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| Date: 08-31-2015 | HC# 081561-527 |
Re: A Phase I Study on Muscadine Grape Skin Extract in Men with Prostate Cancer
Paller CJ, Rudek MA, Zhou XC, et al. A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: safety, tolerability, and dose determination. Prostate. October 2015;75(14):1518-1525.
Prostate cancer affects men throughout the world, and despite treatment, many will experience recurrence of this disease. Prostate cancer recurrence is assessed by measuring prostate-specific antigen (PSA) concentrations. Those with recurrence are treated with radiation and/or androgen deprivation, with the objective of preventing metastasis. Both of these treatments can be associated with adverse side effects (ASEs), therefore alternative or complementary therapies are of interest. Muscadine grape (Vitis rotundifolia, Vitaceae) skin contains many bioactive phytochemicals which have been shown to have anticancer properties. In this phase I and II clinical trial, the safety, tolerability, and dosing associated with muscadine grape skin consumption was evaluated in men that had elevated PSA levels and had previously had prostate cancer; secondarily, this study investigated the potential anticancer activity of this botanical.
This study took place at Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital; Baltimore, Maryland. Included patients were ≥ 18 years old with a diagnosis of ≥ 6 months of life expectancy; patients had been treated for prostate cancer and had evidence of recurrence (increasing PSA by 2 ng/ml or greater from a baseline of > 0.4 ng/ml over 3 or more time points that were separated by 21 days within 12 months) without metastases. Those that showed decreased PSA concentrations or were taking treatments that targeted testosterone concentrations within 6 months of the trial were excluded. Also excluded were those that had other cancer treatments within 4 weeks of the trial, those that had an Eastern Cooperative Oncology Group (ECOG, a measure of functional independence where lower scores indicate better function) performance status of > 2, those with testosterone concentrations < 150 ng/dl, and those who used products containing muscadine grape 2 months prior to the study. Leukocyte concentrations of < 3,000/mcl or platelets < 100,000/mcl were also exclusionary factors. Beginning from 2 months before the study's start, patients did not take any muscadine grape products and consented to not changing any dosage of dietary supplements.
The muscadine grape skin used in this study was from Muscadine Naturals, Inc.; Warsaw, North Carolina. To prepare, skin was dried and ground into powder before placing into 500 mg capsules. Capsules were standardized to contain 1.2 mg of ellagic acid, 9.2 µg of quercetin, and 4.4 µg of trans-resveratrol. Patients took capsules once daily for 28 days and visited the clinic every week during treatment consumption and every 3 months during follow-up. Dosages in this study were increased in a stepwise fashion in a total of 14 patients. Two patients each took 500 mg/day, 1,000 mg/day, 2,000 mg/day, 3,000 mg/day (these 8 patients took the treatment 1 hour before or 2 hours after meals), and 6 patients took 4,000 mg/day. Those taking the highest dosage were included in the pharmacokinetic investigation. Patients in this cohort fasted 8 hours prior to taking the drug and for 1 hour after taking the treatment. Resveratrol, quercetin, ellagic acid, and urolithin A (a metabolite of ellagic acid) were analyzed, and blood was taken before and after treatment for the first 24 hours at multiple time points and on day 14.
The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) was employed for toxicity assessment. This scale ranges from grade 1 (mild ASE) to grade 5 (death related to ASE). This study considered a dose-limiting toxicity (DLT) to be grade 3 or higher, but did not observe grade 3 or 4. This measurement was done at every week for the initial 4 weeks and for every 3 months until the treatment was stopped (physical exams and blood parameters were employed). PSA concentrations from serum were analyzed, and PSA doubling time (PSADT) was measured after the initial 4 weeks, and subsequently every 3 months. Duration of the study was left to the patient, and those that showed a continual > 50% decrease of PSA concentration were determined to be responsive to the treatment. This study defined PSA progression as elevated PSA concentrations > 50% after 6 months with a minimum increase of 5 ng/dl. This was also defined as > 50% of baseline PSA concentrations, or with evidence of metastasis.
The ASEs in this study were all grade 1, and the median duration of treatment was 19.8 months. ASEs occurred in 5 patients (4 of these were in the 4,000 mg/day group) and were flatulence, soft stool, abdominal distension, and eructation (belching). There were grade 2 and 3 ASEs considered unrelated to the treatment, and no new cancer diagnoses were made during the study. Metastasis resulted in 5 patients being withdrawn; 1 patient left the study due to elevated PSA; and 1 patient was withdrawn because of myasthenia gravis (muscle fatigue considered unrelated to the study). The other 7 patients continued the treatment for 21 to over 30 months.
In 64% of patients, PSADT increased; this was seen for > 6 months in 44% of patients. [Note: It is assumed that this is not significant, as no P values are given.] In 5 patients (3 of these in the 4,000 mg/day group), PSADT was decreased with no significant alteration in diagnosis. The median pretreatment PSADT was 9.4 months, with the median posttreatment PSADT of 11.6 months. There were no patients that had significant decreases in PSA. However, 7 patients that had no observed radiographic progression, despite increased PSA concentrations, were thought to be benefiting from the treatment and continued in the study for 21 to over 30 months. In those participating in the pharmacokinetics study, neither conjugated nor unconjugated resveratrol, quercetin, or ellagic acid were detected. Unconjugated urolithin A was measured in a patient at the 30-minute time point, and conjugated urolithin A was seen in 3 patients at baseline (thought to be due to fruit consumption). The compound was also found in 5 patients at 24 hours posttreatment and 4 patients at day 14.
In this trial, the muscadine grape skin dosage of 4,000 mg/day was found to be both safe and tolerable; however, ellagic acid, quercetin, and resveratrol were not observed in patient plasma samples. It is surmised that this indicates low bioavailability and bioconversion, previously seen with these compounds. The presence of urolithin A in patients at 24 hours and 14 days after consumption indicated some bioavailability, but this was not observed in all patients and was seen in the majority of those patients at baseline. PSADT was not significantly different in the study's patients and even decreased in some. Taken together, this study suggests that muscadine grape skin may not be efficacious for the prevention of prostate cancer recurrence. Despite these early results, the phase II trial was begun with the 4,000 mg/day dosage level to further determine efficacy. The authors stated the phase II study will utilize an alternative method of plasma storage and processing, which will prevent breakdown of polyphenols, and increase accuracy of analysis.
One of the authors, Dr. William D. Wagner, is President and Co-Founder of Muscadine Naturals (Clemmons, NC), has an ownership interest in a manufacturer of muscadine grape skin products, and holds a patent on the manufacturing process.
—Amy C. Keller, PhD
