Subject recruitment and demographics
Out of the 614 urology patients who were screened, 131 were randomized to either the placebo (62) or the lycopene (69) intervention group (see flow diagram in ). A majority of the patients who were screened (409 subjects) declined to participate in the clinical trial. Among the 48 subjects who did not meet the inclusion criteria of the study, 40 men were already taking dietary supplements containing lycopene, β-carotene and/or α-tocopherol, four were actively abusing alcohol or other substances, and four were being treated for existing cancers other than prostate cancer. No washout period was allowed for men already taking dietary supplements containing antioxidants such as lycopene, since this would have delayed the diagnostic prostate biopsies in these patients. A group of 26 qualified subjects were screened and agreed to participate, but deferred enrollment since they had recently had prostate biopsies, were not diagnosed with cancer, and were currently engaged in a “watchful waiting” program and would enter the study if their serum PSA increased. However, the study was closed before these deferred subjects returned for randomization.
Among the 131 participants who were randomized, a total of 116 participants completed the study (). Eleven subjects withdrew consent before completing the study without giving any explanation, two complained of gastrointestinal disturbances and dropped out of the study, one subject refused the prostate biopsy, and one subject was withdrawn by the investigators because of a new diagnosis of colon cancer which was among the exclusion criteria. Except for gastrointestinal complaints raised by two subjects who withdrew from the study, no adverse effects were observed.
After receiving oral doses of lycopene or placebo for three weeks, all subjects underwent prostate needle biopsy for the diagnosis of BPH or prostate cancer, and two extra biopsies were obtained for measurement of lycopene and DNA oxidation, respectively. The pathology reports indicated that 51 men were diagnosed with prostate cancer and 65 men were diagnosed with BPH. Within the BPH group, 32 men received placebo while the remaining 33 were randomized to receive lycopene. Among the prostate cancer diagnosis group, 23 men received placebo and 28 men received lycopene. Since more than 90% of the men completing the study were African American veterans (105 out of 116), only the African Americans were included in the data analysis. This information is summarized in .
The demographic characteristics of the 105 African American subjects included in the analysis, each intervention group (lycopene or placebo), and each intervention group by diagnosis (prostate cancer or BPH) are shown in . The subjects ranged in age from 50 to 83 years with a mean age of 66.9 ± 7.5 years, and their mean body mass index (BMI) was 28.5 ± 5.3 kg/m2. Approximately 30% of the subjects were current smokers and 46% consumed alcohol regularly. There were no significant differences between the two intervention groups with respect to age, BMI, smoking status, consumption of alcohol, or consumption of dietary carotenoids, lipids and total energy. Comparing the BPH and prostate cancer diagnosis groups (), there were no significant differences in age, BMI, smoking status or consumption of alcohol. When comparing the men with a diagnosis of BPH with respect to randomization into placebo or lycopene intervention groups, there were again no significant differences in regard to age, BMI, smoking, or alcohol intake. Although the groups of men diagnosed with prostate cancer who had been randomized to receive either placebo or lycopene () were similar with respect to age (P = 0.56), BMI (P = 0.59) and alcohol consumption (P = 0.93), there was a significant difference in the smoking status of these two groups (P = 0.009). Whereas 23.8% of the men diagnosed with prostate cancer and randomized to the placebo group were current smokers, 42.3% of the men with prostate cancer who had been randomized to receive lycopene were current smokers (). For comparison, 26.7% of the men with BPH who received placebo were smokers, and 28.6% of the men diagnosed with BPH were randomized to the lycopene group.
Demographic characteristics of all study subjects included in the analyses, the subjects by intervention group and the subjects by both intervention and diagnosis groups.
The plasma concentrations of lycopene were determined using LC-MS-MS for each subject at the start of the intervention (time 0) and at the end of the 21-day intervention period. Since prostate biopsies were obtained only at the end of the 21-day intervention period, there were no baseline prostate tissue biopsies, and lycopene levels in tissue were measured only at day 21. These data are summarized in for all subjects receiving either placebo or lycopene. shows the lycopene results for the subsets of subjects according to diagnosis of prostate cancer or BPH. When comparing the plasma lycopene concentrations at baseline for both treatment groups and for both diagnosis groups, no significant differences were observed. Furthermore, no significant differences were observed in the mean changes in plasma lycopene concentration (day 0 vs. day 21) between smokers and non-smokers or between men who did or did not consume alcohol.
