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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 76-85

Prevalence of vitamin D deficiency in patients with cancer and the need for routine screening and supplementation of vitamin D in patients with cancer


Department of Radiation Oncology, Omega Hospital, Visakhapatnam, Andhra Pradesh, India

Date of Submission31-Aug-2021
Date of Acceptance11-Nov-2021
Date of Web Publication23-Feb-2022

Correspondence Address:
Dr. Ravishankar Bellala
Department of Radiation Oncology, Omega Hospital, Arilova, Health City, Chinagadili, Visakhapatnam, Andhra Pradesh 530040
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_31_21

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  Abstract 

Context: The prevalence of Vitamin D deficiency in the general population in India ranges between 60% and 80% depending on dietary habits, occupation, and cultural practices. Deficiency of Vitamin D has been associated with an increased risk of colon cancer, breast cancer, prostate cancer, and ovarian cancer. The anticancer effects of Vitamin D have been attributed to its antiproliferative, anti-inflammatory, and antiangiogenic actions. This study aims at observing the magnitude of Vitamin D deficiency in patients with cancer and at stressing the importance of routine screening and supplementation of Vitamin D. Aim: To study the prevalence of Vitamin D deficiency in patients with cancer. Settings and Design: An analysis to study Vitamin D deficiency in patients with cancer. Materials and Methods: A consecutive observational study was conducted at Queen’s NRI hospital, Omega hospital Visakhapatnam, from April 2018 to September 2020. Blood samples of 157 patients attending follow-up clinics and patients receiving active treatment were collected. Serum total Vitamin D was estimated using the electrochemiluminescence (ECL) method on Cobas E411 autoanalyzer. They were categorized into (1) deficient (vitamin D ≤20 ng/ mL), (2) insufficient (vitamin D between 20 and 29 ng/ mL), (3) sufficient (vitamin D ≥30–100 ng/mL), and (4) toxicity (vitamin D ≥30–100 ng/mL) and analyzed statistically. Statistical Analysis Used: Computer-based calculations were used for analysis of the collected data. Results: Among the 157 patients included in the study, 21 (13.3%) were having sufficient level, 21 (13.3%) insufficient, and 115 (73.2%) deficiency of vitamin D. The patients included in this study comprised 44 patients with breast cancer, 40 patients with cervical cancer, 47 patients with head and neck cancer, 10 patients with colon cancer, and 16 patients with cancers of other sites. Conclusion: In our evaluation, we found that more than 70% of patients with cancer attending our hospital are having vitamin D deficiency according to our study.

Keywords: Cancer patients, vitamin D, supplementation, vitamin D and cancer, vitamin D deficiency


How to cite this article:
Bellala R, Bellala VM, Srikanth D, Talluri S, Bellala PR, Bellala R. Prevalence of vitamin D deficiency in patients with cancer and the need for routine screening and supplementation of vitamin D in patients with cancer. J Curr Oncol 2021;4:76-85

How to cite this URL:
Bellala R, Bellala VM, Srikanth D, Talluri S, Bellala PR, Bellala R. Prevalence of vitamin D deficiency in patients with cancer and the need for routine screening and supplementation of vitamin D in patients with cancer. J Curr Oncol [serial online] 2021 [cited 2022 May 17];4:76-85. Available from: https://www.journalofcurrentoncology.org/text.asp?2021/4/2/76/338057




  Introduction Top


Vitamin D is not a vitamin. It is a precursor of the potent steroid hormone calcitriol. It can be obtained from consuming Vitamin D rich foods such as fish oil, mushrooms, and fortified dairy products. It can be synthesized by exposure of the skin to sunlight in the UV-B range. Its active form is 1,25-dihydroxycholecalciferol.

Vitamin D exerts its functions by binding to the nuclear vitamin D receptor (VDR). This is a ligand-activated transcription factor. The VDR is present in most of the cells in the body.[1] The hormone–receptor complex regulates the transcription of a number of genes that are essential for bone mineral metabolism. Vitamin D exerts certain non-genomic effects involving calcium transport in the intestine. Vitamin D deficiency causes various skeletal manifestations such as rickets, osteomalacia, and osteoporosis.

Vitamin D has an extensive range of activities; it can execute and modify many protective mechanisms of the body,[2],[3],[4],[5] and it can limit the progression of many diseases, including heart disease, diabetes mellitus, and cancer.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21] Circulating 25(OH) D is hydroxylated in the kidney by the cytochrome P450 enzyme CYP27B1 to yield calcitriol and it makes the kidney the major source of circulating calcitriol.

