Trial Information

Vitamin D3 Supplementation for Low-Risk Prostate Cancer: A Randomized Trial

The central hypothesis of this grant application is that vitamin D3 (cholecalciferol)
supplementation will benefit Veteran subjects diagnosed with early-stage, low-risk prostate
cancer, who elect to have their disease monitored through active surveillance. Specifically,
we hypothesize that Veterans who take vitamin D3 at a daily dose of 4000 international units
(IU) for a minimum of one year (intervention group) will show an improvement in the number
of positive cores and in Gleason score at repeat biopsy, and a decreased likelihood of
undergoing additional treatment (hormone therapy, prostatectomy or radiation therapy),
compared to Veterans taking placebo (control group).

To test this hypothesis, we propose the following Specific Aims:

1. To determine whether vitamin D3 (4,000 IU per day FOR AT LEAST ONE YEAR) will result in
a significant improvement of the pathology status at repeat biopsy in Veteran subjects
taking vitamin D3, compared to Veteran subjects taking placebo. This hypothesis will be
tested through a randomized clinical trial, which will enroll 136 Veteran subjects (68
participants per arm), diagnosed with early-stage prostate cancer (Gleason score 6,
PSA 10, clinical stage T1C or T2a). The pathology status will be measured by the
change in Gleason score and the number of positive cores in prostate needle biopsy
specimens between baseline and the end of the study. Pre- and post-study biopsies will
be performed as part of the standard medical care for diagnosis and active
surveillance.

2. To determine whether vitamin D3 supplementation, compared to placebo, will result in a
significant decrease in the number of Veteran subjects who will undergo additional
treatment (hormone therapy, prostatectomy or radiation therapy), following the outcome
of repeat biopsy.

3. To analyze changes in the serum levels of cholecalciferol, 25(OH)D, 1,25(OH)2D, and
prostate-specific antigen (PSA) at baseline and at the end of the study, and to
estimate the associations between changes in these measures and pathology outcomes
(Gleason score and number of positive cores).

4. To compare the expression of molecular biomarkers, which are prognostically relevant to
prostate cancer progression, in pre- and post- treatment biopsy tissue specimens.
Paraffin-embedded sections will be processed to assess by immunohistochemical
techniques the expression of the following biomarkers: Vitamin D Receptor (VDR), P21,
Tumor Growth Factor (TGF ), Cyclooxygenase 2 (COX-2), and NF B. All of these protein
products impact growth control and chronic inflammation in prostate cancer progression
and are specifically affected by Vitamin D status.

Implementation of the proposed studies would demonstrate that Vitamin D3 supplementation
provides a welcome addition to active surveillance, since patients who respond to Vitamin D3
supplementation (as indicated by a decrease in score or number of positive cores at repeat
biopsy) can safely continue active surveillance and would not need definitive treatment. In
turn, this would result in a decreased likelihood of overtreatment. On the other hand,
subjects who progress after Vitamin D3 supplementation, as indicated by an increase in
Gleason score or number of positive cores at repeat biopsy, may have more aggressive disease
and may need to consider definitive treatment. Therefore, both groups of patients
(responders as well as non-responders) would benefit from Vitamin D3 supplementation, an
intervention strategy that is extremely cost-effective and easy to implement.