Fang S, Sui D, Wang Y, et al. Association of vitamin D levels with outcome in patients with melanoma after adjustment for C-reactive protein [published online ahead of print March 21, 2016]. J Clin Oncol. doi: JCO641357.
This observational study is part of an ongoing prospective investigation that includes patients with all stages of invasive cutaneous melanoma. Investigators evaluated blood samples for an association between vitamin D levels and outcome measures in patients with melanoma while controlling for systemic inflammatory response (SIR) based on simultaneous C-reactive protein (CRP) measurements.
Plasma samples from 1,042 prospectively observed patients with melanoma were assayed. Average age at blood draw was 54.8 years. The group was 43.4% female (452 patients). Median vitamin D level was 25.0 ng/ml. Of the participants, 24.6% had vitamin D levels <20 ng/ml; 47.7% had levels >20 ng/ml and ≤30 ng/ml; and 27.7 % had levels >30 ng/ml. Median CRP was 1.7. The participants were followed for a median of 7.1 years.
Progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS). In addition, Kaplan-Meier and Cox regression analyses were performed.
Lower vitamin D in patients with melanoma was associated with poorer outcomes. Although lower vitamin D was strongly associated with higher CRP, the associations of low vitamin D with poorer OS, MSS, and PFS were independent of this association.
A lower vitamin D was associated with the blood draw during fall/winter months (P<0.001), older age (P=0.001), increased CRP (P<0.001), increased tumor thickness (P<0.001), ulcerated tumor (P=0.0105), and advanced melanoma stage (P=0.0024).
Their data suggest that higher levels of vitamin D do indeed provide benefit.
On univariate analysis, lower vitamin D was associated with poorer overall survival (OS; P<0.001), melanoma-specific survival (MSS; P=0.0025), and disease-free survival (DFS; P=0.0466). The effect of vitamin D on these outcome measures persisted after adjustment for CRP and other covariates. Multivariable hazard ratios (HRs) per unit decrease of vitamin D were 1.02 for OS [95% confidence interval (CI): 1.01 to 1.04; P=0.0051], 1.02 for MSS (95% CI: 1.00 to 1.04; P=0.048), and 1.02 for DFS (95% CI: 1.00 to 1.04; P=0.0427).
At levels below the optimal cutoff of 16 ng/mL (determined by recursive partitioning) patients had poorer OS (HR: 2.0; 95% CI: 1.50-2.66; P<0.001), MSS (HR: 1.76; 95% CI: 1.22-2.53; P=0.003), and DFS (HR: 1.62; 95% CI: 1.04-2.53; P=0.036) on univariate analysis, and associations remained significant on multivariable analysis.
While the role vitamin D plays in melanoma remains confusing, these findings suggest that interventions to increase vitamin D or to reduce the systemic inflammatory responses might benefit patients with melanoma.
Our general assumption that vitamin D is protective against all cancer has not been clear when it comes to melanoma. We are trying to predict the outcome of 2 competing actions related to sun exposure. Sun exposure increases vitamin D levels, and so could lower melanoma risk, but, at the same time, sun exposure increases skin damage, which could increase risk. Which of these actions will win out?
In vitro, vitamin D looks good; it has antiproliferative effects on melanoma cells, inhibits tumor growth and invasion, and promotes DNA repair.1-4 Yet when it comes to humans, the past studies (in vivo) on vitamin D and melanoma have been conflicting.
A 2012 prospective study by Major et al was the first to look for an association between vitamin D and melanoma risk. They reported no significant association.2
In March of 2013 Reddy reported that vitamin D levels greater than 30 ng/ml were associated with increased risk of melanoma.5 That same month, Afzal reported that the risk of melanoma was 4.7 times higher for those with a vitamin D level over 20 ng/ml compared to those who had levels less than 10 ng/ml.6
Caini et al performed a meta-analysis published in October 2014 in the European Journal of Cancer. They combined data from 20 separate studies and compared highest versus lowest vitamin D levels. While the authors reported a 14% decrease in relative risk (RR) between the highest versus lowest quintile of vitamin D intake (RR=0.86; 95% CI: 0.63-1.13) for cutaneous melanoma, these results did not reach statistical significance.7
It was only last year, in June 2015, that data suggesting that vitamin D was associated with significant benefit in those with a history of melanoma was published.
