domingo, 7 de julio de 2019

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®) 7/10 —Health Professional Version - National Cancer Institute

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version

Vitamin D

Overview

General Information and History

Vitamin D, also called calciferol, cholecalciferol (D3), or ergocalciferol (D2), is a fat-soluble vitamin found in fatty fish, fish liver oil, eggs, and fortified dairy products. Vitamin D is made naturally by the body when exposed to sunlight.
In 1922, researchers discovered that heated, oxidized cod-liver oil, called fat-soluble factor Aand later known as vitamin D, played an important role in curing rickets in rats.[1]
Vitamin D performs many roles in the body, including the following:
Vitamin D is needed for bone growth and protects against osteoporosis in adults.[2] Vitamin D status is usually checked by measuring the level of 25-hydroxyvitamin D in the blood.

Preclinical/Animal Studies

In vitro studies

To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of bone marrow. The study reported that 1,25-alpha-dihydroxyvitamin D3 (1,25-D3) suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,25-D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation.[3]
Vitamin D–binding protein (VDBP) transports vitamin D in the bloodstream. Studies have shown that one of its products, VDBP-macrophage activating factor (VDBP-maf), may have antiangiogenic and antitumor activities. One study examined the effects of VDBP-maf on prostate cancer cells. Treating prostate cancer cells with VDBP-maf resulted in inhibited cellular migration, proliferation, and reduced levels of urokinase plasminogen activatorreceptor (uPAR; activity of this receptor correlates with tumor metastasis). These findings suggest that VDBP-maf has a direct effect on prostate cancer cells.[4]
Studies have reported that 1,25-D3 may play an important role in prostate cancer biology. Studies have suggested that a newly discovered protein, protein disulfide isomerase family A, member 3 (PDIA3), may function as a membrane receptor binding to 1,25-D3. According to one study, PDIA3 is expressed in normal prostate cells as well as in LNCaP and PC-3 prostate cancer cell lines. In addition, their findings suggest that 1,25-D3 may act on prostate cancer cells via multiple signaling pathways, indicating there may be a number of potential therapeutic targets.[5]
Vitamin D has also been combined with radiation in an in vitro study. In this study, prostate cancer cells were treated with valproic acid (VPA) and/or 1,25-D3, followed by radiation. Cells that were treated with VPA and/or 1,25-D3 and radiation had greater decreases in cell proliferation than did cells treated solely with radiation. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,25-D3, and radiation.[6]

In vivo studies

Tumor progression was compared in two murine models of prostate cancer. In vitamin D receptor- knockout animals, rate of tumor progression and cellular proliferation were greater than in wild type animals. However, in mice that were supplemented with testosterone, these differences did not occur, suggesting that there may be significantinteraction between androgen signaling and vitamin D signaling.[7]
In a 2011 study, nude mice were fed a control diet or a diet deficient in vitamin D and were then injected with prostate cancer cells into bone marrow or into soft tissues. Osteolyticlesions were larger and progressed at a faster rate in vitamin D–deficient mice that had bone marrow injected with cancer cells than in mice that had adequate levels of vitamin D. However, there was no difference in soft tissue tumors among mice with different vitamin D levels. Results of this study show that vitamin D deficiency is associated with growth of prostate cancer cells in bone but not in soft tissue.[8]
A 2014 study evaluated calcitriol and a less-calcemic vitamin D analog in an aggressive transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Neither vitamin D analog impacted the rate of development of castration -resistant prostate cancer in mice, whether they were treated before or after castration. However, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant organmetastases after prolonged treatment. In sum, intervention with potent vitamin D compounds in TRAMP mice slowed androgen-stimulated tumor progression but, over time, may have led to more aggressive disease as indicated by increased distant metastases (P = .0823).[9] This preclinical data supports findings of the 2008 retrospective study [10] of an association between serum vitamin D levels and aggressive prostate cancer (refer to the Human Studies section in the Vitamin D section of this summary for more information about this study).

