADT cancer risk and the association was somewhat stronger for esophageal cancer. Consumption of fruits (OR per increasing tertile = 0.68, 95% CI: 0.62–0.75) and vegetables (OR per increasing tertile = 0.73, 95% CI: 0.66–0.81) as well as of olive oil (OR for above versus below median = 0.78, 95% CI 0.67–0.90) and tea (OR for above versus below median = 0.83, 95% CI 0.69–0.98) were significantly associated with reduced risk of UADT cancer. There was no indication that an increase in tea or coffee temperature was associated with increased risk of UADT overall or cancer of the esophagus; in fact, the association was, if anything, inverse. In conclusion, the results of this large multicentric study indicate that diet plays an important role in the etiology of UADT cancer.

Socioeconomic factors associated with risk of upper aerodigestive tract cancer in Europe.

INTRODUCTIONnIn the European Union, there are 180,000 new cases of upper aerodigestive tract (UADT) cancer cases per year--more than half of whom will die of the disease. Socioeconomic inequalities in UADT cancer incidence are recognised across Europe. We aimed to assess the components of socioeconomic risk both independently and through their influence on the known behavioural risk factors of smoking, alcohol consumption and diet.nnnPATIENTS AND METHODSnA multicentre case-control study with 2198 cases of UADT cancer and 2141 controls from hospital and population sources was undertaken involving 14 centres from 10 countries. Personal interviews collected information on demographics, lifetime occupation history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using unconditional logistic regression.nnnRESULTSnWhen controlling for age, sex and centre significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR=1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators--comparing the lowest versus highest International Socio-Economic Index (ISEI) quartile for the longest occupation gave OR=1.60 (1.28, 2.00); and for unemployment OR=1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR=1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries. Associations were broadly consistent for subsite and source of controls (hospital and community).nnnCONCLUSIONnSocioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet.

Spatial clustering of childhood leukaemia: summary results from the EUROCLUS project.

The interpretation of reports of clusters of childhood leukaemia is difficult, first because little is known about the causes of the disease, and second because there is insufficient information on whether cases show a generalized tendency to cluster geographically. The EUROCLUS project is a European collaborative study whose primary objective is to determine whether the residence locations of cases at diagnosis show a general tendency towards spatial clustering. The second objective is to interpret any patterns observed and, in particular, to see if clustering can be explained in terms of either infectious agents or environmental hazards as aetiological agents. The spatial distribution of 13351 cases of childhood leukaemia diagnosed in 17 countries between 1980 and 1989 has been analysed using the Potthoff-Whittinghill method. The overall results show statistically significant evidence of clustering of total childhood leukaemia within small census areas (P=0.03) but the magnitude of the clustering is small (extra-Poisson component of variance (%) = 1.7 with 90% confidence interval 0.2-3.1). The clustering is most marked in areas that have intermediate population density (150-499 persons km[-2]). It cannot be attributed to any specific age group at diagnosis or cell type and involves spatial aggregation of cases of different ages and cell types. The results indicate that intense clusters are a rare phenomenon that merit careful investigation, although aetiological insights are more likely to come from investigation of large numbers of cases. We present a method for detecting clustering that is simple and readily available to cancer registries and similar groups.

Spatial temporal patterns in childhood leukaemia: Further evidence for an infectious origin

The EUROCLUS project included information on residence at diagnosis for 13351 cases of childhood leukaemia diagnosed in the period 1980-89 in defined geographical regions in 17 countries. A formal algorithm permits identification of small census areas as containing case excesses. The present analysis examines spatial-temporal patterns of the cases (n = 970) within these clustered areas. The objectives were, first, to compare these results with those from an analysis conducted for UK data for the period 1966-83, and, second, to extend them to consider infant leukaemias. A modification of the Knox test investigates, within the small areas, temporal overlap between cases in a subgroup of interest at a putative critical time and all other cases at any time between birth and diagnosis. Critical times were specified in advance as follows: for cases of acute lymphoblastic leukaemia aged 2-4 years, the 18-month period preceding diagnosis; for cases of total leukaemia aged 5-14 years, 1 year before to 1 year after birth; and for infant cases (diagnosed < 1 year), 1 year before to 6 months after birth. Each of the analyses found evidence of excess space-time overlap compared with that expected; these were 10% (P = 0.005), 15% (P= 0.0002) and 26% (P= 0.03) respectively. The results are interpreted in terms of an infectious origin of childhood leukaemia.

Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection.

Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.

Vitamin K and childhood cancer: analysis of individual patient data from six case–control studies

To investigate the hypothesis that neonates who receive intramuscular vitamin K are at an increased risk of developing cancer, particularly leukaemia, a pooled analysis of individual patient data from six case–control studies conducted in Great Britain and Germany has been undertaken. Subjects comprised 2431 case children diagnosed with cancer before 15 years of age and 6338 control children. The retrospective assessment of whether or not an individual baby received vitamin K is not straightforward. In many cases no record was found in stored medical notes and two types of analysis were therefore conducted; in the first it was assumed that where no written record of vitamin K was found it had not been given, and in the second, where no written record of administration was found, information on hospital policy and perinatal morbidity was used to ‘impute’ whether or not vitamin K had been given. In the first analysis, no association was found between neonatal administration of intramuscular. vitamin K and childhood cancer: odds ratios adjusted for mode of delivery, admission to special care baby unit and low birth weight were 1.09 (95% confidence interval 0.92–1.28) for leukaemia and 1.05 (0.92–1.20) for other cancers. In the second analysis, the adjusted odds ratios increased to 1.21 (1.02–1.44) for leukaemia and 1.10 (0.95–1.26) for other cancers. This shift did not occur in all studies, and when data from the hypothesis generating Bristol study were excluded, the adjusted odds ratios for leukaemia became 1.06 (0.89–1.25) in the first analysis and 1.16 (0.97–1.39) when data on prophylaxis imputed from hospital policy and perinatal morbidity were used. We conclude that whilst the broad nature of the diagnostic groups and the poor quality of some of the vitamin K data mean that small effects cannot be entirely ruled out, our analysis provides no convincing evidence that intramuscular vitamin K is associated with childhood leukaemia.

Active and involuntary tobacco smoking and upper aerodigestive tract cancer risks in a multicenter case-control study.

Introduction: Several important issues for the established association between tobacco smoking and upper aerodigestive tract (UADT) cancer risks include the associations with smoking by cancer subsite, by type of tobacco, and among never alcohol drinkers and the associations with involuntary smoking among nonsmokers. Our aim was to examine these specific issues in a large-scale case-control study in Europe. Methods: Analysis was done on 2,103 UADT squamous cell carcinoma cases and 2,221 controls in the Alcohol-Related Cancers and Genetic Susceptibility in Europe project, a multicenter case-control study in 10 European countries. Unconditional logistic regression was done to obtain odds ratios (OR) and 95% confidence intervals (95% CI). Results: Compared with never tobacco smoking, current smoking was associated with UADT cancer risks (OR, 6.72; 95% CI, 5.45-8.30 for overall; OR, 5.83; 95% CI, 4.50-7.54 for oral cavity and oropharynx; OR, 12.19; 95% CI, 8.29-17.92 for hypopharynx and larynx; and OR, 4.17; 95% CI, 2.45-7.10 for esophagus). Among never drinkers, dose-response relationships with tobacco smoking pack-years were observed for hypopharyngeal and laryngeal cancers (Ptrend = 0.010) but not for oral cavity and oropharyngeal cancers (Ptrend = 0.282). Among never smokers, ever exposure to involuntary smoking was associated with an increased risk of UADT cancers (OR, 1.60; 95% CI, 1.04-2.46). Conclusion: Our results corroborate that tobacco smoking may play a stronger role in the development of hypopharyngeal and laryngeal cancers than that of oral cavity and oropharyngeal cancers among never drinkers and that involuntary smoking is an important risk factor for UADT cancers. Public health interventions to reduce involuntary smoking exposure could help reduce UADT cancer incidence. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3353–61)

