Vitamin D is a hormone that is synthesised in the skin in the presence of sunlight. Sufficient vitamin D levels are important—not only for a healthy skeleton—but also for a healthy immune system. Many patients with cancer have insufficient vitamin D levels, and low vitamin D levels are associated with increased ‘all-cause mortality’ and especially mortality due to cancer. Low vitamin D levels have also been associated with increased risk of infections, increased pain, depressive disorders and impaired quality of life. We review the role of vitamin D in the immune system, in relation to cancer disease, pain and depression. We have recently performed an observational study in 100 patients with palliative cancer in Sweden. The main result was that low vitamin D levels were associated with higher opioid dose, that is, more pain. We also describe a case report where vitamin D supplementation resulted in radically decreased opioid dose, less pain and better well-being. Vitamin D supplementation is not connected with any adverse side effects and is easy to administrate. Thus, we hypothesise that vitamin D-supplementation to patients with palliative cancer might be beneficial and could improve their well-being, decrease pain and reduce susceptibility to infections. However, more clinical studies in this field are needed before firm conclusions can be drawn.
- Complementary therapy
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In palliative medicine, the aim is to provide relief from symptoms in incurable diseases, and maintain functions and high quality of life despite the disease. Since the aim is to have a high quality of life, it is important that the side effects of any medical treatment do not outweigh possible beneficial effects. Thus, treatments with as few adverse effects as possible are warranted. Patients with palliative cancer often suffer from infections, depression and pain, which require antibiotics, antidepressant medication and opioids. Interestingly, vitamin D has been suggested to have beneficial effects against all these conditions and could thus constitute a complement to traditional treatment with minor side effects and potentially beneficial actions. We review the current knowledge on the role of vitamin D in palliative care, with a focus on infections, depression and pain.
Vitamin D3 is synthesised endogenously in the skin from 7-dehydrocholesterol, and the process is dependent on the presence of sunlight (ultraviolet (UV)B light). The major part of vitamin D is formed in this way but a minor part of vitamin D is supplied through diet, as vitamin D3 (cholecalciferol) in meat and fish, and vitamin D2 (ergocalciferol) in plants or as supplementation.1 Vitamin D needs to be activated in two hydroxylation steps. The first hydroxylation occurs in the liver to the proform 25-hydroxyvitamin D (25OHD), whereas the second step generates active vitamin D (1,25 (OH)2 vitamin D) and occurs via 1-α hydroxylase (CYP27B1), which is expressed in kidney cells but also in many other cells in the body.1 Active vitamin D binds to the vitamin D receptor (VDR), which regulates a large number of genes.2 Vitamin D plays an important role in bone health and calcium homoeostasis; this has been known for a long time.1 In recent years, it has become evident that vitamin D is important for several different functions in the body including the immune system,3 nervous system4 and the cardiovascular system.5
The half life of 25OHD is about 3 weeks, whereas 1,25-dihydroxyvitamin D only has a half life of about 4 h.6 Generally, systemic levels of the more stable 25OHD are considered to reflect vitamin D status in the individual patient.1 The definition of vitamin D insufficiency is debated, but the most common description, proposed by the Institute of Medicine (IOM) in the USA, maintains that serum levels of 25OHD below 50 nmol/L are considered to be insufficient.7 Notably, the Endocrine Society (USA) suggests that levels below 75 nmol/L are insufficient,8 but this view has been challenged.9 Notably, these controversies relate exclusively to the possible extraskeletal effects of vitamin D supplementation. In fact, there is a consensus that very low serum levels of 25OHD (<25 nmol/L) reflect a true vitamin D deficiency, which should be corrected in order to prevent osteomalacia. Here, we adhere to the IOM statement and consider levels below 50 nmol/L to represent vitamin D insufficiency.7
