Background
Bladder cancer is one of the 10 most common cancers in the United States and the fourth most common cancer in men.1,2 Most bladder cancer (70%–80%) is diagnosed at an early stage, known as non–muscle-invasive bladder cancer (NMIBC). NMIBC can be removed; however, up to 50% to 80% of NMIBC recurs within 5 years, with some patients experiencing progression to muscle-invasive disease with poor survival.3–5 Depending on pathologic characteristics, patients with high-risk NMIBC (∼15%) may receive multiple doses of intravesical therapeutic agents, most commonly bacille Calmette-Guérin (BCG).6 However, approximately 30% of these patients will not experience a response to BCG, and the high incidence of local side effects is a concern.7 For most patients with NMIBC, no other treatment is available, yet they are still at risk for recurrence and progression. Current clinical management requires life-long surveillance by cystoscopy, resulting in bladder cancer being the most expensive cancer to treat per patient.8–10 An estimated 696,440 people are living with bladder cancer in the United States,11 most of which are off treatment and under surveillance. Novel and cost-effective strategies to control NMIBC recurrence and progression are urgently needed.
Dietary isothiocyanates (ITCs) are a group of phytochemicals primarily derived from cruciferous vegetables (Cruciferae), with multifaceted anticancer mechanisms. In vitro, in vivo, and epidemiologic studies have demonstrated the important role of dietary ITCs and ITC-rich Cruciferae in preventing bladder cancer recurrence and progression.12–21 The 4 most common dietary ITCs and their primary urinary metabolites potently inhibited the growth of a panel of human bladder cancer cells, including NMIBC cells, with half-maximal inhibitory concentration (IC50) values around 10 μM on average,16,18 which is realistically achievable in the urine with a single oral dose of ITC at 10 μmol/kg weight in rats.21 ITC at 10 μmol/kg (approximately 1 mg/kg) is also readily achievable in humans, with some Cruciferae yielding as much as 3.4 mg ITC per gram.22 Daily oral administration of ITC at the same dose level for 3 weeks significantly inhibits orthotopic bladder cancer growth21 and tumor progression into muscle-invasive disease.19,21 Orally ingested ITCs are rapidly and almost exclusively delivered to the bladder and concentrated in the urine, showing 2 to 3 orders of magnitude higher concentration of ITCs and metabolites in the urine than in the plasma within 3 hours of dosing.19,21 Storage of the urine in the bladder further enhances exposure of malignant cells to ITCs. Therefore, this unique metabolism and disposition pathway makes the bladder the best target for ITCs or ITC-rich Cruciferae. In a retrospective study of 239 patients with bladder cancer,12,13 raw Cruciferae intake was inversely associated with bladder cancer risk and, importantly, associated with significantly improved disease-specific survival (hazard ratio, 0.43; 95% CI, 0.25–0.74).
Although the potential beneficial effect of dietary ITCs in bladder cancer is compelling, the consumption of the primary dietary resource of ITCs—Cruciferae—is generally low among bladder cancer survivors. An average of 0.44 to 0.70 cups per day has been observed in prospective and retrospective studies,13,23,24 with urinary ITC levels far below the 10 µM of ITCs needed to exert anticancer activities in the bladder.16,18 Based on our recent findings on the diverse range of ITC yield from Cruciferae and the various effects of cooking methods on ITC yield,25,26 we hypothesize that at least 1 cup of Cruciferae per day, with guidance on the choice of vegetables and cooking conditions, will increase urinary ITC levels to the desirable doses needed (10 µM) to exert anticancer activities in the bladder.