Population density and childhood leukaemia: results of the EUROCLUS study

The EUROCLUS study assembled incidence data for 13,551 cases of childhood leukaemia (CL) diagnosed between 1980 and 1989 in 17 countries (or regions of countries). These were referenced by location at diagnosis to small census areas of which there were 25,723 in the study area. Population counts, surface area and, hence, population density were available for all these small areas. Previous analyses have shown limited extra-Poisson variation (EPV) of case counts within small areas; this is most pronounced in areas of intermediate population density (150-499 persons/km2). In this study, the data set was examined in more detail for evidence that variations in incidence and EPV of CL are associated with population density. Incidence showed a curvilinear association with population density and was highest in areas which were somewhat more densely populated (500-750 persons/km2), where the incidence rate ratio relative to areas having > or = 1000 persons/km2 was 1.16 (95% confidence interval 1.07-1.26) and the P value for quadratic trend across eight strata of population density was 0.02. Incidence in these areas is uniformly elevated and showed no evidence of heterogeneity (i.e. EPV). Statistically significant evidence of EPV was evident amongst some of the areas previously classified as intermediate density areas (specifically, those with a density of 250-499 persons/km2, P < 0.001 for CL). These results were interpreted in terms of the current aetiological hypotheses for CL which propose that exposure to localised epidemics of one or more common infectious agent may contribute to the development of leukaemia. They suggest that such epidemics arise regularly in moderately densely populated areas and also sporadically in areas which are somewhat less densely populated. Although other interpretations are possible, these results may assist in the identification of characteristics which infectious agents must possess if direct or indirect causes of CL.

Occupational exposure to electromagnetic fields and acute leukaemia: analysis of a case-control study

Aims: To investigate whether the risk of acute leukaemia among adults is associated with occupational exposure to electromagnetic fields. Methods: Probable occupational exposure to electromagnetic fields at higher than typical residential levels was investigated among 764 patients diagnosed with acute leukaemia during 1991–96 and 1510 sex and age matched controls. A job exposure matrix was applied to the self reported employment histories to determine whether or not a subject was exposed to electromagnetic fields. Risks were assessed using conditional logistic regression for a matched analysis. Results: Study subjects considered probably ever exposed to electromagnetic fields at work were not at increased risk of acute leukaemia compared to those considered never exposed. Generally, no associations were observed on stratification by sex, leukaemia subtype, number of years since exposure stopped, or occupation; there was no evidence of a dose-response effect using increasing number of years exposed. However, relative to women considered never exposed, a significant excess of acute lymphoblastic leukaemia was observed among women probably exposed to electromagnetic fields at work that remained increased irrespective of time prior to diagnosis or job ever held. Conclusion: This large population based case-control study found little evidence to support an association between occupational exposure to electromagnetic fields and acute leukaemia. While an excess of acute lymphoblastic leukaemia among women was observed, it is unlikely that occupational exposure to electromagnetic fields was responsible, given that increased risks remained during periods when exposure above background levels was improbable.

Smoking addiction and the risk of upper-aerodigestive-tract cancer in a multicenter case-control study

Although previous studies on tobacco and alcohol and the risk of upper‐aerodigestive‐tract (UADT) cancers have clearly shown dose‐response relations with the frequency and duration of tobacco and alcohol, studies on addiction to tobacco smoking itself as a risk factor for UADT cancer have not been published, to our knowledge. The aim of this report is to assess whether smoking addiction is an independent risk factor or a refinement to smoking variables (intensity and duration) for UADT squamous cell carcinoma (SCC) risk in the multicenter case–control study (ARCAGE) in Western Europe. The analyses included 1,586 ever smoking UADT SCC cases and 1,260 ever smoking controls. Addiction was measured by a modified Fagerström score (first cigarette after waking up, difficulty refraining from smoking in places where it is forbidden and cigarettes per day). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for UADT cancers with addiction variables were estimated with unconditional logistic regression. Among current smokers, the participants who smoked their first cigarette within 5 min of waking up were two times more likely to develop UADT SCC than those who smoked 60 min after waking up. Greater tobacco smoking addiction was associated with an increased risk of UADT SCC among current smokers (ORu2009=u20093.83, 95% CI: 2.56–5.73 for score of 3–7 vs. 0) but not among former smokers. These results may be consistent with a residual effect of smoking that was not captured by the questionnaire responses (smoking intensity and smoking duration) alone, suggesting addiction a refinement to smoking variables.