In this nested case-control study, we carefully controlled for cigarette smoking in the study design to investigate the association between cruciferous vegetable intake and lung cancer risk. Overall, we observed statistically significant inverse associations between higher intake of cruciferous vegetable food intake and lung cancer risk, independent of sex. Similar significant inverse associations were observed for former and current smokers, but not never smokers.
In the present study, we report a 43% lower risk of lung cancer comparing highest-versus-lowest category of cruciferous vegetable food intake. We previously reported the results of a systematic review of the evidence on cruciferous vegetable intake and lung cancer from both cohort and case-control studies, which showed a pooled relative risk of 0.83 (95% CI: 0.62–1.08) for cohort studies (11
). Inclusion of the results from the present study to previous cohort studies showed a pooled relative risk of 0.79 (highest-versus-lowest category: 95% CI: 0.61–1.01). 11 Taken together, the epidemiologic evidence suggests that cruciferous vegetable intake may be inversely associated with lung cancer risk. The results of our study add to this evidence by indicating that the previously observed associations are unlikely to be due to the residual confounding effects of cigarette smoking.
Isothiocyanates and indole-3-carbinol are derivatives of glucosinolates found in cruciferous vegetables. These compounds individually and in combination may reduce the risk of lung cancer through multiple anticarcinogenic mechanisms (30
). Most published report had largely attributed the anticarcinogenic properties of cruciferous vegetables to isothiocyanates although indole-3-carbinol has recently been shown to have chemopreventive characteristics (31
). Previous studies (18
) including a systematic review (11
) have suggested that GSTM1
might modify the association between cruciferous vegetables and lung cancer risk. GSTM1
are part of the Glutathione S-transferase
family, and are involved in isothiocyanate metabolism (2
The present study has several methodological strengths. Compared to other cohort studies, hallmarks of the present study include that it was a nested case-control study carefully matched on cigarette smoking history, had the longest duration of follow-up years (15 years), and was a community-based cohort. The study’s most unique aspect for this topic is that cases and controls were well matched on several smoking characteristics (smoking status and number of cigarettes smoked per day) to minimize the strong confounding effect of cigarette smoking. The prospective nature of the dietary and smoking data minimizes the issue of recall bias by disease status.
There are, however, several limitations to this study. A small percentage of the study participants (<8%) had missing data from either incomplete questionnaire or did not return a dietary questionnaire. Exclusion of these subjects could introduce selection bias and might lead to erroneous inferences. We instead substituted the median values based on the controls distribution of each missing dietary factor. To assess the impact of this imputation approach, we performed sensitivity analyses using other approaches to address missing or incomplete data: 1) multiple imputation method; and (2) only study participants with complete dietary data were included. For similar categorical comparisons, the results based on the sensitivity analyses showed weaker nonsignificant inverse associations. Thus, even with the relatively small percentage of missing data in the present study, the approach to handling this missing data can impact the inferences to a non-trivial degree, and the approach adopted in our primary analyses was less conservative than the other approaches. In the present study we matched as closely as possible on smoking status and smoking history such that smoking is more strongly controlled than in previous studies of this topic. Nevertheless, the possibility of residual confounding by cigarette smoking cannot be completely eliminated. For example, the data on duration of smoking was incomplete for 36% of the cohort population, and thus we could only matched cases and controls on pack-years on a subgroup of subjects. The distribution of histologic types of lung cancer in the present study differs slightly from the Surveillance Epidemiology and End Results data (36
), with slightly higher proportions of squamous cell and small cell lung cancer and a lower proportion of adenocarcinoma. It is uncertain whether this is due to chance, a true population-based difference either in risk factors or diagnostic practices, or other factors, but this should not have had a major impact on the observed inverse associations between cruciferous vegetable consumption and lung cancer risk.
Lastly, even though the Block FFQ had been validated and found to adequately estimates dietary intake of Americans overall (27
), dietary data derived from FFQs are subject to measurement error that may be random or systematic (38
). Dietary intake was obtained prior to lung cancer diagnosis in the present study, so this measurement error would most likely be nondifferential and would most likely have attenuated the associations towards the null. The individual vegetables (broccoli, cole slaw/cabbage/sauerkraut, and mustard greens/turnip greens/collards) that comprised our measure of cruciferous consumption did not cover the full breadth of cruciferous vegetables. Thus, we likely underestimated cruciferous vegetable intake in our population. However, in the United States broccoli is the most commonly consumed cruciferous vegetable, and therefore the major source of isothiocyanates (39
). Particularly in a population with low dietary cruciferous vegetable intake such as the CLUE II cohort, the cruciferous vegetables included in our summary measure probably represented the crucifers commonly eaten in this community.
In summary, after carefully matching lung cancer cases and controls by smoking history, we observed statistically significant inverse associations between consumption of cruciferous vegetables and lung cancer risk that were closely aligned with the previous body of evidence on this topic. Taken together with the existing evidence from prospective cohort studies, at present the totality of the evidence suggests it is tenable that cruciferous vegetable intake is inversely associated with lung cancer risk, and that this association holds true beyond the confounding effects of cigarette smoking.