A small group of randomized controlled trials (RCTs) have examined the effect of dietary interventions in cancer survivors, with most (>85%) conducted in women and focusing on breast cancer.27–29 These interventions have reported modest to moderate increases in diet quality and fruit and vegetable intake but no significant changes in cancer outcomes.27–29 A recent review of prospective studies reported associations between various measures of diet (eg, diet quality, adherence to Mediterranean diet) and improved cancer outcomes in breast, colorectal, and prostate cancer survivors.28 The discrepancy in diet’s relationship with cancer outcomes between intervention trials and prospective cohort studies may be due to the interventions’ inability to increase dietary outcomes to a clinically significant level (eg, prospective studies reporting positive associations between diet and cancer outcomes compared the lowest level of dietary quality to the highest level, whereby the highest level was not achieved by intervention studies).28
Among the handful of RCTs that have included men,30–32 few have included samples that were >25% male.33–36 These studies included survivors of breast, prostate, and colorectal cancers and tested interventions with a focus on overall nutrition. All studies reported modest increases of fruit and vegetable intake. To the authors’ knowledge, only 2 RCTs have focused on dietary change in an entirely male cancer survivor population. Parsons et al37 tested a behavioral intervention designed to increase vegetable intake in 478 men with early-stage prostate cancer on active surveillance. The intervention encouraged participants to eat at least 7 servings of vegetables daily, including 2 servings of cruciferous vegetables and 2 servings of tomatoes. Compared with the control, the intervention significantly increased vegetable intake (2.43 servings/day [95% CI, 2.17 to 2.69] vs 0.45 servings/day [95% CI, 0.19 to 0.70]) and cruciferous servings (43.10 g/d [95% CI, 35.21 to 50.99] vs 6.44 g/d [95% CI, −1.39 to 14.26]) from baseline to 6-month follow-up. However, there were no significant between-group differences in prostate cancer progression, most likely due to the intervention’s inability to increase vegetable and Cruciferae intake to intervention-recommended levels. Parsons et al37 also tested, to the authors’ knowledge, the only dietary RCT for bladder cancer survivors. Compared with control participants (n=18), intervention participants (n=40) significantly increased their daily vegetable intake from baseline to 6 months (from 2.4 to 3.9 servings) but not their Cruciferae intake. The intervention also failed to deliver the corresponding increase in urinary ITC concentrations, showing comparable ITC levels between intervention and control groups at 6-month follow-up.
Thus, given the paucity of effective dietary interventions for male cancer survivors, particularly men with bladder cancer, we developed a 6-month behavioral dietary intervention (Power to Redefine Your Health [POW-R Health]) designed to increase Cruciferae intake and ITC levels in NMIBC survivors, with the long-term goal of reducing bladder cancer recurrence, progression, and mortality.38 We anticipated that consuming at least 1 cup of Cruciferae per day25,26 would be sufficient to increase urinary ITC levels to at least 10 μM. We hypothesized that compared with the control, our dietary intervention would increase Cruciferae intake to at least 1 cup/day and ITC levels to at least 10 μM from baseline to 6-month follow-up. The overall aim of the trial was to test whether our POW-R Health intervention could meaningfully increase urinary ITC levels and Cruciferae intake in NMIBC survivors, with the long-term goal of changing bladder cancer outcomes.
Patients and Methods
We tested the efficacy of a Cruciferae intervention on the outcomes of Cruciferae intake and urinary ITC levels in NMIBC survivors through a blinded 2-arm RCT. NMIBC survivors were randomized to either a 6-month Cruciferae intervention (“treatment”) or a 6-month fruit and vegetable intervention based on NCI guidelines for cancer survivors (“control”) (https://cancercontrol.cancer.gov/ocs/). In addition to serving as an efficacy trial with the primary outcome of urinary ITC levels, we also considered this study a feasibility trial to ascertain recruitment and participant satisfaction for the purpose of informing a subsequent large RCT that would assess the impact of our Cruciferae intervention on bladder cancer recurrence and progression. This study was approved by the Roswell Park Comprehensive Cancer Center Institutional Review Board and registered as an NIH clinical trial (ClinicalTrials.gov identifier: NCT04548193).
Target Population
We enrolled NMIBC survivors in Roswell Park Comprehensive Cancer Center’s catchment area, which includes 8 counties designated as “Western New York” (WNY) with approximately 1.5 million residences. WNY has higher bladder cancer incidence (30.1 vs 23.0 in New York State and 20.1 in the United States) and mortality rates (5.3 vs 4.3 in New York State and 4.4 in the United States, age adjusted per 100,000).39 Eligibility criteria included (1) English-speaking; (2) diagnosed with stage tumor in situ (Tis), Ta, or T1 bladder cancer; (3) resided in the Roswell Park Comprehensive Cancer Center catchment area; (4) did not receive a partial or radical cystectomy; and (5) did not have a previous cancer diagnosis or treatment within 12 months of their bladder cancer diagnosis.