CYP27B1 is expressed on cancer cells and exerts anticancer actions.[22] Expression of this CYP27B1 and its activity in cancer depend on the organ and tumor grade[23],[24] and degree of cellular differentiation. High levels are expressed in well-differentiated tumors compared with poorly differentiated and aggressive tumors.[25]

Anticancer actions of vitamin D

The anticancer actions of calcitriol are intervened by VDR and most of them to control at the genome.[2],[3],[4],[5] Calcitriol binds to VDR, thereby inducing dimerization with retinoid X receptor, binding in multiple regulatory regions located at promoters and distal sites of target genes, and the recruitment of co-modulators.[2],[3],[4],[5] Calcitriol has a wide range of actions ranging from a decrease in the proliferation of cancer cells; by an increase in the expression of P27, P21; and a decrease in the expression of RB, CDKs, cyclins, and MYC. It exerts proapoptotic activity on cancer cells by increasing BAX and decreasing BCL2 proteins, allowing the cell to be more sensitive to radiation and chemotherapy. Calcitriol differentiates the myeloid leukemic cells from monocytes by increased expression of differentiation factors such as E-cadherin, casein adhesion proteins, and lipids. It decreases the invasiveness and metastatic potential of cancer by decreased expression of MMP9, plasminogen activator, and increased expression of E-cadherin, TIMP1.

The calcitriol possesses antiangiogenic properties by decreasing levels of HIF1ɑ, VEGF, IL 8, and PGE.

In addition to these anticancer functions, it regulates specific signaling pathways in breast cancer cells, colon, and prostate tissue, thereby mitigating key drivers on cancer cells.

In the colon, cancer calcitriol inhibits the transcriptional activity of β-catenin.[13] It counters the aberrant action of WNT-β-catenin. This is the most familiar alteration in sporadic colorectal cancer. Calcitriol might have a therapeutic benefit in the prevention and treatment of postmenopausal ER +ve breast cancer by selective suppression of aromatase expression in breast adipose tissue[26],[27] and lower downregulation of ERα in breast cancer cells.[28],[29],[30],[31] There is a crosstalk between calcitriol and androgen signaling; it includes the expression of androgen receptors together with androgen-responsive genes[32] along with the regulation of VDR by androgens.[33]


  Materials and Methods Top


General details of the study

The study was conducted in Queen’s NRI hospital and Omega hospital, which are tertiary referral cancer hospitals in Visakhapatnam located in the southern part of India. For this study, we offered individual patient registration between April 2018 and September 2020 in the department of radiation oncology testing for baseline vitamin D levels. This test was recommended after obtaining informed consent, in addition to routine workup. Patients attending follow-up visits with prior history of radiotherapy, chemotherapy, and hormonal therapy were also included in this study. These patients were informed about the test, and their consent was obtained. Patients with a history of rickets, renal osteodystrophy, and osteoporosis were not eligible to participate in our study. The patients who are on an oral or injectable form of vitamin D supplementation are excluded from the study.

Procedure

Sample collection

Blood samples were drawn from an accessible peripheral vein about 3 ml into a vacutainer. The plasma was separated and stored at 2–8 C refrigeration. The sample was centrifuged for 3000 g/min to maintain consistency in samples and results. Samples without any particulate matter, bubbles, were processed for testing.

Serum total Vitamin D was evaluated by using the ECL method on Cobas E411 autoanalyzer. The average turnaround time was 72 h for reporting.

Categorization

The details of patients, including age, sex, type of cancer, stage of cancer, and biopsy report for the grade of cancer, were recorded.

The patients were categorized into four standard groups based on the serum vitamin D levels: (1) deficient (vitamin D ≤20 ng/ mL), (2) insufficient (vitamin D between 20 and 29 ng/ mL), (3) sufficient (vitamin D ≥30–100 ng/mL), and (4) toxicity.

The reports were notified to the patients, and replacement therapy was offered for the patients with deficiency. Patients were instructed that this replacement therapy would not have any influence on the plan of primary modality treatment for cancer.

Statistical considerations

Statistical analysis was performed using SPSS v.17(SPSS, USA) and SAS v9.4.

