Department of Research & Evaluation News

Non-muscle invasive bladder cancer patients whose treatment included the immunotherapy Bacillus Calmette-Guerin (BCG) after surgery were less likely to have their cancer recur if their diet included raw cruciferous vegetables like broccoli, a new Kaiser Permanente study found.

The research, published in the Journal of Urology, analyzed data from patients enrolled in the Bladder Cancer Epidemiology, Wellness, and Lifestyle (Be-Well) Study, one of the largest prospective studies to examine the effects of nutrition, lifestyle, and genetics on bladder cancer survivorship.

“One of the reasons we launched Be-Well was because we were interested in learning if diet, particularly cruciferous vegetables, could affect prognosis in non-muscle invasive bladder cancer, which has a high risk of recurrence  — from 50 to 70%,” said lead author Marilyn L. Kwan, PhD, a research scientist and cancer epidemiologist at the Kaiser Permanente Division of Research. “It’s gratifying to see that our findings suggest that for these patients, raw cruciferous vegetables could fit into the category of food as medicine.”

The study included 1,158 Be-Well participants. Of these 448 (40%) were treated with the chemotherapy mitomycin C and 565 (50%) were treated with BCG. Both treatments are liquids that are delivered directly into the bladder through a catheter. Nearly 2 years after completing treatment, 343 (30%) of the patients had a recurrence.

A prior Be-Well study found that bladder cancer patients with high levels of Isothiocyanates (ITCs) — naturally occurring molecules found in cruciferous vegetables —

had a lower risk of developing multiple recurrences and progression. This is the first study to look at whether ITC intake improved outcomes for patients treated with mitomycin C or BCG at the time of surgery.

“Since we measured nutrients from diet questionnaires, our results are based on foods consumed by the patients, and not by supplemental vitamins or pills,” said study co-author Reina Haque, PhD, MPH, a cancer epidemiologist in the Kaiser Permanente Southern California Department of Research & Evaluation. “It’s important for patients and their providers to know that non-pharmaceutical factors such as a good diet can help improve cancer-related outcomes.”

The study found that, overall, mitomycin C was associated with an over 40% lower risk of recurrence, while BCG was associated with about a 30% lower risk of recurrence. Eating 2.4 servings or more a month of raw cruciferous vegetables further reduced recurrence risk in the patients receiving BCG compared with patients who ate less than 2.4 servings per month. These patients had a 44% lower risk of recurrence than those who ate fewer cruciferous vegetables.

Biological connections

Mitomycin C is a chemotherapy drug that kills cancer cells by inhibiting DNA synthesis. But before that can occur, the drug must be activated by a specific enzyme. BCG is an immunotherapy that activates the immune system. Laboratory studies have shown that they have anti-cancer effects. Cruciferous vegetables that contain ITCs increase the enzyme mitomycin C uses; they also enhance the immune system. This led the research team to question whether patients receiving these therapies who ate these vegetables might have a better prognosis.

The Be-Well participants completed a comprehensive dietary survey when they enrolled in the study, shortly after their diagnosis.  The survey included questions about consumption of 22 cooked or raw cruciferous vegetables as well as 4 condiments that contain ITCs. The researchers used this self-reported consumption of raw and cooked cruciferous vegetables to estimate their ITC intake. Dietary levels were categorized as high or low based on the median level of the group. (A standard serving size is half a cup of non-leafy vegetables and 1 cup of leafy vegetables). In addition, the patients’ urine was tested for ITC metabolites.

The researchers said there are likely biological reasons why the study found a reduced risk only in the patients treated with BCG. “ITCs show immunomodulatory activities at low dose ranges, which could potentially improve the efficacy of BCG,” said senior author Li Tang, MD, PhD, a molecular epidemiologist at the Roswell Park Comprehensive Cancer Center in Buffalo, New York. “But it takes high doses of ITCs to induce the important part of phase II enzyme activation that makes mitomycin C effective, and, in general, most of the people we studied consumed lower amounts of these vegetables.”

Reducing recurrence risk

About 3 in 4 patients with bladder cancer have non-muscle invasive bladder cancer. These patients have a 5-year survival rate of close to 90%. However, more than half of these patients will have one or more recurrences. Of these, 10% to 20% will have cancers that progress to muscle-invasive cancer.

“Patients are always looking for advice on lifestyle changes they can make to help them deal with their cancer diagnosis,” said David Aaronson, MD, a clinician advisor on the Be-Well Study and a urologist with The Permanente Medical Group. “Our study suggests that this may be a reasonable response to answer those patients’ questions. A clinical trial would be needed to confirm if this is truly the case, but it does seem that eating your vegetables is again looking like good advice.”

The study was funded by the National Cancer Institute.

Co-authors include Valerie S. Lee, MHS, Janise M. Roh, MPH, MSW, Isaac J. Ergas, PhD, Charles P. Quesenberry, PhD, and Lawrence H. Kushi, ScD, of the Division of Research; Zinian Wang, Rachell Pratt, Maciej Goniewicz, PhD, PharmD, and Christine B. Ambrosone, PhD, of the Roswell Park Comprehensive Cancer Center; Kimberly L. Cannavale of the Kaiser Permanente Southern California Department of Research & Evaluation;  Ronald K. Loo, MD, of Kaiser Permanente Southern California; David S. Aaronson, MD, of The Permanente Medical Group; and Yuesheng Zhang, MD, PhD, of the Massey Comprehensive Cancer Center.