Recruitment
We recruited patients from eligible cases diagnosed in 2018 through 2019 and reported to the New York State Cancer Registry (NYSCR) and from eligible cases in 2015 through 2020 who were currently under surveillance at Roswell Park Comprehensive Cancer Center. Qualifying patients were identified from databases based on the study’s eligibility criteria, and physicians of qualifying patients were asked whether their patient was ineligible for the study. If patients were still eligible, they were sent an informational packet, whereby they were asked permission to be contacted by research staff. Patients who agreed to further contact were provided with a general study overview and attended a screening interview to confirm eligibility; research staff obtained informed consent from eligible patients.
Figure 1 shows the flow of participants through the study from initial eligibility assessment through 6-month follow-up. Of 155 participants contacted for eligibility, 49 were randomized; 7 participants were subsequently excluded due to death, loss of interest, other medical problems, they underwent a cystectomy, or loss to follow-up. Thus, a total of 42 participants completed both baseline and 6-month follow-up assessments, yielding a retention rate of 86%.
POW-R Health CONSORT diagram.
Citation: Journal of the National Comprehensive Cancer Network 22, 2; 10.6004/jnccn.2023.7086
Interventions
The primary goal of the treatment intervention was to increase Cruciferae intake by 1 cup per day. Grounded in social cognitive theory and evidence-based behavioral change strategies, and codeveloped with NMIBC survivors, the 6-month POW-R Health intervention consisted of (1) mailed educational materials about the importance of consuming Cruciferae, how to maximize urinary ITC levels, serving size goals (1 cup of Cruciferae each day), the importance of self-monitoring, and strategies to increase intake, along with booklets to record daily Cruciferae intake; (2) a live phone call (∼30 minutes) to verify understanding of the educational information and help participants identify barriers and facilitators to meeting identified goals; and (3) 11 interactive voice response phone calls that provided tailored messages to help participants meet their Cruciferae goal based on the number of Cruciferae cups participants consumed the previous week. Tailored messages consisted of strategies to overcome identified barriers to meeting the intervention’s Cruciferae intake goals. Each participant received the mailed materials, and 2 weeks after the materials were mailed, staff conducted the live phone call. One week after the live phone call, the interactive voice response calls were delivered, first on a weekly basis, then on a biweekly basis for the remainder of the 6-month intervention. More details regarding the intervention’s creation and components have been reported elsewhere.38
Participants in the control group received a fruit and vegetable intake intervention that contained the same components, delivery method, and contact schedule as the treatment intervention, except the focus was on eating at least 2.5 to 3.0 cups of vegetables and 1.5 to 2.0 cups of fruit each day. Vegetables of all types and whole fruits were promoted.40,41 To avoid potential contamination with the treatment arm, Cruciferae were not mentioned or illustrated in the educational materials, and staff were instructed to not initiate discussions about Cruciferae. Data collectors were also asked to not probe for Cruciferae intake in control participants.
Measurements
Trained staff blinded to treatment condition collected participant data at baseline and 6 months. All data were collected over the phone except for urinary ITC levels. The participant assessment consisted of sociodemographic factors, health-related measures, Cruciferae intake, fruit and vegetable intake, and urinary ITC levels.
Sociodemographic factors were assessed by self-report, including sex, age, race, ethnicity, education, income, employment status, marital status, insurance status, and number of people in the household.
Health-related measures included NMIBC diagnosis date, tumor stage and related treatments, self-reported body mass index, smoking status (yes/no), and the number of days engaging in exercise for ≥20 minutes in the past 30 days. Self-reported general health and quality of life were assessed by asking participants to indicate their general health or quality of life as excellent, very good, good, fair, or poor.
