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Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 78-80

Association of Vitamin D with cancer – Catch me if you can!

Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India

Date of Submission02-Feb-2020
Date of Decision02-Feb-2020
Date of Acceptance04-Feb-2020
Date of Web Publication24-Feb-2020

Correspondence Address:
Ullas Batra
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_49_20

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How to cite this article:
Batra U, Sharma M. Association of Vitamin D with cancer – Catch me if you can!. Cancer Res Stat Treat 2020;3:78-80

How to cite this URL:
Batra U, Sharma M. Association of Vitamin D with cancer – Catch me if you can!. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Aug 11];3:78-80. Available from: http://www.crstonline.com/text.asp?2020/3/1/78/279144

Vitamin D is probably one of the most commonly studied factors in cancer, and multiple studies have tried to elucidate its role in carcinogenesis and cancer prevention, its relation with prognosis; and as a method of increasing survival. These studies have drawn varying conclusions, and the house is still divided about its beneficial role. Data from the Indian subcontinent regarding the same are also lacking. In spite of the fact that India is a country with abundant sunlight, most of the general population in India has been found to be deficient in Vitamin D, and studies have reported a deficiency prevalence of 50%–94%. This may be due to various factors such as increasing urbanization, decreased sun exposure, and change in dietary habits.[1] A simple measure such as supplementation with Vitamin D in such a scenario may prove to be a cost-effective and excellent strategy to improve patient outcomes, if such a beneficial effect can indeed be confirmed.

The present prospective non-interventional observational study by Pandey et al. looked at baseline serum 25-hydroxy Vitamin D levels in 252 patients diagnosed with cancer over a 5-month period and found that 67% of the patients were Vitamin D deficient, and another 21% of patients had Vitamin D insufficiency. The mean Vitamin D level was 18.94 ng/mL. The study noted a higher prevalence of Vitamin D deficiency in women as compared to men (76% vs. 55%) and in patients with esophageal and stomach cancers (84%). The authors hypothesized that this may be due to poor oral intake, cancer cachexia, and dysfunctional absorption. Deficient patients were offered supplementation if agreeable, with either oral weekly cholecalciferol (Vitamin D3) 50,000 international units (IU) for 8 weeks or a single intramuscular injection of 600,000 IU of cholecalciferol in an Arachis oil depot formulation. This was followed by a maintenance dose of 800 IU of Vitamin D3 and 500 mg of elemental calcium daily supplement for 6 months. The study was non-interventional, and the patients were not followed up for outcomes.[2]

The study is an important step in the right direction, in an attempt to identify an often-neglected, clinically relevant, but seldom researched topic in India. However, the limitations of the study were its observational design with no follow-up. The investigators did not look at the comorbidities, complete nutritional status of the patient, body mass index, and its correlation with Vitamin D levels. Even though patients were offered intervention, they were not followed up for outcomes. The study answers the single question that many patients diagnosed with cancer in India are Vitamin D deficient and paves the way for further research in this area. Other questions, however, remain unanswered, including:

  1. Whether there is an increased risk of developing cancer in Vitamin D-deficient Indian individuals?
  2. Whether these Vitamin D-deficient individuals with cancer have a worse prognosis?
  3. Whether supplementation of Vitamin D will decrease the risk or improve outcomes or decrease toxicities related to cancer therapy in Indian patients?
  4. Which dose, preparation of Vitamin D, and which mode of supplementation (oral/intravenous/parenteral) to be used?
  5. Whether dosing needs to be different for women and nutritionally at-risk patients?
  6. How do we standardize Vitamin D testing?
  7. What blood levels do we consider sufficient to achieve a therapeutic target in the Indian population?
  8. What is the current role of testing for Vitamin D receptor (VDR) variations?

