Recently published evidence supports a survival benefit in patients with higher vitamin D levels at diagnosis in many malignancies….— Jonathan W. Friedberg, MD, MMSc
Tweet this quote
Vitamin D is a steroid-like hormone involved primarily in human calcium homeostasis. Obtained through sun exposure as well as food and dietary supplements,1 vitamin D in humans is metabolized in the liver and kidneys to its active form, 1,25-dihydroxyvitamin D (1,25[OH]2D).2 Other cell types, including immune cells, also express both the 1-α-hydroxylase needed to activate vitamin D and the nuclear vitamin D receptor.2,3 This extrarenal 25(OH)D activation and binding of the vitamin D receptor leads to transcriptional regulation of downstream target genes containing the vitamin D response elements.4 That in turn results in autocrine and paracrine effects biologically relevant to immune responses in the settings of infections and cancer, including regulation of cell proliferation, apoptosis, and differentiation.2
Recently published evidence supports a survival benefit in patients with higher vitamin D levels at diagnosis in many malignancies, including melanoma,5 aggressive prostate cancer,6-8 colorectal cancer,9,10 myelodysplastic syndrome/acute myeloid leukemia,11 and breast cancer.12,13 Several studies also indicate a relationship between lymphoma outcomes and pretreatment vitamin D levels.
For example, in an international SWOG/LYSA collaborative analysis of newly diagnosed patients with follicular lymphoma uniformly treated with standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy plus anti-CD20 therapy, there was a significant association between low vitamin D levels and inferior lymphoma outcomes.14 The magnitude of the association was stronger than the individual clinical prognostic factors,15 and this is the strongest association reported to date of a pretherapy prognostic factor in follicular lymphoma.
Data from the Mayo Clinic extended this observation in follicular lymphoma to patients treated with therapies other than chemotherapy, including single-agent rituximab.16 An analysis from a German study in diffuse large B-cell lymphoma demonstrated that the observed association between vitamin D deficiency and inferior outcome appears limited to patients treated with chemoimmunotherapy compared with chemotherapy alone.17
German Study in Hodgkin Lymphoma
As reviewed in the December 10, 2019, issue of The ASCO Post, in a study recently reported in the Journal of Clinical Oncology, Borchmann and colleagues leveraged several randomized trials from the German Hodgkin Lymphoma Study Group in both early and advanced-stage Hodgkin lymphoma. The investigators demonstrated that vitamin D deficiency at diagnosis (as defined by a level < 30 nmol/L) was prognostic for both progression-free and overall survival.
These findings held even with adjustment for clinical risk factors.18 Moreover, the researchers performed preclinical studies with cultured Hodgkin lymphoma cell lines and showed additive antiproliferative activity of chemotherapy when combined with vitamin D compared with chemotherapy alone.
Clinical Implications
Taken together, it is clear that, across many lymphomas, low vitamin D level at diagnosis is prognostic for inferior outcome, defined by either progression-free or overall survival. Whether this represents a modifiable risk factor or is simply a surrogate for advanced illness is unknown.
At present, I do not recommend widespread vitamin D testing and supplementation for patients with newly diagnosed lymphoma.19 We do not even know what vitamin D level is protective, as each of the aforementioned trials used a different definition of vitamin D deficiency. Ongoing randomized trials are currently addressing key questions, such as the threshold level of vitamin D to define insufficiency, and, most importantly, whether vitamin D supplementation can indeed overcome the inferior prognosis associated with a low vitamin D level at diagnosis of lymphoma.
The IlyAD trial (ClinicalTrials.gov identifier NCT03078855) is one such trial currently enrolling and randomly assigning patients with a low tumor burden follicular lymphoma who are receiving rituximab to either vitamin D at 2,000 IU daily or placebo daily for up to 3 years. The primary endpoint is progression-free survival, and the study includes important correlative endpoints.
