F. Sturmans

A large-scale prospective cohort study on diet and cancer in the Netherlands

In 1986, a prospective cohort study on diet and cancer was started in The Netherlands. The cohort (n = 120, 852) of 55-69 year old men (48.2%) and women (51.8%) originates from 204 computerized municipal population registries. At baseline, participants completed a self-administered questionnaire on diet and potential confounding variables. In addition, about 67% of the participants provided toenail clippings. Cancer follow-up consists of record linkage to a pathology registry and to cancer registries. The initial interest is in stomach, colorectal, breast and lung tumors. A case-cohort approach is applied, in which detailed follow-up information of a random subcohort (n = 5000) provides an estimate of the person-time experience of the cohort. Exposure data of the subcohort will be combined with those of incident cases, yielding exposure-specific incidence rate ratios. The intraindividual variation in determinants is estimated by annually repeated measurements (n = 250) within the subcohort. The rationale, efficiency aspects and study characteristics are discussed.

Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study

Association between breast cancer risk and the intake of vitamins C and E, retinol, beta (beta)-carotene, dietary fibre, vegetables, fruit and potatoes was examined in The Netherlands Cohort Study, for 62,573 women aged 55-69 years. After 4.3 years of follow-up, 650 incident breast cancer cases were identified. After adjusting for traditional risk factors, breast cancer risk was not influenced by the intake of beta-carotene, vitamin E, dietary fibre, supplements with vitamin C, vegetables or potatoes. Fruit consumption showed a non-significant inverse association with breast cancer risk (RR highest/lowest quintile = 0.76, 95% CI 0.54-1.08). A small reduction in risk was also observed with increasing intake of dietary vitamin C (RR highest/lowest quintile = 0.77, 95% CI 0.55-1.08). For retinol, a weak positive association was observed (RR highest/lowest quintile = 1.24, 95% CI 0.83-1.83). Among subjects with a high intake of polyunsaturated fatty acids (PUFAs), both beta-carotene and vitamin C intake showed a non-significant inverse association with breast cancer risk (P-trend = 0.15 and 0.16 respectively). Our findings do not suggest a strong role, if any, for intake of vitamins C and E, beta-carotene, retinol, dietary fibre, vegetables, fruit and potatoes in the aetiology of breast cancer.

Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on diet and cancer

AbstractObjective: The purpose was to study the association between vegetable and fruit consumption and lung cancer incidence using 1074 cases after 6.3 years of follow-up in the Netherlands Cohort Study. Methods: Dietary intake was assessed using a 150-item food-frequency questionnaire. Multivariate models were used including age, sex, family history of lung cancer, highest educational level attained, and smoking history. Results: Statistically significant inverse associations were found with total vegetables and most vegetable groups. Rate ratios (RRs) based on consumption frequency showed the strongest effect of vegetables from the Brassica group (RR 0.5, 95% confidence interval (95% CI) 0.3–0.9, for consumption ≥3 times per week versus ≤ once a month). RR of highest versus lowest quintile of total vegetable consumption was 0.7 (95% CI 0.5–1.0, p-trend 0.001). Statistically significant inverse associations were found for all fruits listed in the questionnaire. RRs for quintiles of total fruit intake were 1.0, 0.7, 0.6, 0.6 and 0.8 respectively (p-trend < 0.0001). Protective effects of fruits and vegetables were stronger in current than in former smokers, and weaker for adenocarcinomas than for other types of tumors. Conclusions: Inverse associations with lung cancer are found for both vegetable and fruit intake, but no specific type of vegetable or fruit seems to be particularly responsible.

Garlic and its significance for the prevention of cancer in humans : a critical view

Recently published results of epidemiologic case-control studies in China and Italy on gastric carcinoma in relation to diet suggest that consuming garlic may reduce the risk of gastric cancer. Chemical constituents of garlic have been tested for their inhibiting effect on carcinogenesis, using in vitro and in vivo models. In most experiments inhibition of tumour growth was established using fresh garlic extract, garlic compounds or synthetically prepared analogs. In this review the strengths and weaknesses of the experiments are discussed and the outcomes are evaluated to assess the possible significance of garlic or garlic compounds for the prevention of cancer in humans. It is concluded that evidence from laboratory experiments and epidemiologic studies is presently not conclusive as to the preventive activity of garlic. However, the available evidence warrants further research into the possible role of garlic in the prevention of cancer in humans.

Interobserver variation in histopathological grading of cervical dysplasia

In order to assess the variability among histopathologists in grading cervical dysplasia, four experienced histopathologists examined the same set of 106 biopsy specimens and assigned them to one of five diagnostic categories. These were: no dysplasia, mild dysplasia, moderate dysplasia, severe dysplasia and carcinoma in situ. The histopathologists did not discuss the grading criteria beforehand. There was considerable disagreement among the pathologists: unweighted group kappa 0.28, weighted group kappa 0.56. It appeared that all grades of dysplasia were equally difficult to distinguish from adjacent categories. Various explanations for this interobserver variation are put forward.

Current use of thiazide diuretics and prevention of femur fractures.