Multiple other studies in varying populations have tried to answer these questions; however, the association between Vitamin D and cancer so far is multifaceted and inconclusive. To begin with, in-vitro and preclinical studies have suggested a cancer inhibitory effect of Vitamin D. It is an important factor regulating key biological processes, with anti-proliferative, anti-inflammatory, and pro-apoptotic effects. It decreases tumor invasiveness and the ability to metastasize and has anticarcinogenic effects.[3]

Epidemiological studies as well as meta-analyses have shown a higher incidence of ovarian, prostate, colorectal, and breast cancers with lower serum 25-hydroxy Vitamin D levels.[4],[5],[6] Randomized placebo-controlled trials have thereafter prospectively assessed the impact of Vitamin D supplementation on the incidence of developing cancer. The VITAL study included 25,871 patients with a median follow-up of 5.3 years. The trial results showed that supplementation with Vitamin D (2000 IU/day) did not result in a lower incidence of invasive cancer than placebo. The trial did find a statistically significant 25% reduced risk of dying from colon cancer with supplementation.[7] In a recent meta-analysis, Haykal et al. evaluated the association of cancer incidence and cancer-related mortality in more than 79,000 patients in multiple randomized controlled trials that compared the use of Vitamin D to a placebo over at least a 3-year period. Vitamin D supplementation was associated with a significant reduction of cancer-related mortality; however, there was no significant association with the reduction of cancer incidence as compared to placebo.[8]

The vitamin has also been studied with regard to defining prognosis in patients with cancer. A meta-analysis of 25 studies with 17,332 cases noted that higher Vitamin D levels at or near the time of cancer diagnosis were significantly associated with reduced cancer-specific mortality for patients with colorectal cancer and lymphoma and an improved disease-free survival for patients with breast cancer. Favorable benefit was also seen with higher Vitamin D levels in patients with lung cancer, gastric cancer, prostate cancer, leukemia, melanoma, or Merkel cell carcinoma, but this was not statistically significant.[9] However, other trials have not confirmed such an association.[10],[11]

These conflicting results may be due to the fact that higher Vitamin D levels may be an indirect marker of healthier patients, hence leading to better outcomes. However, it has also been hypothesized that variation in Vitamin D pathway genes and molecular expression and structure of the VDR (especially polymorphisms in the VDR gene) may determine cancer risk and outcomes. These variants are constant, and hence their association with cancer may remove the confounding effects of other modifiable factors, leading to changes in Vitamin D levels. In a meta-analysis by Vaughan-Shaw et al., the outcomes of 44,165 cases of cancer from 64 trials were studied with regard to Vitamin D status or genetic factors known to affect Vitamin D concentration, metabolism, or pathways. Higher Vitamin D levels were associated with better overall survival and progression-free survival. The study also looked at polymorphisms in the VDR gene and its association with cancer-specific mortality. The most commonly studied polymorphisms were rs2228570 (FokI), rs1544410 (BsmI), rs731236 (TaqI), rs11568820 (Cdx2), and rs7975232 (ApaI). A 40% higher rate of death was observed in TT genotype carriers at rs1544410 locus and 26% higher rate in TT carriers at rs2228570, while 29% increased risk of disease progression was observed in AA carriers at rs7975232 and 22% in GG carriers at GC locus.[12]

Trials have also tried to assess if supplementation with Vitamin D will improve outcomes in patients with cancer. The SUNSHINE trial was a Phase II trial that prospectively evaluated the effect of supplementation with Vitamin D in 139 patients with metastatic colorectal cancer who received chemotherapy (mFOLFOX6 plus bevacizumab). Only 9% of the trial population had sufficient Vitamin D levels at the beginning of treatment. Patients in the high-dose Vitamin D group (8000 IU a day for 14 days, and then 4000 IU a day) had a better progression-free survival as compared to those patients who took 400 IU daily during all cycles. Overall survival and response rates showed no difference.[13] The AMATERASU trial was a randomized, double-blind, placebo-controlled trial conducted in 417 patients, which evaluated supplementation with 2000 IU Vitamin D in patients with Stages I to III cancers of the digestive tract. The trial did not show any significant improvement in relapse-free survival at 5 years.[14]

All these trials were widely heterogeneous with regard to patient population; methods of Vitamin D level testing; definitions of sufficiency, insufficiency, and deficiency; target therapeutic blood levels; and dosing. With such a deluge of data, it is extremely important to sift through all the information with a thin sieve so as to cast further light onto this enigma.

