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The risk of aggressive prostate cancer
(palpable mass or Gleason score 7–10) in men in the top
quartiles of serum 25(OH)D and 1,25(OH)2D was
extremely low (relative risk 0.03, not significant) in men
older than 57 years of age (the median age of the cohort)
(9). These effects were not present in younger men or forserum 25(OH)D alone. Earlier studies of vitamin D status
and prostate cancer risk had mixed results (62).
A nested case-control study of the PLCO cohort by Ahn
et al. (16) found no association between serum 25(OH)D
and odds ratios for prostate cancer. The results from the
PLCO study of prostate cancer conflict with studies that
used longer median periods of follow-up, such as 11 to 12
years (9, 10), suggesting that the follow-up interval in the
PLCO cohort studies may have been too short for reliable
detection of the association.
Cancer of the Ovary
Ecological studies first identified higher ovarian cancer
mortality rates in areas of higher latitude and lower levels
of solar irradiance (63–66). These have been supported by
observational studies of dietary intake of vitamin D (25)
and of prediagnostic serum 25(OH)D (6). Lower prediagnostic
serum 25(OH)D was associated with high risk of
ovarian cancer in overweight women, although not in
thinner women (6).
Cancer of Other Sites
Ecological studies also have reported inverse associations of
total solar or UVB irradiance with risk of renal (67) and endometrial
(68) cancers. These associations have generally persisted
after adjustment for potential confounders, such as
dietary factors and/or per capita health care expenditures. A
complete listing of cancers inversely associated withUVBirradiance
in theUnited States is available that includesmultivariate
adjustment usingmultiple regression to control for several
pertinent demographic and behavioral covariates (69)
Clinical Trials
Geographic studies of the inverse association of sunlight
with colon cancer (70) and breast cancer mortality (71–
74) and of dietary vitamin D and calcium with colon cancer
incidence (19–22) stimulated initiation of randomized
controlled prevention trials that provided measurements of
the effects of vitamin D and calcium on human cancer incidence
(55, 75, 76). The most recent randomized controlled
trial (RCT), by Lappe et al. (76), found that supplementation
of postmenopausal women with 1,100 IU/day of vitaminD3, in conjunction with 1,450 mg/day of calcium, yielded
a 60% reduction in incidence of all invasive cancers
combined (relative risk 0.40, 95% CI 0.20–0.82, p ! 0.03)
(Fig. 5). There was a 77% reduction in incidence when cases
diagnosed during the first year of follow-up were excluded
(relative risk 0.23, 95% CI 0.09–0.60, p ! 0.01) (Fig. 6)
(76). These profound reductions in incidence of all invasive
cancers occurred within the 4-year duration of the study.
There were parallel trends in the Lappe et al. RCT (76)
for cancers of the breast, colon, lung, and hematopoieticmalignancies, although the trends are based on fewer events
than all cancers (76). About half the reduction in incidence
of all cancers combined appeared to be due to vitamin D3,
and about half to calcium supplementation. Two earlier
negative trials examined data derived from the same study
(55, 75) that used a minimal dose of vitamin D (400 IU)
that was too little to increase serum 25(OH)D by more
than approximately 1 to 3 ng/mL (2–7 nmol/L) by mid-study
in the intervention group compared to the control group.
This trial also experienced substantial noncompliance and
lost considerable power because of a factorial design that
did not take into account an unexpected interaction for
colorectal cancer between the vitamin D–calcium intervention
and a hormone replacement intervention (77).