Page 199 - Vitamin D and Cancer

186 S.A. Mazzilli et al.

There are limitations to this trial. The dose of vitamin D may not have been
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large enough to substantively change vitamin D status, to the range seen in epide-
miologic studies. Since the start of the WHI, other supplementation studies have
used doses more in the range of 800–2,000 IU vitamin D/day. This is compounded
by compliance issues. Particularly in the colorectal analysis, the authors suggest
that since participants were not discouraged from taking additional calcium and
vitamin D supplements and reported an increased in supplementation that was
greater than the national average, the drop-in to the treatment would make differ-
ences in CRC between treatment groups more difficult to detect. Finally, the length
of follow-up was in the range of 7 years. It may be that the length of treatment to
change to course of CRC progression may be more in the range of 10–20 years.
Designing a chemoprevention trial with treatment phases of 1–2 decades is not
feasible. To continue to investigate vitamin D and calcium for CRC prevention,
alternative designs could include forms of these agents that have greater expected
effect sizes or the use of intermediate biomarkers as endpoints, such as colorectal
adenomas or genetic changes, may be employed.

8.3.2 Colon Cancer Prevention

A study by Lappe et al. was a 4-year double-blind, placebo-controlled randomized
trial of 1,179 postmenopausal women from rural Nebraska [38]. These women were
randomized to either 1,400–1,500 mg/day of calcium alone, calcium plus 1,100 IU of
vitamin D , or matched placebo. Subjects were 55 years or older, no history of cancer
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and capable of 4 years of participation. Mean age was 66.7 years, mean body mass
index was 29 (±5.7) nmol/L and baseline 25(OH)D was 71.8 (±20.3) nmol/L. The
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primary outcome was fracture but colon cancer was a formal secondary endpoint. The
vitamin D intervention was sufficient to raise the serum 25(OH)D to >80 nmol/L.
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Overall, both the calcium alone and calcium with vitamin D groups showed a signifi-
cant difference (Chi-square = 7.3; p value < 0.03) and the calcium plus vitamin D
group showed a relative risk (RR) of 0.40 (95% CI = 0.20–0.82; p = 0.013). When
participants with cancers that developed within the first year were excluded, the cal-
cium plus vitamin D group showed a relative risk (RR) of 0.23 (95% CI = 0.09–0.60;
p = 0.013). This restriction of cases had no effect on the risk estimates for the calcium
alone group, suggesting that the benefit of the vitamin D supplements on new cancers
was attenuated by cancers that were most likely preclinical at the time of
randomization.
Serious adverse events and toxicities: No serious adverse events were reported.
There was no difference in the reports of renal calculi between treatment groups.
A study by Fedirko et al. reported a pilot, randomized, double-blind trial with a
factorial design to evaluate the effects of vitamin D (800 IU/day) and calcium (2 g/day)
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on biomarkers in the normal colorectal mucosa [39, 40]. Ninety-two women and men
were recruited and treated for a period of 6 months. Several markers, including p21,
MIB-1, hTERT, Bcl-2 and Bax were evaluated in the colonic crypts. Results showed