As noted by Noronha, “clear ethnic differences exist between oncology patients from different countries.” Indian cancer patients are known to differ in terms of epidemiology and response to therapy and may have unique toxicities to drugs.[15] It is even more important to carry out research on this subject in Indian patients, in order to understand our patient outcomes and formulate our own guidelines. Disease-specific collaborative research networks across various institutions will be the way forward.[16]

To conclude, we would like to affirm the fact that baseline lower Vitamin D levels seem to have a negative association with cancer outcomes. Well-designed randomized trials with longer follow-up time are needed to establish its place in patient management strategies and hopefully catch that elusive association!

  References Top

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Pandey A, Singh A, Singh S. Prevalence of Vitamin D deficiency in treatment-naive individual consecutive cancer patients. Cancer Res Stat Treat 2020;3:25-31.  Back to cited text no. 2
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Bandera Merchan B, Morcillo S, Martin-Nuñez G, Tinahones FJ, Macías-González M. The role of vitamin D and VDR in carcinogenesis: Through epidemiology and basic sciences. J Steroid Biochem Mol Biol 2017;167:203-18.  Back to cited text no. 3
Tworoger SS, Lee IM, Buring JE, Rosner B, Hollis BW, Hankinson SE. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of incident ovarian cancer. Cancer Epidemiol Biomarkers Prev 2007;16:783-8. DOI: 10.1158/1055-9965.EPI-06-0981  Back to cited text no. 4
Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 2000;11:847-52.  Back to cited text no. 5
Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B 2010;101:130-6.  Back to cited text no. 6
Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2019;380:33-44.  Back to cited text no. 7
Haykal T, Samji V, Zayed Y, Gakhal I, Dhillon H, Kheiri B, et al. The role of vitamin D supplementation for primary prevention of cancer: Meta-analysis of randomized controlled trials. J Community Hosp Intern Med Perspect 2019;9:480-8.  Back to cited text no. 8
Li M, Chen P, Li J, Chu R, Xie D, Wang H. Review: The impacts of circulating 25-hydroxyvitamin D levels on cancer patient outcomes: A systematic review and meta-analysis. J Clin Endocrinol Metab 2014;99:2327-36.  Back to cited text no. 9
Holt SK, Kolb S, Fu R, Horst R, Feng Z, Stanford JL. Circulating levels of 25-hydroxyvitamin D and prostate cancer prognosis. Cancer Epidemiol 2013;37:666-70.  Back to cited text no. 10
Meyer F, Liu G, Douville P, Samson E, Xu W, Adjei A, et al. Dietary vitamin D intake and serum 25-hydroxyvitamin D level in relation to disease outcomes in head and neck cancer patients. Int J Cancer 2011;128:1741-6.  Back to cited text no. 11
Vaughan-Shaw PG, O'Sullivan F, Farrington SM, Theodoratou E, Campbell H, Dunlop MG, et al. The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: Systematic review and meta-analysis. Br J Cancer 2017;116:1092-110.  Back to cited text no. 12
Ng K, Nimeiri HS, McCleary NJ, Abrams TA, Yurgelun MB, Cleary JM, et al. Effect of high-dose vs. standard-dose vitamin D3 supplementation on progression-free survival among patients with advanced or metastatic colorectal cancer: The sunshine randomized clinical trial. JAMA 2019;321:1370-9.  Back to cited text no. 13
Urashima M, Ohdaira H, Akutsu T, Okada S, Yoshida M, Kitajima M, et al. Effect of vitamin D supplementation on relapse-free survival among patients with digestive tract cancers: The Amaterasu randomized clinical trial. JAMA 2019;321:1361-9.  Back to cited text no. 14
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