Cruciferae intake was assessed using a questionnaire adapted from Thomson et al42 to capture both intake and cooking styles and through 3 nonconsecutive 24-hour dietary recalls (2 weekdays, 1 weekend day) delivered by trained staff using the interview-administered Nutrition Data System for Research (NDSR).43 Dietary ITC intake was estimated from Cruciferae intake by considering ITC yields from individual Cruciferae and weighting factors for cooking conditions.25,26
Fruit and vegetable intake was assessed through 3 nonconsecutive 24-hour dietary recalls (2 weekdays, 1 weekend day) delivered by trained staff using the interview-administered nutrition data system for research.43
Urinary ITC levels were assessed using urine samples collected at baseline and 6-month follow-up. The urine collection package was mailed to each participant and included 3 urine collection devices, each consisting of a 10-mL container and sponge with a plastic holder, ice packs, and Styrofoam containers. Participants were instructed to collect first-void urine continuously for 3 days at home and mail the samples back. A high-performance liquid chromatography–based cyclocondensation assay was used,15,44 which measures ITCs and metabolites as low as a few picomoles. The results were adjusted by urinary creatinine level using creatinine assay kits (Cayman Chemical) to ensure that urinary ITC levels between the intervention and control group were not due to variability in fluid intake.
Statistical Analyses
Descriptive statistics were used to summarize demographic and baseline characteristics by treatment group. The baseline characteristics between groups were compared using Wilcoxon rank-sum tests for continuous variables and Fisher exact tests for categorical variables. Within-group differences between 2 timepoints were compared using Wilcoxon signed-rank tests, whereas between-group differences at each timepoint was analyzed using Wilcoxon rank-sum tests. Changes in behavioral characteristics were analyzed using McNemar’s test. The comparisons of posttreatment measurements were further made by analysis of covariance (ANCOVA), where the treatment group was used as factors and the baseline variables were used as covariates. The ANCOVA was performed in accordance with the intention-to-treat principle, and the multivariate imputation by chained equations (MICE) algorithm was used to impute the missing values under the missing-at-random assumption, which is a Markov chain Monte Carlo method. The algorithm was implemented using the R mice package with 30 imputations. Due to the skewed distribution of the outcome variables, the data were log10 transformed before analysis. Although the significance of between-group and within-group analyses in complete case analyses were retained, the estimated group means corresponded to geometric means after being transformed back to the original scale. These data were difficult to interpret and therefore were not reported. All tests were 2-sided at a significance level of 0.05.
We planned to enroll 40 patient for each group, with which the ANCOVA can achieve 80% power to detect a 0.57 difference in within-group standard deviations (SDs) between groups assuming the correlation of postintervention and baseline outcome is R2=0.2. Based on a within-group SD of 8.9 µM for urinary ITCs and 62 g/d for Cruciferae intake from our Be-Well Study,24 we expected to detect a difference equivalent to 5.1 μM in urinary ITC and 35.3 g/d of Cruciferae intake between groups. With an actual sample size of 42 total participants with both baseline and follow-up assessments, the analysis could achieve 80% power to detect a difference of 0.8 SD between the 2 groups.
Results
Participant Characteristics
The characteristics of participants who completed the intervention and 6-month follow-up (n=42) are reported in Table 1. There were no significant differences between arms in demographic characteristics, general health-related measures, fruit and vegetable intake, or Cruciferae intake at baseline. Urinary ITC levels were higher in the treatment group compared with the control group (mean [SD], 12.1 [16.5] vs 4.8 [11.4] μmol/g creatinine).
Characteristics of Study Participants at Baseline
Changes in Cruciferae Intake
Results of Cruciferae intake are reported in Table 2. Based on 3-day dietary recall data, Cruciferae intake was 0.94 cups/day higher from baseline to 6-month follow-up in the treatment arm compared with the control arm (P=.0098). Similar results were obtained when Cruciferae intake was assessed by survey, with the treatment arm reporting 0.72 cups/day higher from baseline to 6 months compared with the control arm.
Cruciferae, Total Fruit and Vegetable, and ITC Levels Comparing Intervention to Control Arms
There was no significant within-group change for the control arm in Cruciferae intake (0.49 vs 0.56 cups/day; P=.41) or for the treatment arm in fruit and vegetable intake (394.3 vs 421.1 g/d; P=.80) when assessed by 3-day dietary recall data.