A Mann-Whitney U test (sometimes called the Wilcoxon rank-sum test) is used to compare the differences between two independent samples (Age_group and Cancer_Type) when the sample distributions are not normally distributed and the sample sizes are small (n < 30). It is considered to be the nonparametric equivalent to the two-sample independent T-test. We have grouped the age into three groups (age group 18 to 40, age group 41 to 60, and age group 61 and above) and performed the Mann-Whitney U test for an independent sample.

We have compared another set of independent samples (Sex and Cancer_Type) using a Mann-Whitney U test. We have grouped the sex into two groups (male and female).

The Chi-Square test is a test of statistical significance for categorical variables (here, VitaminD_Level and Cancer). The Chi-Square test assumes that the data for the study are obtained through random selection, that is, they are randomly picked from the population. The categories are mutually exclusive, that is, each subject fits in only one category. The data should not consist of paired samples or groups or we can say the observations should be independent of each other. When more than 20% of the expected frequencies have a value of less than 5, then Chi-square cannot be used. To tackle this problem: Either one should combine the categories only if they are relevant or obtain more data to check the relationship between “VitaminD_Level” and “Cancer_Type.” We have used the Chi-Square test to understand the statistical significance.


  Result Top


A total of 157 patients were tested for levels of serum 25 (OH)D. Of the 157 patients, there were 45 (28.6%) male and 112 (71.3%) female patients [Figure 1]. Among these 157 patients included in the study, 21 (13.3%) patients had sufficient level, 21 (13.3%) patients had insufficient level, and 115 (73.2%) patients showed a deficiency of Vitamin D [Figure 2]. Age distribution among the 157 patients showed that 32 were younger than 41 years, 97 were between 41 and 60 years, and 28 were older than 60 years of age [Figure 3].
Figure 1: Total patients

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Figure 2: Vitamin D level

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Figure 3: Age distribution

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Among the 115 deficient cases, 30 (26%) were male subjects and 85 were female subjects; 24 (20.8%) were younger than 41 years, 74 (64.3%) were aged between 41 and 60 years, and 17 (14.7%) were older than 60 years [Table 1].
Table 1: Age distribution of deficient cases

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Tumor aggressiveness and the stage were also correlated among the 157 patients with available data; it was found that 14 patients (i.e., 8.9%) had well-differentiated tumors, 56 patients (35.6%) were found to have moderately differentiated tumors, 62 patients (39.4%) showed poorly differentiated tumors, and in about 25 patients (15.9%) the grade could not be commented due to the nonavailability of reports in follow-up visits [Figure 4].
Figure 4: Grade of tumor in total study population

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Tumor aggressiveness among the deficient 115 patients was as follows. Patients with well-differentiated tumors were only seven (6.0%), those with moderately differentiated tumors were 40 (34.7%), and those with poorly differentiated tumors were 51 (44.3%). In about 17 (14.7%) patients, the grade could not be commented on [Figure 5].
Figure 5: Grade of tumor among deficient patients

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Tumor stage was correlated among the 157 patients; our study showed that two patients (1.2%) had stage 1, 39 patients (24.8%) had stage 2, 63 patients (40.12%) had stage 3, and 49 patients (31.2%) had stage 4 tumors [Figure 6]. In about four patients (2.5%), the staging could not be done as the patients were on follow-up and the data from the documents were insufficient for staging. We had a high number of patients with stage 4 tumors in our study, and this was due to the patients with head and neck cancer. Most of our patients with head and neck cancer presented with locally advanced disease and metastasis to the lymph nodes.
Figure 6: Tumor stage in total study population

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Among the 21 insufficient cases, seven were male subjects and 14 were female subjects; five (25%) were younger than 41 years; 14 (56%) were aged between 41 and 60 years; and two (9.5%) were older than 60 years [Table 2].
Table 2: Age distribution of insufficient cases

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Among the 21 sufficient cases, eight were male subjects and 13 were female subjects; three (14.2%) patients were younger than 41 years of age; nine (42.8%) of these subjects were aged between 41 and 60 years; and nine (42.8%) were older than 60 years [Table 3].
Table 3: Age distribution of sufficient cases

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Among the 157 patients included in the study [Figure 7], 44 patients had breast cancer; 40 patients had cervical cancer; 47 had head and neck cancer; 10 had colon cancer; and the remaining 16 comprised cancers of other sites such as the esophagus, lung, stomach, bladder, endometrium, and soft tissue sarcoma. Measurement of vitamin D in relation with various sub-sites and its distribution is shown in [Figure 8].
Figure 7: Tumor site

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Figure 8: Distribution of Cancer_Category by VitaminD_Category