Vitamin D and the immune system
Vitamin D affects the human immune system in several ways, including induction of antimicrobial peptides (AMPs) at mucosal surfaces and in immune cells10 as well as downregulating proinflammatory cytokines.11 AMPs are part of the ‘first-line defence’ on mucosal surfaces to defeat invading bacteria and viruses. Observational studies have shown that low levels of 25OHD are associated with an increased risk of tuberculosis12–14 and respiratory tract infections (RTIs).15 ,16 Moreover, several clinical trials show beneficial effects of vitamin supplementation against RTIs.15 ,17 ,18 We recently completed a randomised and placebo-controlled trial where patients with primary immunodeficiency and frequent RTIs, were randomised to vitamin D (4000 IE/day) or placebo for 1 year.19 In this study (n=140), we could show that patients supplemented with vitamin D had a reduced infectious burden and a 60% reduction of antibiotic consumption compared with the placebo group. In addition, the total number of RTIs was reduced in the vitamin D group (86 RTIs) compared with the placebo group (120 RTIs, p=0.05).20 Furthermore, the time to the first RTI was significantly longer in the vitamin D group (HR 1.68, 95% CI 1.03 to 2.68, p=0.0376).20
AMPs are not only important for the defence against bacteria but might also be important for killing malignant cells. In a recent study, it was demonstrated that macrophages kill proliferating high-grade B-cell lymphoma cells by releasing AMPs in a vitamin D-dependent fashion.21 Furthermore, rituximab-mediated cytotoxicity of macrophages was dependent on AMPs. The data indicated that activation of the vitamin D signalling pathway activates antitumour activity of macrophages and improves the efficacy of antibody-dependent cellular cytotoxicity with rituximab.21
To summarise, sufficient vitamin D levels are important for a healthy immune system and for our defence against bacterial and viral infections but might also play a role in the body’s eradication of malignant cells.
Vitamin D and cancer
Several observational studies show that patients with cancer generally have lower vitamin D levels than healthy controls.22–25 If the low 25OHD levels are caused by cancer, for example, by fewer out-door activities and less sunlight exposure during the disease, or if participants with low 25OHD levels are more susceptible to cancer, is not known. Observational studies have also shown that low vitamin D levels are associated with increased all-cause mortality.26 ,27 In a meta-analysis of 159 randomised controlled trials, it was shown that treatment with vitamin D3 was associated with decreased all-cause mortality and especially that mortality caused by cancer was significantly reduced (RR 0.88 (95% CI 0.78 to 0.98); p=0.02; n=44.492).28
We recently performed an observational study on 100 patients with palliative cancer recruited from ASIH Stockholm Södra, Långbro Parks Palliative Home Care Team and Hospice Ward in Stockholm, Sweden. The aim of this study was to test the hypothesis that low 25OHD levels are associated with higher opioid dose, higher infectious burden and impaired quality of life in patients with palliative cancer.29 The 25OHD levels were generally low among the patients, median 40 nmol/L (IQR 22–58 nmol/L). Patients with lung cancer had even lower levels, median 24 nmol/L (unpublished data). Patients who were still alive at the end of the study had a significantly higher 25OHD level (median 50 nmol/L) than those who died during the study period (median 36 nmol/L, p=0.013, Mann-Whitney U test). Notably, younger patients with cancer had generally lower levels than older patients. The most interesting finding in this study was a significant association between opioid dose and 25OHD levels, that is, low 25OHD levels were associated with increased pain and opioid dose,29 which will be discussed in detail below.
