Vitamin D Deficiency in Metastatic Melanoma

Retrospective study finds association

By Michael Traub, ND, DHANP, FABNO, and Miranda LaBant, ND

Reference

Timerman D, McEnery-Stonelake M, Joyce C, et al. Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma. Oncotarget. 2017;8(4):6873-6882.

Study Objective

To determine whether vitamin D deficiency and repletion are associated with melanoma outcome. Patients with 25-hydroxyvitamin D3 (25[OH]D3) <21 ng/mL were advised to take 50,000 IU vitamin D3 per week for 8 weeks and then continue with 4,000 IU per week.

Design

Retrospective single-center study of medical records from January 2007 through June 2013.

Participants

Records from 252 individuals with a 25(OH)D3 level recorded within 1 year after histopathological diagnosis of melanoma were included in the study. Individual and melanoma characteristics such as age, sex, Breslow’s thickness, ulceration, stage, mitotic rate, and lactate dehydrogenase (LDH) levels were obtained from medical records. Subgroup analysis included 168 patients with a subsequent 25(OH)D3 level that had been recorded at any time (ie, patients with more than 1 vitamin D level in their records).

Study Parameters Assessed

Vitamin D deficiency status was based on current practice guidelines from the Endocrine Society. For comparison, the analysis included effects of changes in 25(OH)D3 levels on survival.

Primary Outcome Measures

Vitamin D levels, markers of melanoma growth (LDH levels, mitotic growth, ulceration, stage), and survival/death.

Key Findings

Patients who died were more likely to have vitamin D deficiency (<21 ng/mL; P=0.012), LDH>240 U/L (P<0.001), older age (>50 years; P=0.007), higher stage (P<0.001), ulceration (P=0.001), and higher mitotic rate (P=0.001) compared to those who were alive or lost to follow-up at the end of the study. Patients with vitamin D deficiency (<21 ng/mL) were more likely to have a higher stage of disease (P=0.01) as well as higher mortality (P=0.012). Patients with metastatic melanoma who were deficient and taking vitamin D but did not obtain ≥20 ng/dL increase in serum levels had a worse prognosis (hazard ratio [HR]: 4.68; 95% confidence interval [CI]: 1.05-20.88) than those who were vitamin D replete and had >20 ng/mL increase in vitamin D. Collectively, these results suggest that initial vitamin D deficiency and insufficient repletion is associated with a worse prognosis in patients with metastatic melanoma.

Practice Implications

Melanoma diagnoses in the United States increased at a rate of 3.1% per year from 1992 to 2004.1 Lifetime risk of melanoma in the United States is 1 in 39 for Caucasian men and 1 in 58 for Caucasian women.2 The increased risk for this commonly fatal skin cancer has driven research in both prevention and treatment.

Much debate surrounds the relationship between vitamin D and cancer, including melanoma.3-5 This study confirms earlier studies that found lower serum 25(OH)D levels were associated with increased melanoma risk, greater Breslow thickness, and worse overall survival,6 and that 25(OH)D level during follow-up was an independent prognostic marker.7 The association of vitamin D and risk of melanoma, however, is confounded by other studies showing no association between vitamin D levels and mortality, and studies that show increased melanoma incidence in patients with high levels of vitamin D.8,9 Yet in this regard, it is important to consider that melanoma risk is related to repeated overexposure to ultraviolet B (UVB) radiation (blistering sunburns) rather than cumulative lifetime exposure.

Collectively, these results suggest that initial vitamin D deficiency and insufficient repletion is associated with a worse prognosis in patients with metastatic melanoma.

Given that patients with melanoma are counseled to avoid sun exposure and take supplemental vitamin D, this study provides an evidence basis for such a recommendation. One of these reviewers (Traub) has published a study providing evidence that a repletion strategy of 10,000 IU of vitamin D3 for 3 months is safe and effective.10

The authors of the study reviewed here suggest that since serum 25(OH)D has been associated with a robust immune response, it might be considered a marker of immune sufficiency in patients with metastatic melanoma. Similarly, UV radiation, in particular the UVB range, is known to be immunosuppressive to the skin. DNA damage induced by UVB is not only a carcinogen but also a major trigger of UV-induced immunosuppression.11

We were unable to verify the sources and dosage of vitamin D supplements taken by participants in the study. We also acknowledge that large prospective clinical trials of patients with melanoma receiving vitamin D supplementation are necessary to prove a causal relationship.

The main takeaway is that we should obtain 25(OH)D3 levels for all patients with melanoma, and for those who are deficient, supplement with vitamin D3 until repletion. We should maintain repletion with 2,000 to 4,000 IU daily. Use the same strategy for patients with a history of melanoma, to prevent recurrence.

About the Authors

Michael Traub ND, DHANP, FABNO, has been practicing in Hawaii since 1985. He is past-president of the American Association of Naturopathic Physicians (AANP) and received the AANP’s Naturopathic Physician of the Year award in 2006. He is the author of Essentials of Dermatological Diagnosis and Integrative Therapeutics. His website is www.michaeltraubnd.com.

Miranda LaBant, ND, graduated from National University of the Health Sciences in Lombard, IL, in December 2016. This spring she began her 2-year naturopathic oncology residency program at Lokahi Health Center under the direction of Michael Traub, ND, DHANP, FABNO, in Kailua Kona, HI. She was born and raised in Northeast Ohio, where she completed her masters of health sciences degree at Cleveland State University. LaBant is passionate about endocrine and gastrointestinal health, integrative oncology, and preventive health and wellness, as well as the use of botanical medicine and biotherapeutic drainage therapies. In her time outside of the office she can be found exploring and hiking the many landscapes of the Big Island.

References

  1. Linos E, Swetter SM, Cockburn MG, Colditz GA, Clarke CA. Increasing burden of melanoma in the United States. J Invest Dermatol. 2009;129(7):1666-1674.
  2. Rigel DS, Russak J, Friedman R. The evolution of melanoma diagnosis: 25 years beyond the ABCDs. CA Cancer J Clin. 2010;60(5):301-316.
  3.  Jensen JD, Wing GJ, Dellavalle RP. Nutrition and melanoma prevention. Clin Dermatol. 2010; 28(6):644-649.
  4. Tong LX, Young LC. Nutrition: the future of melanoma prevention? J Am Acad Dermatol. 2014; 71(1):151-160.
  5. Reddy KK, Gilchrest BA. The role of vitamin D in melanoma prevention: evidence and hyperbole. J Am Acad of Dermatol. 2014;71(5):1004-1005.
  6. Bade B, Zdebik A, Wagenpfeil S, et al. Low serum 25-hydroxyvitamin D concentrations are associated with increased risk for melanoma and unfavourable prognosis. PloS One. 2014; 9(12):e112863.
  7. Saiag P, Aegerter P, Vitoux D, et al. Prognostic value of 25-hydroxyvitamin D3 levels at diagnosis and during follow-up in melanoma patients. J Natl Cancer Inst. 2015;107(12):djv264.
  8. 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.
  9. van der Pols JC, Russell A, Bauer U, et al. Vitamin D status and skin cancer risk independent of time outdoors: 11-year prospective study in an Australian community. J Invest Dermatol. 2013; 133(3):637-641.
  10. Traub M, Finnell J, Bhandiwad A, et al. Impact of vitamin D3 dietary supplement matrix on clinical response. J Clin Endocrinol Metab. 2014;99(8):2720-2728.
  11. Schwarz T. Mechanisms of UV-induced immunosuppression. Keio J Med. 2005;54(4):165-171.