Vitamin D and Melanoma: What Do We Tell Our Patients?

Although at one time vitamin C was touted as a potential cure for cancer, no vitamin has received more attention in recent years—perhaps even notoriety—for its possible association with cancer causation and outcomes than vitamin D. Given the wellknown role of UVexposure in vitamin D synthesis, it is natural that studies would seek to shine light on the relationship of vitamin D levels on incidence and outcome of melanoma and other skin cancers. Despite the obvious significance of this line of scientific inquiry, there is at present more (infrared) heat than (UV) light. In this issue, Fang et al present a well-conducted study of 1,042 patients from a prospectively observed cohort of patients with melanoma who had plasma available for subsequent testing of 25-hydroxyvitamin D and C-reactive protein levels. Most patients had specimens drawn well after the time of initial diagnosis, sometimes more than a year after (interquartile range, 0.1 to 2.4 years), but all samples were drawn before the initiation of any systemic therapy; the median follow-up time from blood draw was an impressive 7.1 years. There was a nonsignificant trend toward lower vitamin D levels with increasing time from diagnosis (P 5 .0872), but, in 66 patients who had more than one specimen available for serial analysis, there was no evidence of such a decline with time. The median vitamin D level was 25.0 ng/ml, which was less than the authors’ arbitrarily selected level of insufficiency (, 30 ng/ml); one quarter of patients were vitamin D deficient on the basis of the conventional threshold of less than 20 ng/ml. The authors constructed a multivariable model that included standard histologic prognostic factors, stage, season of blood draw (vitamin D levels were significantly higher when drawn in spring or summer than in fall or winter), and C-reactive protein. The authors had previously shown in the same cohort of patients with melanoma that C-reactive protein was an independent prognostic factor, and the authors found an inverse association in this analysis between C-reactive protein levels and vitamin D levels. In this multivariable model, vitamin D levels were significantly associated with overall survival, melanoma-specific survival, and disease-free survival. The optimal cutoff level, as defined by recursive partitioning, was 16 ng/ml (a widely accepted deficient vitamin D level). Patients with melanoma who had a level less than 16 ng/ml were 1.62 times more likely to experience recurrence and were 1.76 times more likely to die as a result of melanoma. These results closely mirror another recently published, large, cohort study from England, in which patients with 25-hydroxyvitamin D levels (not adjusted for C-reactive protein level) less than 20 nmol/L (8 ng/ml) were 1.52 times more likely than those with higher levels to die as a result of melanoma. Given these data, several questions should be raised that have implications for our patients and our practices. Should our patients be worried that sun avoidance is actually increasing their chance of dying of melanoma? This question is easy to answer with an emphatic no. First, the available cohort-based evidence is insufficient in itself to establish a cause-and-effect relationship between vitamin D and melanoma recurrence and death or to define the potential mechanisms for such an effect, if it were to exist. More important, prolonged unprotected sun exposure does not guarantee a high serum vitamin D level: a study of 93 surfers in Hawaii with self-reported sun exposure averages of 22.4 hours per week and little or no sunscreen use found that their median vitamin D level was only 30 ng/ml, and one quarter of them had levels in the deficient range (, 20 ng/ml) that was associated with the poorer melanoma outcomes cited above. The message to our patients should be clear: if you are worried about your vitamin D level, or if you have been found to have insufficient or deficient levels, oral supplementation, rather than unprotected sun exposure, is the appropriate approach. Is there any harm from taking vitamin D supplements? This question can also be answered emphatically: yes. The health effects of excessively elevated levels of vitamin D have not been well studied, but adverse risks of supplementation, including hypercalcemia, are well documented. Patients who take supplementation, particularly in high doses (eg, . 5,000 IU/day), should be aware of the risk of overdosing and should have their vitamin D levels monitored periodically. Should every newly diagnosed patient with melanoma have a serum vitamin D level determined? This is a more difficult question to answer, and certainly no definitive statement can yet be made, although evidence to support this approach seems to be mounting. Although one might think that the high sun exposure and fair skin coloration of the typical patient with melanoma would mean that most patients would have normal vitamin D levels at diagnosis, a significant number of patients with melanoma in the cohorts studied were serologically vitamin D deficient; as noted above, sun exposure alone does not guarantee vitamin D sufficiency.