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With the Mann-Whitney U Test, we have analyzed the relationship between the age group and the type of cancers being studied, and we have achieved a p-value 0.5, which is greater than the alpha value (i.e., 0.05). Hence, we are accepting the null hypothesis that there is no relationship between the two variables (the age group and the type of cancer) being studied (one variable does not affect the other) [Figure 9]. The hypothesis states that the results are due to chance and are not significant in terms of supporting the idea and hence reject the alternative hypothesis.
Figure 9: Distribution of Wilcoxon scores for Cancer_Type by Age_Group

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With the Mann-Whitney U Test, we have analyzed the relationship between sex and the type of cancers being studied, and we have achieved a p-value of 0.0001, below the threshold of significance. Hence, we are strongly rejecting the null hypothesis and accept the alternative hypothesis that the independent variable did affect the dependent variable, and the results are significant in terms of supporting the theory being investigated (i.e., not due to chance), which means that females are more affected compared with males [Figure 10].
Figure 10: Distribution of Wilcoxon scores for Cancer_Type by sex

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We have used the Chi-Square test, and the obtained p-value = 0.0105 indicates that the association is statistically significant at the 0.05 alpha level. To determine what the association is, we looked at the row percentages [Table 4] and noticed that the largest differences between percentages are in the deficient group. The patients with Vitamin D deficiency (73.25%) were more likely to acquire cancer than those with Vitamin D insufficiency (13.38%) and patients with sufficient Vitamin D (13.38%).
Table 4: Table of cancer category by Vitamin D category (the FREQ procedure)

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  Discussion Top


The prevalence of Vitamin D deficiency in the general population in India ranges from 60% to 80% depending on the dietary habits, occupation, and cultural practices. Inadequate levels of Vitamin D have been associated with an increased risk of colon cancer, breast cancer, prostate cancer, and ovarian cancer. The anticancer activity of Vitamin D has been attributed to its antiproliferative, anti-inflammatory, and antiangiogenic actions. This study aims at assessing the prevalence of Vitamin D deficiency in the patients with cancer.

The prevalence of vitamin D deficiency was about 73.2%, and vitamin D insufficiency is prevailing in about 13.3% of our study. The study confirms that the deficiency prevalence is almost similar to the frequency among the normal healthy individuals in India.[34],[35],[36] Most of these patients were suffering from common malignancies; for instance, 28% with breast cancer, 30% with head and neck cancer, 26% with cervical cancer, 6% with colon cancer, and 10% with other cancers.

India is a tropical country with copious exposure to sunlight; despite this, there is a very high incidence of vitamin D deficiency in healthy people.[37],[38] There are very limited data on the prevalence of vitamin D deficiency among patients with cancer. Our study exemplifies the high occurrence of low vitamin D levels in patients with cancer.

There are several proposed hypotheses on Vitamin D deficiency being most commonly found among high-grade tumors and in those with advanced disease. In our study, it was evident that the deficiency was more among the patients with moderately differentiated and poorly differentiated tumors compared with well-differentiated tumors.

Vitamin D supplementation has been shown to reduce the toxicity of cancer-directed therapy in some literature. In patients with hormone-positive breast cancer, the supplementation has reduced the drug interruptions and discontinuation by decreasing the musculoskeletal pains and increased compliance with aromatase inhibitors.[39] Vitamin D decreased the incidence of oral mucositis and improved swallowing in patients with head and neck cancer on chemoradiotherapy.[40]

The data are very favorable to recommend routine testing of vitamin D in all patients, irrespective of the site and stage of the disease. Being an observational study certainly, our study had some limitations. We did not evaluate the study with respect to toxicity rates and response rates to treatment based on vitamin D levels. In our study, we observed a significant number of patients with no active disease or distant metastasis to explain their symptoms were diagnosed to have a deficiency of vitamin D and they recovered completely from symptoms significantly after supplementation.


  Conclusion Top


Our conclusions are based on our evaluation that more than 70% of patients with cancer are having Vitamin D deficiency. Preclinical findings allude to how Vitamin D regulates the crucial pathways in the development and progression of various cancers. It is prudent to measure Vitamin D levels in all patients and especially important to measure in young patients with advanced high-grade disease. Supplementation in patients with deficiency would improve cancer-related outcomes as well as compliance during cancer-related treatments.

Acknowledgement

We would like to thank our oncology team, the Lab medicine department of the institute for helping us to conduct this study. We would like to also thank all the patients who are part of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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