The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. In this installment, Channing Paller, MD, explores the role of pomegranate- and grape-based supplements in treating men with a recurrence of prostate cancer.
Channing Paller, MD
The evidence is in: It is okay to say “no, it’s not for everyone” when patients with prostate cancer ask whether to spend money on pomegranate- or grape-based dietary supplements (containing ellagic acid) to slow the growth of their disease. Two placebo-controlled trials (N = 183 and N = 125) found prostate-specific antigen (PSA) doubling time was not significantly lengthened by pomegranate or grape skin extract treatment in the PSA-recurrent prostate cancer patient population.1,2
Findings from these two large trials contrasted sharply with findings from earlier single-arm or uncontrolled trials. However, preplanned subset analyses in the two more recent placebo-controlled trials did show that patients with a specific genotype of manganese superoxide dismutase (MnSOD) seemed to benefit from the supplements. Moreover, a food supplement with a combination of four polyphenol-rich compounds showed significant reduction in PSA growth on treatment vs placebo in the PSA-recurrent population (n = 78) as well as in patients being managed with active surveillance prior to local treatment (n = 121).3
Early Days: 2006–2015
MANY PATIENTS with prostate cancer ask their physicians whether they should use pomegranate or other antioxidant-rich dietary supplements to slow the progression of their disease. Until 2015, physicians and patients discussing pomegranate and other forms of polyphenol supplementation relied primarily on a 2006 study by Pantuck and his colleagues, which reported treatment with 8 oz of pomegranate juice daily, until disease progression, resulted in lengthening of the mean PSA doubling time from 15 to 54 months in prostate cancer patients who were experiencing PSA recurrence following prostatectomy and/or radiation.4 That 2006 study, cited more than 450 times in scientific journals and noted on thousands of websites, made a compelling case for PSA-recurrent patients with prostate cancer to supplement their diet with phytochemical-rich supplements such as pomegranate juice or pills.
In 2013, our group completed a dose-finding study of 18 months of pomegranate extract treatment in the PSA-recurrent patient population. PSA doubling time increased from 12 months at baseline to 18 to 19 months on treatment. No significant difference was seen between the low- and high-dose arms.5 These results were of unclear significance given the lack of dose effect and absence of placebo.
Alternative Explanation for PSA Doubling Time Lengthening
THE LACK OF a dose effect in our 2013 study raised questions about whether something besides the supplement might be causing PSA doubling time lengthening. That concern increased when we noted that patients on placebo arms of two randomized controlled trials experienced a significant increase in PSA doubling time that was not induced by any active therapy.6,7
In response, we launched a retrospective analysis of the natural history of two cohorts of patients with PSA-recurrent prostate cancer: 205 Johns Hopkins Hospital patients who chose to defer treatment and 108 patients on the placebo arm of a randomized clinical trial. We performed 2,000 simulations of hypothetical single-arm, 50-patient studies using change in PSA doubling time from baseline as the primary outcome and found that 27% to 62% of those trials reported significant lengthening of PSA doubling time. Simulated two-arm randomized controlled trials, on the other hand, found a significant difference around 5% of the time, as expected for a 5% significance level test.8
Randomized, Placebo-Controlled Trials Are Negative
IN 2015, Pantuck et al completed the first large randomized placebo-controlled trial of pomegranate extract treatment in PSA-recurrent men. They reported that men on the extract (n = 102) had a nonsignificant PSA doubling time lengthening from 13 months at baseline to 15 months on treatment, whereas in the placebo group (n = 64), the increase was from 11 months to 16 months.2
“Fifty-one percent of patients with prostate cancer have reported using complementary medical products, and half of those who use dietary supplements started consuming new supplements after being diagnosed with cancer.”— Channing Paller, MD
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Similarly, in our group’s multisite randomized placebo-controlled trial of muscadine grape skin extract in PSA-recurrent men, published in 2017, we reported no difference in the change in PSA doubling time between the placebo arm and either the low- or high-dose arm.1
Two Unanswered Questions
INCREASED EXOGENOUS antioxidant status has been shown to be associated with a significant reduction in the risk of aggressive prostate cancer in men with the alanine/alanine genotype of MnSOD, whereas the association was not significant in men with alanine/valine and valine/valine genotypes.9 Further, in men with the valine allele, but not those homozygous for alanine, higher selenium levels are associated with an increased risk of aggressive prostate cancer.10
In our 2017 study of muscadine grape skin extract, we determined each patient’s genotype of MnSOD, the primary endogenous mitochondrial enzyme that converts reactive oxygen species to hydrogen peroxide and oxygen and reduces oxidative stress. Among the 26% of men with the alanine/alanine MnSOD genotype, those treated with high-dose grape skin extract showed a median PSA doubling time increase of 10.4 months, pooled high- and low-dose recipients showed 6.4 months of increase, and placebo recipients showed 1.9 months of increase.