Newton-Bishop followed a group of 2,182 melanoma patients for almost 8 years and reported that higher vitamin D levels at diagnosis were associated with lower risk of death from melanoma, and that low levels of vitamin D were associated with a greater than 50% increase in risk.8
While it remains unclear whether or not vitamin D levels will be associated with the risk of developing melanoma, this current paper by Fang et al answers a different question: Does vitamin D affect prognosis for someone with melanoma? Their data suggest that higher levels of vitamin D do indeed provide benefit, although it may not take much vitamin D to do so. Note again that their data analysis found that serum levels above 16 ng/ml were associated with significantly better outcomes.
While we tend to consider vitamin D “the good guy” in these scenarios, both the Newton-Bishop paper and the Fang paper speak of vitamin D as a possible biomarker. Both research groups ask whether the action of vitamin D depends on its effect as an anti-inflammatory. Both studies also looked at CRP levels in their cohorts. In melanoma patients there is an inverse association between vitamin D and CRP. Even the slightly lower vitamin D levels measured during the winter months were associated with higher CRP levels. Fang showed that after adjustment for CRP, vitamin D remained an independent predictor of OS, MSS, and DFS, suggesting that although vitamin D and CRP are highly correlated with each other, they act independently to predict clinical outcome in melanoma patients. While it is not proven yet, we can and should consider both markers as targets for our clinical intervention in this patient population.
Several clinical trials are underway that may eventually provide better answers. In Australia, there is the MEL-D Trial, a prospective placebo-controlled trial in which patients diagnosed with cutaneous melanoma receive vitamin D as an adjuvant therapy after completing primary treatment. In this study, patients receive a large oral loading dose of vitamin D (500,000 IU) followed by a lower dose of 50,000 IU once a month for 2 years.9
Another clinical trial, the MelaViD Trial, is underway in Europe. Patients will receive 100,000 IU of vitamin D3 every 50 days for 3 years. Expected completion of this study is in 2025.10
In the meantime, we should continue to monitor our patients for vitamin D deficiency, which certainly appears to worsen prognosis.
- Seifert M, Rech M, Meineke V, Tilgen W, Reichrath J. Differential biological effects of 1,25-dihydroxyVitamin D3 on melanoma cell lines in vitro. J Steroid Biochem Mol Biol. 2004;89-90(1-5):375-379.
- Major JM, Kiruthu C, Weinstein SJ, et al: Pre-diagnostic circulating vitamin D and risk of melanoma in men. PLoS One. 2012;7(4):e35112.
- Meyskens FL Jr, Farmer PJ, Anton-Culver H. Diet and melanoma in a case-control study. Cancer Epidemiol Biomarkers Prev. 2005;14(1):293.
- Millen AE, Tucker MA, Hartge P, et al. Diet and melanoma in a case-control study. Cancer Epidemiol Biomarkers Prev. 2004;13(6):1042-1051.
- Reddy KK. Vitamin D level and basal cell carcinoma, squamous cell carcinoma, and melanoma risk. J Invest Dermatol. 2013;133(3):589-592.
- Afzal S, Nordestgaard BG, Bojesen SE. Plasma 25-hydroxyvitamin D and risk of non-melanoma and melanoma skin cancer: a prospective cohort study. J Invest Dermatol. 2013;133(3):629-636.
- Caini S, Boniol M, Tosti G, et al. Vitamin D and melanoma and non-melanoma skin cancer risk and prognosis: a comprehensive review and meta-analysis. Eur J Cancer. 2014;50(15):2649-2658.
- Newton-Bishop JA, Davies JR, Latheef F, et al. 25-Hydroxyvitamin D2 /D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort. Int J Cancer. 2015;136(12):2890-2899.
- Saw RP, Armstrong BK, Mason RS, et al. Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial (ANZMTG 02.09 Mel-D). BMC Cancer. 2014;14:780.
- European Institute of Oncology. MelaViD: A Trial on Vitamin D Supplementation for Resected Stage II Melanoma Patients (MelaViD). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Last updated October, 2015. Accessed May 26, 2016. Available from: https://clinicaltrials.gov/ct2/show/NCT01264874.