A case control study of a defined population from The Netherlands was performed to evaluate the risk of femur fractures associated with the use of thiazide diuretics. Included were 386 patients hospitalized for femur fractures between 1986 and 1990 who were residents and 45 years of age and older. Per case, one age-, sex-, pharmacy-, and general practitioner-matched control was chosen from the general population. Drug use was ascertained from computerized pharmacy records. The adjusted odds ratio of current use of thiazide diuretics was 0.5 (95% confidence interval, 0.3-0.9). The protective effect of thiazide diuretics was greatest for use of 1 year or longer at relatively high doses of thiazides (odds ratio, 0.3; 95% confidence interval, 0.1-0.9). We also found that patients who discontinued thiazide use longer than 2 months were not protected against femur fractures. These results support the hypothesis that use of thiazide diuretics protects against femur fractures.

Prospective study on alcohol consumption and the risk of cancer of the colon and rectum in the Netherlands.

The association between alcohol consumption and cancer of the colon and rectum was investigated in a prospective cohort study, conducted in the Netherlands from 1986 onwards among 120,852 men and women, aged 55 to 69 years. During 3.3 years of follow-up, 312 and 166 cases of colon and rectal cancer had accumulated, respectively. After exclusion of cases diagnosed in the first year of follow-up the analysis was based on 217 incident cases of colon cancer (107 men and 110 women) and 113 cases of rectal cancer (75 men and 38 women). For colon cancer, no association with total intake of alcohol nor with the consumption of beer and wine, specifically, could be demonstrated; for liquor intake, a significant (P=0.04) decreasing risk with increasing consumption was observed. For rectal cancer in men, positive trends were observed for total alcohol intake (P=0.04), beer (P=0.05), and liquor (P=0.06). Results for rectal cancer in women were consistent with those in men, but data were too sparse to provide stable estimates. Simultaneous adjustment for beverage type and quantity appeared to strengthen the association of rectal cancer with drinking beer (relative rate (yes/no)=2.0, 95 percent confidence interval=1.1–3.9), although, a dose-response effect was not observed. When alcohol intake from beer, wine, and liquor were included as continuous variables, the association was somewhat stronger for liquor than for beer, but none of the associations were statistically significant. It is concluded that consumption of alcoholic beverages (beer, in particular) is associated with an increased risk for rectal but not colon cancer.

The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment.

In order to gain insight into the causality of the relation between beta-carotene and cancer, we performed a randomized placebo-controlled trial in which the effect of beta-carotene on the regression and progression rates of cervical dysplasia were examined. The experimental group (n = 137) received a supplemental dose of 10 mg of beta-carotene daily for 3 months. The control group (n = 141) received placebo capsules. As the outcome parameter, two definitions of regression and progression were used, which were based on the degree of dysplasia before and after the medication period. The number of patients who showed progression was too small to allow conclusions. No effect of beta-carotene on the regression percentages was observed: OR = 0.68 (95% CI: 0.28-1.60) using the broad definition; and OR = 1.22 (95% CI: 0.43-3.41) with the strict definition. A secondary analysis, in which the effect of the total intake of beta-carotene (diet + medication) on the regression percentages of cervical dysplasia was studied, did not show a positive effect either. The paper discusses to what extent issues in the study design may have masked a potential effect and how our results affect the evidence for a causal relation between beta-carotene and cancer.

Sources of interobserver variation in histopathological grading of cervical dysplasia

The present study aimed to assess where the interobserver variation in grading cervical dysplasia stems from. Four experienced pathologists examined 93 histological slides, after they agreed on which morphological characteristics should be considered relevant for grading. They scored 6 morphological characteristics for each slide and assigned it to a degree of dysplasia. Compared to a previous study, the interobserver variation showed a statistically significant improvement: the weighted group kappa value increased from 0.55 to 0.69. For the scores of the individual characteristics considerable interobserver variation was observed: weighted group kappa values ranged from 0.28 to 0.49. The pathologists slightly differed in which characteristics they considered most important for their grading. The agreement on the degree of dysplasia turned out to be better than the agreement on the morphological characteristics on which this diagnosis is based. In the discussion, a few explanations for this paradoxical finding are put forward.

Indications and requirements for the use of prerandomization

BACKGROUND AND OBJECTIVE Although in effectiveness studies, the conventional randomized trial, in which informed consent is obtained before randomization, is the first choice, this design is not the panacea for all research questions. To counter contamination problems, prerandomization designs might be an alternative. Prerandomization implies that the randomization takes place before seeking informed consent, and because of this, prerandomization designs are controversial among ethicists, health lawyers, methodologists, and clinicians. However, in the Netherlands, these designs are becoming more accepted since the Dutch State Secretary of Health, Welfare and Sport decided that, under certain circumstances, prerandomization is admissible and not in conflict with the law. RESULTS Based on well-defined indications and requirements, guidelines for the optimal application of prerandomization designs are presented. Designs in which prerandomization is used are outlined; methodological considerations useful when conducting trials using conventional designs or prerandomization designs are discussed, in addition to ethical and judicial aspects. CONCLUSION In certain situations, prerandomization designs have an essential contribution to achieve evidence-based medicine. Banning prerandomization a priori implies that information about the effectiveness of numerous public health and medical interventions will not be forthcoming. Therefore, every design should be based on a balance between maximizing the potential for patient autonomy and minimizing the bias caused by contamination. This balance cannot be reached by formulating general rules, but an independent group of experts, like members of research ethics committee (REC), should decide whether this balance is acceptable.