Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance

Abstract

Context: We wanted to investigate vitamin D in low-risk prostate cancer.

Objectives: The objective of the study was to determine whether vitamin D(3) supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen (PSA) or in the rate of progression.

Design: In this open-label clinical trial (Investigational New Drug 77,839), subjects were followed up until repeat biopsy.

Setting: All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, both in Charleston, SC.

Patients and other participants: All subjects had a diagnosis of low-risk prostate cancer. Fifty-two subjects were enrolled in the study, 48 completed 1 yr of supplementation, and 44 could be analyzed for both safety and efficacy objectives.

Intervention: The intervention included vitamin D(3) soft gels (4000 IU).

Main outcome measures: Adverse events were monitored throughout the study. PSA serum levels were measured at entry and every 2 months for 1 yr. Biopsy procedures were performed before enrollment (for eligibility) and after 1 yr of supplementation.

Results: No adverse events associated with vitamin D(3) supplementation were observed. No significant changes in PSA levels were observed. However, 24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score.

Conclusion: Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3) supplementation at 4000 IU/d.

Fig. 1.

Entry vs. exit (after treatment) serum values of 25(OH)D, PTH, and PSA. Each black point represents an individual subject. A–C, Entry values are read off the horizontal x-axis (baseline); exit values are read off the vertical y-axis (exit). D–F, Change in serum values of 25(OH)D, PTH, and PSA, respectively. The marked empty square ([X]) in each panel represents the mean entry and posttreatment value (A–C) and the mean change in value for each parameter (D–F). Note the significant increase in 25(OH)D serum values (P < 0.00001), the significant decrease in PTH serum values (P = 0.00002), and the overall stability of PSA serum values after vitamin D₃ supplementation (P = 0.27).

Fig. 2.

Comparison of repeat biopsy outcome in vitamin D₃-supplemented subjects. Estimates (in percent) of progression (A) and improvement (B) for all analyzable subjects (n = 44, y-axis) and by entry values of serum 25(OH)D (<20 ng/ml vs. >20 ng/ml, x-axis) are shown. Bars are exact 95% confidence intervals (CI). Progression (CI in parentheses): 34% of all subjects (0.20, 0.50); 45% of vitamin D-deficient subjects (0.17, 0.77); and 30% of nondeficient subjects (0.16, 0.49). Improvement (CI in parentheses): 55% of all subjects (0.39, 0.70); 36% of vitamin D-deficient subjects (0.11, 0.69); and 61% of nondeficient subjects (0.42, 0.77).

Fig. 3.

Comparison of repeat biopsy outcome between vitamin D₃-supplemented subjects and historical controls. A, Supplemented subjects appeared to have a lower rate of progression (P = 0.0514) compared with baseline. B, Supplemented subjects appeared to have a significantly higher rate of improvement (P = 0.0257) compared with baseline. Bars are exact 95% confidence intervals (CI).

Fig. 4.

Trajectories of number of positive cores over time in subjects supplemented with vitamin D₃ (A) and untreated historical control subjects (B). A and B, Gray lines represent individual patient data, and thick solid black lines are the fitted estimate including all data within 48 months of baseline. The gray circles at the ends of some of the gray lines refer to subjects with an increase of Gleason score at repeat biopsy or a decrease of Gleason score from baseline. A, The thick solid black lines are the fitted estimates including all data for 24-, 36-, and 48-month follow-up period, respectively. The slopes are identical between the 24- and 48-month time thresholds (b = −0.0146), whereas the slope of the 36-month threshold is slightly flatter (−0.0125). All corresponding P values are significant: 0.0090 (24 months); 0.0098 (36 months); 0.00093 (48 months). B, The slope is not significantly different from 0 (P = 0.17). However, the slopes in A and B (based on all follow-up data) are significantly different from each other (P = 0.002).

Fig. 5.

Change in serum levels of cholecalciferol (left panel) and calcitriol (right panel) between baseline (visit 1) and exit (visit 8). Black lines and open circles represent individual values at baseline and exit; thick lines and closed circles show mean values at baseline and exit. Testing that there is a difference in visit 1 vs. visit 8 values, both measures show significance, although cholecalciferol levels (in nanograms per milliliter of serum) increased more dramatically than 1,25(OH)₂D levels (in picograms per milliliter of serum) (calcitriol: P = 0.023 based on paired t test; P = 0.016, based on nonparametric signed rank test; cholecalciferol: P < 0.0001 based on paired t test; P = 0.0003 based on nonparametric signed rank test).