Vitamin D and depressive disorder
Cancer is often connected with depression and thus it is of notable interest that vitamin D supplementation may be beneficial in depressive disorders.25 ,30 In a recent randomised, double-blind and placebo-controlled study in n=40 patients with major depressive disorder, there was a trend towards a larger decrease in the depressive score (Beck Depression Inventory) in the vitamin D group compared with the placebo group (−8.0 and −3.3, respectively, p=0.06).31
Other parameters, closely related to depression and often measured in studies on patients with palliative cancer, are ‘quality of life’ and ‘well-being’. We recently performed a post hoc analysis of the clinical trial aforementioned, in which patients with frequent RTIs were randomised to placebo or vitamin D.19 At the last visit of the study, patients were asked to perform a general assessment of their well-being during the study.32 The patients who stated ‘a better’ well-being during the study (n=72) had a significant increase in 25OHD levels during the study; mean levels increased from 50 to 87 nmol/L (p<0.001); 95% CI before 45 to 55; after 76 to 99. Among patients who stated ‘no change’ or ‘worse’ well-being during the study (n=46), there was no significant increase in 25OHD levels. Furthermore, a reading of a 25OHD level above 100 nmol/L at the end of the study, was associated with a higher chance of experiencing ‘better’ well-being (p<0.01, χ2 test).32 Four patients on antidepressive treatment could terminate their antidepressant medication during the study. These patients had a significant increase in 25OHD levels from low levels (19–57 nmol/L) at start of the study to above 100 nmol/L at the end of the study.32
However, well-being in patients with cancer is highly dependent on the burden of symptoms, stage of the disease and prognosis, as well as social and psychological factors.33 In our observational study on patients with palliative cancer, there was no association between well-being, measured by Edmonton Symptom Assessment Scale (ESAS), and 25OHD levels.29 In contrast, a recent study on patients with terminal cancer with solid tumours, found an association between low 25OHD levels and fatigue as well as with physical and functional well-being.34 However, this study was small (n=30) and cross-sectional, and lacked a control group, but still encouraging for further research into this area.
Vitamin D and pain
There are several pieces of evidence supporting a role of vitamin D in pain control, both in observational29 ,35–38 and in interventional studies.39 ,40 In a recent randomised, double-blinded and placebo-controlled study in rheumatic patients with musculoskeletal pain, it was shown that vitamin D (4000 IU/day) for 3 months resulted in faster decline of consecutive visual analogue scale (VAS) scores and a decrease in the levels of inflammatory-related and pain-related cytokines.39 We have shown, in a prospective observational study, that patients with 25OHD levels <50 nmol/L before starting on statin treatment had four times higher risk of developing muscular symptoms, including muscular pain, compared with individuals with 25OHD levels >50 nmol/L (RR 4.2; 95% CI 1.7 to 10.2; p <0.01).36 We could also observe a significant association between vitamin D levels and opioid doses in the study in patients with palliative cancer aforementioned.29 A linear regression analysis between vitamin D levels and opioid dose showed a β coefficient −0.67 (95% CI −1.24 to −0.10; p=0.02); that is, a low 25OHD level was associated with a higher opioid dose. For every nmol of increase in 25OHD levels, the fentanyl dose decreased by 0.67 µg/h. This association remained significant after adjustment for the stage of the cancer disease in a multivariable analysis, that is, the results could not simply be explained by the fact that patients with more advanced disease have more pain.
The mechanism behind the role of vitamin D in pain physiology remains largely unknown. A recent study showed that patients with insufficient 25OHD levels (<50 nmol/L) had more pain and exhibited pathological nerve conduction.41 Vitamin D insufficiency is also associated with peripheral neuropathy and autonomic nerve dysfunction in patients with type 2 diabetes.42 From animal studies, it is reported that vitamin D may contribute to remyelination after nerve damage.43 Taken together, there is increasing evidence from observational, interventional and experimental studies, that vitamin D could have a beneficial role against pain in various settings.
Nevertheless, it can also be argued that vitamin D does not have any direct or causal role in pain. It is possible that vitamin D levels only serve as a marker for UVB exposition that in turn might be important for relief of pain. In a recent article, it is suggested that UVB light has strong analgesic effects by induction of endogenous endorphins with pain relieving actions.44 Given these novel and exciting data, it is possible that our finding of a clear association between vitamin D levels and opioid use can be fully or partly explained by exposure to the sun and endogenous synthesis of endorphins. Since patients with palliative cancer often are less exposed to sunlight, it could be speculated that this will lead to lower endorphin levels and increased risk of pain.