Vitamin D as adjuvant therapy

Cryotherapy may be used for treating prostate cancer. Studies have been conducted to identify potential agents that may help improve efficacy of the freezing procedure. In a 2010 study, mice were injected with prostate cancer cells and treated with calcitriol, cryoablation, or both. The combination treatment group experienced larger necrotic areas, more apoptosis, and less cell proliferation than did the other experimental groups.[11] A subsequent study corroborated these findings, showing that combining calcitriol and cryoablation resulted in more cell death than cryotherapy alone.[12]

Human Studies

Epidemiological studies

The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies. Vitamin D levels were analyzed annually for 5 years in patients with nonmetastatic prostate cancer. Results showed that throughout the course of the study, vitamin D insufficiency was prevalent among these cancer patients.[13] Levels of vitamin D metabolites in prostate cancer patients were examined in a 2011 study. Analysisrevealed that patients with the lowest concentrations of prediagnostic plasma 25-hydroxy vitamin D [25(OH)D] levels had a higher risk of developing metastatic prostate cancer than did patients with higher levels of 25(OH)D. However, there was no association between metastatic prostate cancer and circulating levels of 1,25(OH)D.[14] In another study, serum levels of 25(OH)D in prostate cancer patients were assessed. Results suggest that medium or high levels of serum 25(OH)D may be associated with better prognoses than lower levels of serum 25(OH)D. These findings indicate that 25(OH)D may play a role in disease progression and may be a marker of prognosis in prostate cancer patients.[15] Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study who had been diagnosed with prostate cancer and control participants were selected for analysis and monitored for up to 20 years. Results suggested that men with a higher vitamin D status (assessed via serum 25(OH)D concentrations) had a greater risk of developing prostate cancer than did men with lower vitamin D status.[16] A 2008 retrospective study of 749 men with prostate cancer diagnosed 1 to 8 years after blood draw and 781 matched controls found higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.[10] Both of these studies [10,16] were included in a meta-analysis of 21 studies, involving 11,941 cases and 13,870 controls, that found a 17% elevated risk of prostate cancer in men with higher levels of 25(OH)D.[17] One explanation offered for this finding may be a potential detection bias with men from higher socio-economic groups who have higher vitamin D levels and who are more likely to undergo prostate-specific antigen (PSA) testing, resulting in higher reported incidence rates.
In one case-control study of men who had undergone prostate biopsies, men who had lower vitamin D levels before biopsy were more likely to have cancer detected at biopsy than did men whose prebiopsy vitamin D levels were not lower.[18] Serum 25(OH)D levels were obtained from 667 men in Chicago undergoing first prostate biopsy for an elevated PSA or an abnormal digital rectal exam.[18] Severe vitamin D deficiency (<12 ng /mL) was associated with increased risk of a prostate cancer diagnosis on biopsy among African American men. Severe deficiency was positively associated with higher Gleason score(≥4+4), higher clinical stage (>cT2b), and overall risk category in both white American and African American men. In contrast, baseline serum 25(OH)D levels obtained in a case (n = 1,731)–cohort (n = 3,203) analysis from the Selenium and Vitamin E Cancer Prevention Trial found significantly reduced risks among men who had moderate concentrations (45–70 nmol/L) compared with men who had lower or higher values.[19] This U-shaped association was most pronounced for cancers with Gleason scores of 7 to 10. One hundred ninety men who participated in a large epidemiologic study underwent radical prostatectomy for clinically localized prostate cancer.[20] At the time of prostatectomy, 87 men (45.8%) exhibited adverse pathology, defined as primary Gleason 4, any Gleason 5 or extraprostatic extension. Men with adverse pathology had lower median serum 25(OH)D (22.7 ng/mL), compared with their counterparts (27.0 ng/mL), and were also more likely to have a serum 25(OH)D level less than 30 ng/mL.
