Reviewed: Pantuck AJ, Leppert JT, Zomorodian N, 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. 2006;12(13):4018-4026.

Although the 5-year survival rate for men with prostate cancer has increased dramatically, from a 67% survival rate in the 1970s to over 90% in recent years when caught and treated early, prostate cancer is still the most common cancer (excluding skin cancer) and the second leading cause of cancer-related death in men in the United States.

Primary management of the disease for most men is either radical surgery or radiation therapy. In a significant number of men, the disease metastasizes. According to the authors, patients who have undergone primary management to cure the disease and who have progressive elevation of their prostate-specific antigen (PSA) without documented evidence of metastatic disease have limited treatment options.

In this study, the authors sought to determine the effects of pomegranate juice consumption on PSA progression in those patients. The pomegranate (Punica granatum L., Punicaceae) fruit has been used for centuries in ancient cultures for its medicinal purposes.¹ Commercial pomegranate juice shows potent antioxidant^2,3 and antiatherosclerotic⁴ properties attributed to its high content of polyphenols, including ellagic acid in its free and bound forms and other flavonoids.

To study the possible therapeutic effects of pomegranate juice on prostate cancer, the authors conducted a 2-year, single-center, phase II, Simon two-stage clinical trial at the Clark Urologic Center, David Geffen School of Medicine at the University of California at Los Angeles. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL that was documented as raising enough pretreatment PSA time points to calculate a baseline PSA doubling time (PSADT), no hormonal therapy before entering the study, no evidence of metastatic disease, and Gleason score (test used to grade the severity of prostate cancer, based on the 5 distinct patterns that prostate tumor cells go through as they change from normal cells) ≤ 7 (lower scores indicate less dangerous tumors).

PSA is an antigen in the blood that is measured and used to track the progression of prostate cancer. Elevated PSA (usually over 4 points) usually signifies presence or growth of cancer. The time required for the PSA level to double is the indicator of the rate of growth of the cancer. In general, PSA rises slowly, matching the fact that prostate cancer is a slow-growing cancer—so slow growing, in fact, that many older men with prostate cancer will die of other causes first. When the amount of time required to double the PSA level decreases, this can indicate that the rate of disease progression is slowing; it could theoretically slow down enough to become non-threatening, or to prolong the life of the patient.

Each patient had a minimum of 3 pretreatment PSA values measured over a minimum of 6 months before entering the study. Patients were treated with 8 ounces of pomegranate juice by mouth daily (Wonderful variety, POM Wonderful 100% pomegranate juice, Los Angeles, CA; equivalent to 570 mg total polyphenol gallic acid equivalents daily) until their disease progressed. A positive response was defined as a ≥ 50% decrease in measured serum PSA levels. Progressive disease was defined as either a >100% increase in PSA (with a minimum value of 1.0 ng/mL) compared with the best response observed (nadir) or any documentation of metastatic or recurrent disease. Patients were followed in 3-month intervals for serum PSA, and blood and urine were (P<0.02) reduction in the basal oxidative state and a significant 15% reduction (P<0.02) in the resistance of their serum samples to AAPH-induced lipid peroxidation after pomegranate juice consumption. In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP (prostate cancer cells) showed a 12% decrease in cell proliferation (P=0.0048) and a 17% increase in apoptosis (programmed cell death, P=0.0004), as well as significant (P<0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after vs. before pomegranate juice consumption. A 23% increase in serum nitric oxide (P = 0.0085) was also reported, which would suggest a possible vasodilating effect resulting in lowered blood pressure. No serious adverse events were reported and the treatment was well tolerated.

The authors conclude that “this study shows statistically significant effects [of pomegranate juice] on PSADT coupled with corresponding effects on prostate cancer in vitro cell growth and apoptosis,” but that the “proposed benefits shown in this study are in assays that are as yet unvalidated, and further research is needed to prove the validity of these tests and to determine whether improvements in such biomarkers (including PSADT) are likely to serve as surrogates for clinical benefit.” Their results are being further tested in a randomized, double-blind, three-arm, placebo-controlled study (begun in April 2006), in which the ability of two pomegranate juice doses to produce a predefined alternation in PSA kinetics is being compared with the change observed in a control group. If the results of that study are positive, “a strong rationale would exist for research on other plant polyphenols that might mediate similar effects,” say the authors.

—Shari Henson

References

1. Longtin R. The pomegranate: nature’s power fruit? J Natl Cancer Inst. 2003;95:346-348.

2. Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem. 2001;48:4581-4589.

3. Fuhrman B, Aviram M. Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr Opin Lipidol. 2001;12:41-48.

4. Aviram M, Rosenbalt M, Gaitini D, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr. 2004;23:423-433.