Changes in ITC Levels
We estimated dietary ITC intake and measured urinary ITC levels (Table 2). With the exception of urinary ITC levels in µM, the treatment arm had a significantly higher increase in levels in all variables compared with the control arm from baseline to 6-month follow-up. When assessed based on 3-day dietary recalls, the estimated dietary intake of ITC was 5.75 (95% CI, −5.37 to 16.86) µmol/d higher in the treatment group compared with the control group from baseline to 6-month follow-up (P=.0068), with the treatment group reporting a mean [SD] dietary ITC intake of 13.34 [17.14] μmol/d postintervention. When assessed by survey, the treatment group had a 20.86 (95% CI, −50.95 to 92.67) µmol/d higher dietary ITC intake compared with the control group from baseline to 6-month follow-up (P=.002), with the treatment group reporting a mean [SD] dietary ITC intake of 65.93 [50.5] μmol/d postintervention.
The increase in dietary ITC intake also translated to an increase in urinary ITC levels. Adjustment for creatine levels was done to ensure that the urinary ITC levels between the intervention and control groups were not due to variability in fluid intake. The treatment group had 11.1 μmol ITC per gram creatinine higher levels in the treatment arm compared with the control arm at baseline versus 6-month follow-up (P=.03). The statistical significance of the comparisons was also retained by ANCOVA on the intention-to-treat population.
Discussion
Our POW-R Health intervention increased Cruciferae intake by 0.94 cups/day and urinary ITC levels by 11.1 μmol/g creatinine compared with the control arm, with an average increase of urinary concentration of 10.4 μM, the desirable dose level of urinary ITCs needed to stop or kill at least 50% of bladder cancer cells in in vitro models.16,18 To our knowledge, this is the only study that showed an intervention’s success in significantly and meaningfully increasing both Cruciferae intake and urinary ITC levels among NMIBC survivors. The only other known study that we are aware of that tested a dietary intervention in bladder cancer survivors reported no changes in either Cruciferae intake or urinary ITC levels.23
Our study is one of the few dietary interventions tested in male cancer survivors. Consistent with other studies that included at least a 40% male sample, our intervention significantly increased vegetable intake; however, in contrast to these other studies, our intervention achieved the level of intake (ie, Cruciferae intake) that we hypothesize would significantly change bladder cancer outcomes. Other interventions increased vegetable intake, but not to the levels recommended by the intervention. Our intervention’s singular focus on Cruciferae intake may have been easier for participants to change because of the message’s simplicity, in contrast to the majority of other interventions that asked participants to change a myriad of dietary behaviors simultaneously (eg, fat intake, fiber intake, vegetable intake, fruit intake). Our engagement of NMIBC survivors in creating the Cruciferae intervention may have also increased the intervention’s saliency and thus adherence, resulting in higher levels of dietary change. Future dietary interventions for cancer survivors may benefit from focusing on one aspect of dietary change and engaging survivors in the development and pilot testing of the intervention.
To the authors’ knowledge, only one study examined the impact of a dietary intervention on cancer outcomes and reported null results.37 However, the intervention did not increase vegetable intake to levels that the study recommended. Our intervention successfully increased Cruciferae and urinary ITC levels to study recommended amounts and is ready to be tested in a double-blinded RCT in NMIBC survivors, whereby patients with newly diagnosed NMIBC would be enrolled and the primary outcome would be recurrence and progression, which would be assessed at 6, 12, and 24 months via medical chart review. Unlike the study by Parsons et al,37 this future trial would test a dietary intervention with proven efficacy to increase Cruciferae intake to meaningful levels.
The limitations of our study include the predominately White and male sample, despite our efforts to recruit all race, ethnicity, and sex groups, which limits external validity. Given that Cruciferae is a vegetable, there may have been contamination between the treatment and control arms; however, the nonsignificant within-group change of Cruciferae intake in the control group and fruit and vegetable intake in the treatment group suggests that there was minimum contamination between groups. If there was contamination, the magnitude of the intervention’s effect on Cruciferae intake may have been larger. Despite these limitations, our study employed rigorous methods, gold standard measurements of Cruciferae intake and urinary ITC levels, and an adequate sample size to demonstrate the intervention’s efficacy on Cruciferae intake and ITC levels.
Conclusions
Our simple dietary intervention only requires NMIBC survivors to consume 1 cup of Cruciferae a day, is of low cost to participants (cost of Cruciferae), and is easily accessible (available at grocery stores). If a future RCT demonstrates that the intervention significantly reduces bladder cancer recurrence and progression, it would be an easily scalable strategy to prevent NMIBC recurrence and progression, which occurs within 5 years in most NMIBC survivors.
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