An important means of obtaining vitamin D is via sunlight. Studies have investigated the potential link between sunlight exposure and prostate cancer. According to a 2006 study, PSA levels rise at a slower rate during spring and summer than at other times of the year; this may be related to higher vitamin D levels obtained during those months.[21] One study found that while men with low levels of sun exposure had increased risk of all prostate cancers, among men with prostate cancer, less sun exposure was associated with lower risk of advanced disease. Results of a meta-analysis, published in the same report, showed that men with low sun exposure had an increased risk of incident and advanced prostate cancer.[22] Analysis of mortality rate data from 1950 to 1994 revealed that the geographic distribution of prostate cancer mortality in the United States is inversely related to UV radiation. In addition, this relationship is more evident in areas north of 40 degrees N latitude.[23] Likewise, a study in France reported that UV radiation may be associated with reductions in cancer risk and mortality.[24]
A number of studies have explored a possible connection between the vitamin D receptor (VDR) and risk of prostate cancer. A 2011 prospective study examined VDR expression in prostate tumors. Patients with high levels of VDR expression had lower PSA at diagnosis, less advanced tumor stage, and reduced risk of lethal prostate cancer compared with patients with lower levels of VDR expression in tumors.[25] In a 2009 study, geneticvariants in VDR were analyzed in prostate cancer patients participating in the Prostate Testing for Cancer and Treatment (ProtecT) trial. Five polymorphisms of VDR were identified in the participants. A meta-analysis, published in the same report, revealed no association between specific variants and prostate cancer stage (TNM staging system), but found that three genotypes (BSML, APAL, and TAQL) may be associated with cancer grade (Gleason score), suggesting there may be a link between specific VDR polymorphisms and advanced prostate cancer at diagnosis.[26] Polymorphisms in the VDR receptor, the vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) were examined in a 2010 study. Variations in the three genesinvestigated were associated with changes in risk of recurrence and progression of prostate cancer as well as prostate cancer mortality.[27] A case-control study analyzed the correlation between VDBP single nucleotide polymorphisms (SNPs) and prostate cancer risk. Two SNPs in VDBP were associated with increased prostate cancer risk and high Gleason grade.[28] However in another large cohort-consortium study, statistically significant association was not observed for either 25(OH)D or vitamin D-related SNPs with fatal prostate cancer.[29]
A 2008 meta-analysis of 45 observational studies found no association between intake of vitamin D and prostate cancer risk.[30] A meta-analysis published in 2011 reviewed 25 studies examining the link between prostate cancer incidence and indicators of vitamin D. Analysis of those studies found no association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.[31] However, in a cross-sectional analysis of 119 men (88 African American and 31 European American men) undergoing prostatectomy, tumor proliferation as indicated by Ki-67 measured in prostate tissue demonstrated an inverse correlation between serum 1,25(OH)D and Ki-67 in tumor cells, providing early evidence of antiproliferative property of vitamin D. No correlation was observed between 25(OH)D and biomarker of tumor proliferation (Ki-67).[32]