Immunologic Considerations
In addition to the effects on calcium homeostasis, vitamin D has important immunologic effects, which may be the primary mechanism of activity in lymphomas, including Hodgkin lymphoma. Vitamin D downregulates TLR2 and TLR4 in monocytes, decreasing inflammatory responses in the setting of infections.20 Vitamin D exposure in vitro enhances monocyte activity and activation in the setting of tuberculosis infection.21
The role of vitamin D in adaptive immunity is better understood and has important effects on Th1 cytokine inhibition as well as regulatory T cells. Studies have suggested that vitamin D may impact the homing of T cells to specific tissues, potentially through upregulation of CCR10.22
The degree to which these pleiotropic effects of vitamin D affect specific immune responses to conditions like cancer in humans requires further study. The findings of Borchmann and colleagues suggest that Hodgkin lymphoma may represent an excellent model system for study, given the variable immune infiltration in this diagnosis and the responsiveness of this disease to checkpoint inhibitor therapy.18
DISCLOSURE: Dr. Friedberg has been compensated for data and safety monitoring board activities from Bayer and Ascerta. He is funded for work on vitamin D and lymphoma from the National Cancer Institute (R01CA214890).
REFERENCES
1. Holick MF: Vitamin D deficiency. N Engl J Med 357:266-281, 2007.
2. Bikle DD: Vitamin D: Newly discovered actions require reconsideration of physiologic requirements. Trends Endocrinol Metab 21:375-384, 2010.
3. Zehnder D, Bland R, Williams MC, et al: Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86:888-894, 2001.
4. Samuel S, Sitrin MD: Vitamin D’s role in cell proliferation and differentiation. Nutr Rev 66:S116-S124, 2008.
5. 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. J Clin Oncol 34:1741-1747, 2016.
6. Fang F, Kasperzyk JL, Shui I, et al: Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS ONE 6:e18625, 2011.
7. Hendrickson WK, Flavin R, Kasperzyk JL, et al: Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol 29:2378-2385, 2011.
8. Nyame YA, Murphy AB, Bowen DK, et al: Associations between serum vitamin D and adverse pathology in men undergoing radical prostatectomy. J Clin Oncol 34:1345-1349, 2016.
9. Ng K, Meyerhardt JA, Wu K, et al: Circulating 25-hydroxyvitamin D levels and survival in patients with colorectal cancer. J Clin Oncol 26:2984-2991, 2008.
10. Zgaga L, Theodoratou E, Farrington SM, et al: Plasma vitamin D concentration influences survival outcome after a diagnosis of colorectal cancer. J Clin Oncol 32:2430-2439, 2014.
11. Radujkovic A, Schnitzler P, Ho AD, et al: Low serum vitamin D levels are associated with shorter survival after first-line azacitidine treatment in patients with myelodysplastic syndrome and secondary oligoblastic acute myeloid leukemia. Clin Nutr 36:542-551, 2017.
12. Goodwin PJ, Ennis M, Pritchard KI, et al: Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clin Oncol 27:3757-3763, 2009.
13. Kim HJ, Lee YM, Ko BS, et al: Vitamin D deficiency is correlated with poor outcomes in patients with luminal-type breast cancer. Ann Surg Oncol 18:1830-1836, 2011.
14. Kelly JL, Salles G, Goldman B, et al: Low serum vitamin D levels are associated with inferior survival in follicular lymphoma: A prospective evaluation in SWOG and LYSA studies. J Clin Oncol 33:1482-1490, 2015.
15. Solal-Céligny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004.
16. Tracy SI, Maurer MJ, Witzig T, et al: Vitamin D insufficiency is associated with an increased risk of early clinical failure in follicular lymphoma. Blood Cancer J 7:e595, 2017.
17. Bittenbring JT, Neumann F, Altmann B, et al: Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab. J Clin Oncol 32:3242-3248, 2014.
18. Borchmann S, Cirillo M, Goergen H, et al: Pretreatment vitamin D deficiency is associated with impaired progression-free and overall survival in Hodgkin lymphoma. J Clin Oncol 37:3528-3537, 2019.
19. Manson JE, Brannon PM, Rosen CJ, et al: Vitamin D deficiency—Is there really a pandemic? N Engl J Med 375:1817-1820, 2016.
20. Sadeghi K, Wessner B, Laggner U, et al: Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 36:361-370, 2006.
21. Rook GA, Steele J, Fraher L, et al: Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57:159-163, 1986.
22. Sigmundsdottir H, Pan J, Debes GF, et al: DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 8:285-293, 2007.
