In this study of 239 bladder cancer patients seen at RPCI between 1980 and 1998, survival was not associated with total fruits, total vegetables, or total cruciferous vegetable intake prior to diagnosis. However, intake of raw cruciferous vegetables was significantly associated with reduced disease-specific (57% reduction) and overall mortality (43% reduction), a result largely driven by raw broccoli intake. The reduction was observed with consumption of at least one serving raw broccoli per month (average intake 3.9 servings/month), indicating the feasibility of this type of diet intervention strategy. Our findings are consistent with experimental evidence demonstrating that isothiocyanate exposure, as measured by urinary metabolite concentrations, is three to four fold higher in individuals after consumption of raw compared with cooked broccoli (21
). Experimental studies in animals and cell lines indicate that isothiocyanates may be promising chemopreventive agents against bladder cancer (10
Contrary to the findings observed with broccoli intake, no associations were observed with other individual cruciferous vegetables regardless of whether they were consumed raw or cooked. As usual consumption of individual cruciferous vegetables in the study was similar (means of broccoli, cabbage, and cauliflower consumption were 4.1, 3.9, and 3.3 servings per month, respectively), it is unlikely that this null association was the result of the small range of exposure. It is unclear whether the differential associations observed between individual cruciferous vegetables and bladder cancer survival are related to specific types of isothiocyanates or the amount of isothiocyanates derived from each vegetable. For example, the major isothiocyanate derived from broccoli is sulforaphane, while cabbage and cauliflower are abundant in allyl isothiocyanate (22
). The two isothiocyanates share the characteristic –N=C=S structure but differ in their side chains, resulting in varied anti-cancer potencies as well as the underlying mechanisms observed in human bladder cancer cells (12
). Investigation of the in vivo
efficacy of individual isothiocyanates against bladder cancer would offer more clues to understanding these observed associations. Moreover, isothiocyanate yield differs substantially among different cruciferous vegetables due to their wide range of glucosinolate concentration. Jiao et al. showed that total isothiocyanate yield from nine types of cruciferous vegetables in Singapore varied as much as 16-fold (23
). The isothiocyanate content in broccoli was 40% higher than that in cabbage and 2.3-fold higher than that in cauliflower. Furthermore, it is noteworthy that, in addition to isothiocyanates, cruciferous vegetables contain many other compounds with anti-cancer potential including indoles, vitamins, dietary fiber, and other phytochemicals, which could also contribute to the observed associations either independently and/or in combination with isothiocyanates.
Several limitations need to be taken into consideration in this study. Firstly, questionnaire data, including cruciferous vegetable intake, were collected at the time of diagnosis, which may not represent dietary habits after the disease diagnosis. Cancer survivors are often motivated to modify their diet with the hope of improving prognosis (18
). However, such diet modifications tend to be healthy changes such as eating less meat and fat and increasing vegetable and fruit intake (24
). Therefore, it is possible that our findings have been underestimated. Validation of the findings in a prospective study using cruciferous vegetable intake after diagnosis would provide more conclusive evidence.
Secondly, due to the relatively small sample size, we have limited statistical power to examine potential interactions between cruciferous vegetable and other prognostic factors. Cigarette smoking is the strongest risk factor of bladder cancer. Consistent with the potent detoxification effect of isothiocyanates on cigarette-related carcinogens, a strong inverse association was observed between cruciferous vegetable intake and bladder cancer risk among smokers (7
). Smoking was an independent prognostic factor for bladder cancer survival in the current study. It is possible that cruciferous vegetable intake may modify the associations between cigarette smoking and bladder cancer survival.
Thirdly, outcome data were collected retrospectively, which could introduce the possibility of misclassification. Moreover, due to the incomplete recurrence data, we were unable to investigate the associations between cruciferous vegetable intake and bladder cancer recurrence, while high risk of recurrence is the most common event occurring in bladder cancer patients. Therefore, such information may have a great impact on bladder cancer survivorship.
To our knowledge, this is the first study to investigate the role of cruciferous vegetables in bladder cancer survival. A strong inverse association between broccoli intake and bladder cancer mortality was observed. The strong preclinical evidence of broccoli sprout extract in both in vitro and in vivo bladder cancer models, supports the validity of this association. Further large-scale prospective studies are warranted to confirm the potential role of cruciferous vegetables in bladder cancer prognosis.