Intervention studies

Calcitriol, the hormonally active form of vitamin D, has been the focus of some studies in prostate cancer patients. In an open-label, phase II study, patients with recurrent prostate cancer were treated with calcitriol and naproxen for 1 year. The combination of calcitriol and naproxen was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression.[33] In a 2010 study, patients with castration-resistant prostate cancer were treated with calcitriol and dexamethasone. The results indicated that while the treatments were well tolerated, they did not have an effect on participants' PSA levels.[34]
In a 2009 study, patients with locally advanced or metastatic prostate cancer and asymptomatic progression of their PSA levels were treated with vitamin D2 (ergocalciferol) at either 10 μg or 25 μg daily. The investigators reported that about 20% of these patients had at least a 25% drop in PSA level 3 months after initiating the vitamin D2.[35]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

Vitamin D toxicity

In most cases, symptoms of vitamin D toxicity are caused by hypercalcemia, but limited evidence suggests high concentrations of vitamin D may also be expressed in various organs, including the kidneys, bones, central nervous system, and cardiovascular system. Symptoms of toxicity may be observed at an intake of 10,000 to 50,000 IU per day over a period of many years. Hypercalcemia results from the vitamin D–dependent increase in intestinal absorption of calcium, leading to rapid increases in blood calcium levels. Side effects include loss of the urinary concentrating mechanism of the kidney tubule (resulting in polyuria and polydipsia), decrease in growth factor receptor, hypercalciuria, and the metastatic calcification of soft tissues. The central nervous system may also be affected, resulting in severe depression and anorexia.[36]
A systematic review of the interactions and pharmacokinetics of vitamin D and drugs used for the treatment of cancer was published.[37] Based on the review, 26 articles met the inclusion criteria. Calcitriol was the most commonly administered form of vitamin D, and adults with prostate cancer and solid tumors were the most well-represented populations in this systematic review. Hypercalcemia (at a dose of 74 μg/wk [3,000 IU]; 125 μg/wk [5,000 IU] with the addition of dexamethasone) was the most frequently reported side effect. Hypophosphatemia was also observed in two studies [38,39] that administered vitamin D in conjunction with docetaxel in men with prostate cancer. The authors concluded that no adverse effects were experienced beyond what was expected from high-dose calcitriol supplementation and was denoted as having a low risk of interaction. Some chemotherapeutic regimens appear to reduce serum 25(OH)-D3 and/or 1,25-D3.
A number of studies evaluated the safety and efficacy of high-dose calcitriol in conjunction with chemotherapy drugs in men with androgen-independent prostate cancer, hormone-refractory prostate cancer, and metastatic castration-resistant prostate cancer.[39-41] In the studies utilizing docetaxel plus calcitriol for men with androgen-independent prostate cancer, no increased toxicity was observed when compared with docetaxel alone.
In men with hormone-refractory prostate cancer, one study examined the activity and tolerability of weekly high-dose calcitriol (32 μg/wk [1,300 IU]) with docetaxel in patients who had previously received docetaxel treatment.[38] Calcitriol was given orally in three divided doses, and docetaxel was given intravenously (30 mg /m2) with dexamethasone (8 mg) orally 12 hours before, at the time of, and 12 hours after docetaxel administration. Most of the side effects were expected toxicities related to the chemotherapy. Grade 2 hypercalcemia was observed in one patient. Administration of calcitriol was discontinued until hypercalcemia resolved. Supplementation was restarted after two weeks. In another patient, persistent grade 3 fatigue was observed, and treatment of calcitriol was discontinued as docetaxel was reduced.

Phase I trials

Phase I studies have looked at the maximum tolerated dose (MTD) of weekly intravenous and oral calcitriol in conjunction with various chemotherapy drugs for cancer treatment. One study examined the MTD of calcitriol in conjunction with gefitinib at 250 mg/day (oral chemotherapy used to treat lung cancer) in 32 patients with advanced solid tumors that were metastatic or unresectable.[42] At doses up to 74 μg (3,000 IU) per week, no dose-limiting toxicities were observed. Grade 2 hypercalcemia was observed in two of four patients receiving 96 μg per week (3,900 IU) of calcitriol and was denoted nontolerable. No significant bone marrow suppression was observed at any dose. A dose of 74 μg (3,000 IU) per week was denoted as the MTD. The study suggests no major interaction between calcitriol and gefitinib.
A second phase I study examined the MTD and pharmacokinetics of calcitriol when administered with paclitaxel over the course of 6 weeks.[43] Thirty-six patients (heterogenous diagnoses) were enrolled in the trial and received escalating doses of oral calcitriol starting at 4 μg (160 IU) for 3 consecutive days, and increasing to 38 μg (1,520 IU) with an 80-mg/m2 infusion of paclitaxel given weekly. Results demonstrate that very high doses of calcitriol can be safely administered with paclitaxel. There was no dose-limiting toxicity in the trial, and at a dose of 38 μg/wk, no clinically significant hypercalcemia occurred. However, it is important to note that participants were administered from 8 to 76 capsules of calcitriol with no report of adherence to the prescribed dose of calcitriol.
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