Clinical outcomes of the entire study group.
Clinical outcomes of the prostate cancer and BPH groups.
Men who received lycopene at 30 mg/day for 21 days showed a significant increase in mean plasma lycopene concentration (mean difference 0.69 ± 0.59 μM) compared with the placebo group (mean difference -0.013 ± 0.260 μM) (P < 0.0001). Mean plasma lycopene concentration increased 1.93-fold in the lycopene intervention group from 0.741 ± 0.388 μM at day 0 to 1.428 ± 0.613 μM at day-21 (P < 0.0001). In the placebo group, the mean lycopene concentration was essentially unchanged () between baseline (0.599 ± 0.373 μM) and day 21 (0.588 ± 0.392 μM). For subjects who were diagnosed with prostate cancer or BPH (), plasma lycopene concentrations also increased approximately 2-fold in the lycopene intervention group but not in the placebo group, and these differences were also significant (P < 0.0001).
Lycopene levels in prostate biopsy tissue from men who received lycopene for 21-days were compared with prostate biopsy tissue from men who received placebo (). Lycopene levels in prostate tissue were significantly higher in the lycopene intervention group compared with the placebo group (; P = 0.005). This was confirmed using non-parametric, Kruskal-Wallis one-way analysis of variance. When changes in lycopene levels in prostate biopsy tissue due to lycopene supplementation were compared for the prostate cancer group or for the BPH group (), lycopene still increased in men who received 30 mg/day lycopene, but the differences between the treatment and placebo control groups were less significant due to the smaller sample size.
Levels of the DNA oxidation biomarker 8-oxo-dG were measured in prostate tissue as an indication of oxidative stress in the prostate, and the lipid peroxidation product malondialdehyde was measured in plasma as an indication of systemic oxidative stress. The mean levels of 8-oxo-dG were determined in prostate tissue biopsies obtained at the end of the 21-day intervention with lycopene or placebo. The mean concentration of 8-oxo-dG for the entire study group of African Americans was 35% lower in the lycopene treatment group (125 ± 83 8-oxo-dG/106 dG) compared with the placebo group (193 ± 341 8-oxo-dG/106 dG), but this difference was not significant (P = 0.22) ().
The levels of 8-oxo-dG in prostate tissue of men diagnosed with BPH () were 48% lower in the men receiving 30 mg/d lycopene for 21 days (117 ± 89 8-oxo-dG/106 dG) compared with the placebo group (245 ± 425 8-oxo-dG/106 dG). Although not significant (P = 0.15), this difference suggested a trend of lower 8-oxo-dG levels in men diagnosed with BPH receiving lycopene intervention. In the men diagnosed with prostate cancer (), levels of 8-oxo-dG in prostate tissue were essentially identical in men receiving lycopene or placebo for 21 days. Possible differences in prostate 8-oxo-dG levels due to smoking were investigated, but there were no significant differences observed between men who smoked and those who did not smoke.
The mean concentrations of malondialdehyde in the entire study group before and after intervention with lycopene are shown in . Since the concentrations of malondialdehyde did not follow a normal distribution, the values were log-transformed for statistical evaluation. At baseline, there was no difference between the subjects randomized to receive placebo and those randomized to lycopene, and after 21-day intervention with 30 mg/day lycopene, there was no significant change in plasma malondialdehyde levels in the placebo or the lycopene groups ().
Among the men diagnosed with BPH, mean malondialdehyde levels in plasma decreased 5.1% (from 0.195 ± 0.140 μM to 0.185 ± 0.152 μM) after treatment with lycopene but were unchanged after receiving placebo for 21 days (). However, these differences were not significant. Although mean malondialdehyde levels increased 34.8% in the plasma of men diagnosed with prostate cancer and randomized to the placebo group (from 0.132 ± 0.097 μM to 0.178 ± 0.136 μM) but only increased 5.1% in men receiving lycopene (from 0.235 ± 0.150 μM to 0.247 ± 0.159 μM), this difference was also not significant (P= 0.34).
Smoking did not affect malondialdehyde levels in the placebo group or in the lycopene treatment group. Smoking also did not alter the variation of malondialdehyde levels in either the BPH diagnosis group or the prostate cancer diagnosis group. No effects of alcohol consumption were observed in these groups.