The negative 2015 study of pomegranate by Pantuck et al also showed an exploratory positive trend in the alanine/alanine patient population. Thus, one unanswered question that would provide important information for patients is whether polyphenol-rich food supplements significantly increase PSA doubling time in alanine/alanine PSA-recurrent patients. We are currently validating a Clinical Laboratory Improvement Amendments–certified test for the MnSOD genotype and, through the Department of Defense Prostate Cancer Clinical Trials Consortium, planning a much larger multisite study to answer that question and to determine whether baseline antioxidant status modulates the outcome.
The second unanswered question concerns Pomi-T, a supplement composed of a blend of green tea, pomegranate, broccoli, and curcumin, which was reported in 2014 to lower the rate of PSA increase (8.8% PSA rise on treatment vs 80.3% PSA rise on placebo, P = .001) in a trial of 78 PSA-recurrent patients randomized 2:1 to receive Pomi-T and placebo.3 Pomi-T treatment showed similar results in 121 patients being managed with active surveillance prior to local therapy. Since one of the Pomi-T four components, pomegranate, has already been shown to have no effect on PSA doubling time in the PSA-recurrent patient population, a multiarm trial of the other three components in parallel with a replication of the original study would help determine which component(s) are effective or whether only the combination should be recommended.
Closing Thoughts
AMERICANS SPEND $12.6 billion on dietary supplements each year, an amount that equals nearly 25% of their out-of-pocket expenditures for prescription drugs.3 Fifty-one percent of patients with prostate cancer have reported using complementary medical products,11 and half of those who use dietary supplements started consuming new supplements after being diagnosed with cancer.12
Patients look to their physicians to offer evidence-based advice on which supplements are likely to help with their disease without causing harmful drug interactions. We may be on a path toward finding a genotype that predicts for benefit from antioxidants in patients with prostate cancer and perhaps other cancers. ■
DISCLOSURE: Dr. Paller reported no conflicts of interest.
REFERENCES
1. Paller CJ, et al: Muscadine grape skin extract in men with biochemically recurrent prostate cancer. Clin Cancer Res. November 7, 2017 (early release online).
2. Pantuck AJ, et al: A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis 18:242-248, 2015.
3. Thomas R, et al: A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer. Prostate cancer and prostatic diseases. Prostate Cancer Prostatic Dis 17:180-186, 2014.
4. Pantuck AJ, et al: Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12:4018-4026, 2006.
5. Paller CJ, et al: A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 16:50-55, 2013.
6. Smith MR, et al: Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer 101:1569-1574, 2004.
7. Smith MR, et al: Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol 24:2723-2728, 2006.
8. Paller CJ, et al: The effect of the frequency and duration of PSA measurement on PSA doubling time calculations in men with biochemically recurrent prostate cancer. Prostate Cancer Prostatic Dis 17:28-33, 2014.
9. Li H, et al: Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. Cancer Res 65:2498-2504, 2005.
10. Chan JM, et al: Plasma selenium, manganese superoxide dismutase, and intermediate- or high-risk prostate cancer. J Clin Oncol 27:3577-3583, 2009.
11. National Institutes of Health/National Center for Complementary and Integrative Health: Americans spend $30 billion a year out-of-pocket on complementary health approaches. Available at nccih.nih.gov/research/results/spotlight/americans-spend-billions. Accessed January 12, 2018.
12. Patterson RE, et al: Changes in diet, physical activity, and supplement use among adults diagnosed with cancer. J Am Diet Assoc 103:323-328, 2003.
