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ORLANDO -- Prostate cancer patients had a six-month gain in PSA doubling time when treated with pomegranate extract, according to data reported here.

The median PSA doubling time increased from 12 months before treatment to 18 months afterward. Consistent with a previous study of pomegranate juice, 13% of patients had a PSA negative slope, reflecting a decline in PSA level, Michael Carducci, MD, of Johns Hopkins, told attendees at the Genitourinary Cancers Symposium.

However, 35% to 40% of the patients had a reduction in PSA doubling time, providing some reason for concern.

"The results show that [pomegranate extract] slows PSA doubling time by more than six months in a broad patient population with a rising PSA post-local therapy," Carducci said.

"We observed apparent benefit across all PSA doubling times, although some shortening of the doubling time was seen," he added. "The treatment had no apparent effect on testosterone, and the safety of pomegranate extract was confirmed."

The results add to those of a previous investigation of pomegranate juice that showed more than a threefold increase in PSA doubling time (Clin Cancer Res 2006; 12: 4018-4026).

Pomegranate has a long history of use in folk medicine. Laboratory studies have shown that it has antiangiogenic and antitumor activity.

In fact, polyphenols found in pomegranate have the most potent antioxidant and free-radical scavenging effects among juices and teas that have been evaluated, including red wine.

As compared with the juice, pomegranate extract controls the growth of prostate cancer more effectively, said Carducci.

The accumulation of laboratory and clinical-trial data provided a rationale to study pomegranate extract in men with prostate cancer with a rising PSA after initial curative treatment.

Investigators chose to evaluate the extract in a broader patient population as compared with the study of pomegranate juice: any previous definitive therapy, any PSA level ≥0.4 ng/mL, and no limit on Gleason score.

Investigators enrolled 104 patients who had rising PSA values confirmed on three consecutive measurements within the past year. Patients were randomized to three daily capsules of pomegranate extract or to one capsule of the extract and two placebo capsules.

Each capsule contained 1,000 mg of pomegranate polyphenol, equivalent to one eight-ounce serving of pomegranate juice.

Blinded treatment continued for 18 months, and the primary endpoint was the change from baseline in PSA doubling time.

The intention-to-treat analysis included 101 patients who had an average Gleason score of 6.5 (median 7.0). About 70% of the men had a baseline PSA doubling time greater than nine months.

No patient developed grade 3-4 toxicity during the study. The most common adverse effect was mild to moderate diarrhea in 7.7% (13.5% with the higher dose, 1.9% with the lower dose). No significant changes in testosterone occurred.

In the overall population, PSA doubling time increased from 11.9 months at baseline to 18.5 months at the end of the study (P<0.001).

Patients taking one capsule of pomegranate extract had an increase from 11.9 to 18.8 months versus 12.2 to 17.5 months for the group randomized to three active capsules.

Carducci said the between-group values did not differ significantly.

About 80% of patients in each group had stable PSA values during the study.

Acknowledging the limitation of no placebo control group, Carducci said a 200-patient placebo-controlled trial of pomegranate extract is ongoing.

Invited discussant Michael Morris, MD, drew attention to the study's endpoint and to the proportion of patients who derived no apparent benefit from pomegranate extract.

"It's true that the median PSA doubling time [increased] for both groups, but a third or 40% of patients had their PSA doubling times shortened while on therapy," said Morris, of Memorial Sloan-Kettering Cancer Center in New York.

"If you believe that a prolonged PSA doubling time is clinically beneficial, what do you say about patients whose disease appears to accelerate as a result of taking the pomegranate extract? Do we say that 30% to 40% of patients might be done some harm or might have an earlier clinical endpoint? I don't know, but I think that's an issue of concern."

The results also should be considered with the understanding that "a treatment-induced alteration in PSA doubling time has never been shown to confer a clinical benefit, even in animal models," Morris added.

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