Vitamin D supplementation to patients with palliative cancer—a case report
Vitamin D supplementation is not connected with any adverse side effects.45 In our clinical trial in patients with frequent RTIs, there were, in fact, more adverse events reported from the placebo group than from the vitamin D supplemented group.19 Vitamin D is easy to administrate, and oil and tablet preparations are both available on the market. The oil preparation could be advantageous in patients with cancer, since it is also easy to administrate to patients who have difficulty swallowing tablets.
One patient with gastrointestinal cancer and multiple metastases in the liver and bone was admitted to our hospice ward. He was suffering from severe muscular and skeletal pain, and his pain VAS score was 8 at the time of admission. He was treated with an opioid dose of 75 µg fentanyl/h. He had no active oncological treatment ongoing at this time due to impaired performance status. His lifetime expectancy was assessed to be less than 3 months. His 25OHD level was unmeasurable (<8 nmol/L) and treatment with 2000 IE vitamin D/day was initiated. During the coming months, his pain improved day by day and the opioid dose could be successively reduced. After 3 months, his 25OHD level was 56 nmol/L. He had better self-assessed well-being according to ESAS, from 9 to 2, his appetite also improved and the albumin levels increased from 28 to 35 g/L. His VAS score varied between 0 and 2. After 4 months of vitamin D treatment, he could terminate regular opioid treatment and was down to 5–10 mg oxycodone when needed. He was now starting oncological treatment again with palliative chemotherapy using temozolamid. After 6 months, he was discharged from the ward and admitted to a home care team. His 25OHD level was 76 nmol/L at this time point. He is still alive today (December 2015), 1 year after the first admission to the hospice ward. His cancer disease is stable and he has ongoing treatment with temozolamid. His liver metastases have somewhat diminished in size but the skeletal metastases are unchanged, according to the latest X-ray. Today, he is still without any regular pain treatment.
Even though this case report only represents anecdotal evidence, it encouraged us to initiate an interventional, open-label vitamin D study where we will include at least n=100 patients with palliative cancer with 25OHD levels <75 nmol/L. The patients will be supplemented with 4000 IE/day depending on the vitamin D levels at study start. We will follow the patients with regular 25OHD measurements and register pain, infectious burden and self-assessed well-being as well as survival time. The results from this first pilot study will provide data for a future large-scale interventional trial, where we need data on the least clinically meaningful effect, a measure of the magnitude and variance of any observed effect, in order to perform a bona fide sample size calculation and study design.
We suggest that supplementation of vitamin D to patients with palliative cancer with vitamin D insufficiency (<50 nmol/L) might reduce susceptibility to infections, improve their well-being and decrease pain. Vitamin D supplementation is a safe and well-tolerated treatment that will do no harm, but might improve health, which is a good option in palliative care. However, more clinical studies in this field, preferable with a double-blinded design, are needed before firm conclusion can be drawn and general recommendations for patients with palliative cancer can be determined.
Financial support was provided through the Regional agreement on training and clinical research (ALF) between Karolinska Institutet and Stockholm County Council, The Swedish Cancer Society, Magnus Bergwall Foundation, Karolinska Institutet and the Swedish Research Council.
Contributor LB-B and PB reviewed the literature and wrote the manuscript.
Funding Cancerfonden, Swedish Research Council, (grant number 2013-2709) Magnus Bergwall Foundation, regional agreement on training and clinical research (ALF) between Karolinska Institutet and Stockholm County Council.
Competing interests None declared.
Ethics approval All studies described in this review have been carried out in accordance with the Declaration of Helsinki and have been approved by the Regional Ethics Committee in Stockholm.
Provenance and peer review Not commissioned; externally peer reviewed.
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