Questions as to whether or not the prognosis of cancer patients is influenced by hypovitaminosis D status and whether or not vitD supplementation can improve outcomes are attracting increasing interest from clinical investigators.
The published data on circulating vitD levels are generally very sparse and of rather low quality, with eight studies involving patients with different diagnoses or disease stages. Of these studies, five showed a significant negative prognostic role for low serum vitD level, whereas three did not. As a whole, serum vitD level had a prognostic role in two different studies for colon cancer patients; data on breast cancer were conflicting, with one study showing a positive result and one study showing a negative result; and two studies involving NSCLC patients were both negative. The two positive studies involving prostate cancer patients and melanoma patients had no confirmation in an additional case series.
With the exception of colon cancer patients, these results fail to provide support for a large amount of data from ecologic studies showing a prognostic benefit in cancer patients after sun exposure indirectly assessed either by season or latitude [34
These studies suffer from several limitations. First, 25(OH)D levels were determined in blood samples obtained only at one time point, and because circulating 25(OH)D has a half-life of approximately 2 weeks [36
], they are not representative of long-term chronic 25(OH)D levels nor do they reflect the nadir of 25(OH)D reached during the year. In addition, there are no data on whether a change in 25(OH)D level over time influences clinical outcomes in cancer patients. Second, not all trials adjusted for age, race, body mass index, physical activity, and season, which can influence 25(OH)D levels as well as clinical outcomes. Third, hypovitaminosis D is associated with secondary hyperparathyroidism, which could have contributed to the negative prognostic role observed. Parathyroid hormone (PTH) is similar to parathyroid hormone–related peptide, which is a potent growth factor [37
], and both molecules interact with the same receptor that is expressed in several neoplastic cells [38
]. None of the studies assessing circulating vitD levels concomitantly assessed serum PTH. Fourth, different assays were used to determine circulating vitD levels. The assay to determine vitD is not standardized and large variability in 25(OH)D results, both between methods and between laboratories, has been published [39
]. This makes the study results difficult to reproduce in routine clinical practice.
Another important consideration is that not all tumor cells express VDR [19
], and the presence of VDR
polymorphism implies individual susceptibility to vitD biological activity [40
]. These issues further complicate the relationship between circulating vitD level and cancer outcome.
polymorphisms were associated with prognosis in five of 10 papers. These studies suffer several drawbacks: (a) the statistical power is relatively poor; (b) the panel of polymorphisms tested varies among the studies; (c) polymorphisms were tested in blood in some studies and in tumor tissues in others, leading to different interpretations of the results; and (d) some discrepancies between studies involving the same tumor histologies were recorded. That is, Fok1
polymorphism showed prognostic significance in patients with advanced NSCLC [10
] but not in NSCLC patients with early disease [29
Surprisingly, most studies did not measure circulating vitD levels, rendering interpretation of the results difficult. Of the two studies [10
] that assessed both vitD and VDR, only one [16
] explored their prognostic interaction. However, the prognostic significance of several VDR
polymorphisms was limited to patients with very low serum vitD levels. These data suggest that the greater functional activity of some VDR
polymorphisms could protect patients against the negative effects of low vitD levels, but there is no effect in patients with higher vitD levels.
Association does not mean causality, and the serum vitD level might merely be a marker for another causal relationship [41
]. The key question is to understand whether low vitD status increases the risk for death from cancer or is simply a consequence of poor health resulting from neoplastic disease. If the first hypothesis is true, then supplementation with vitD is likely to improve the prognosis for cancer patients.
Three prospective RCTs explored the prognostic role of vitD supplementation in prostate cancer patients with advanced castration-resistant disease. In the two randomized phase II studies, vitD supplementation was found to lead to a significantly longer OS time in one, and essentially superimposable survival results were obtained in the other. Following on the encouraging results from the positive study, a prospective phase III trial was designed but then was prematurely discontinued because of an excessively high mortality rate in the control arm.
The most interesting finding to emerge from the meta-analysis was the striking heterogeneity in trial results. How are we to interpret these contradictory data? These clinical trials used either a synthetic vitD analog (Hectoral®) or activated vitD (DN-101), rather than parent vitD (cholecalciferol), which would influence serum 25(OH)D levels.
Moreover, if we look at the prognostic role of serum vitD and classify patients by the percentile distribution of values (), it appears that prognosis progressively improves with increasing serum levels: the greater the vitD serum level attained, the better the prognosis. This relationship may not necessarily hold true, however. A study by Goodwin et al. [13
] explored the prognostic role of vitD considering the serum level as a continuous variable. The results showed that the relationship between vitD serum level and cancer prognosis may not be linear, but may be U-shaped instead, with a greater hazard for death both at a serum vitD level <32 ng/mL and at a serum vitD level >44 ng/mL. Of note is the fact that a similar nonlinear relationship was found between vitD status and cardiovascular events [42
]. Accordingly, not only hypovitaminosis D but also hypervitaminosis D could have a negative effect on prognosis. The finding that both low and high vitD levels are associated with a higher prostate cancer risk [43
] suggests a stimulatory role of cancer growth in both conditions.
Finally, because the efficiency of the biological activity of vitD is mediated by the inheritance of VDR polymorphisms, the alleles associated with better vitD function can be protective against poor prognosis in cases of hypovitaminosis D, but they may have an opposite effect when high vitD levels result from supplementation.
In summary, the heterogeneity in VDR expression in prostate cancer patients, the nonlinear relationship between the serum vitD level and prognosis, together with an individual's susceptibility to vitD biological effects linked to VDR polymorphisms could account for the higher mortality observed in the ASCENT-II prospective trial in vitD-treated patients than in their non–vitD-treated counterparts.
Unfortunately, neither serum vitD nor VDR polymorphism was measured in patients enrolled in the prospective trials, precluding any exploratory prognostic analysis in the populations of supplemented and nonsupplemented patients.
From a methodological perspective, several potential limitations should be considered when interpreting the results of our systematic review of observational studies. Of particular relevance are the problems we encountered with identifying all studies, with assessing the risk for bias in each study because of poor reporting, and with determining the presence of residual confounding. Even more importantly, we needed to take into account multiplicity of analyses and selective reporting and publication, because most of the studies were exploratory in nature and without confirmatory results.
Also, the three RCTs evaluating the potential benefit of vitD administration in advanced prostate cancer patients suffered from some limitations. Two of them were phase II studies with biochemical response as the primary endpoint [31
] and the third used different schedules of docetaxel in the two arms [33
]. Moreover, these clinical trials used either a synthetic vitD analog (Hectoral®) or activated vitD (DN-101), which are not the standard replacement therapy for low vitD.