Vitamin D and Cancer: The Missing Link Oncology Keeps Ignoring

A Tier 1 Anticancer Drug

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The benefits of Vitamin D (which extend beyond cancer) have been proven in multiple RCT’s; the “Gold Standard” of the ivory tower; yet almost all oncologists keep ignoring this data. The only possible explanation is that this hormone is cheap (I pay $15 for a years supply of high quality Vitamin D3) and therefore the oncologist, hospital and big Pharma are not going to make any money prescibing this agent; this is called the blinder syndrome.

Vitamin D is synthesized in human skin after the photoisomerization of 7-dehydrocholesterol to pre-vitamin D3 under the influence of UV B radiation (wavelength, 280-315 nm). (1) The major factors influencing this process are either environmental (latitude, season, time of day, ozone and clouds, reflectivity of the surface) or personal (skin type, age, clothing, use of sunscreen, genetics). (2) From the skin, parental vitamin D3 (cholecalciferol) finds its way into the general circulation, and it is then metabolized in the liver to 25-hydroxyvitamin D3 [25(OH)D3] (calcifediol). 25(OH)D3 is an immediate precursor metabolite to the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol), that is the product of the mitochondrial CYP27B1-hydroxylase confined primarily but not entirely to the proximal tubular epithelial cell of the kidney. (2, 3)

As vitamin D has a much shorter half-life than 25(OH)D3 (1-2 days versus 2-3 weeks), 25(OH)D3 is considered the best indicator of vitamin D status; hence 25(OH)D3 is the most widely used test indicating vitamin D status. (2, 3) A vitamin D level > 30 ng/ml is widely considered “normal” while a level between 20-30 ng/l is considered vitamin D insufficient and a level <20 ng/ml is considered vitamin D deficient. (2-4) However, more recent data suggests that a level > 50 ng/ml is desirable, and ideally targeting a level between 55- 90 ng/ml is preferable.(1, 5-7)

It may take many months or even years to achieve optimal levels in patients with low vitamin D levels (< 20 ng/ml) taking the standard recommended dose of 5,000 IU/day. It is therefore important that the optimal regimen for vitamin D supplementation be followed to achieve adequate circulating levels (see Table 1). (6, 7) Since the highest dose of commercially available vitamin D3 is 50,000 IU capsules, and due to its affordability (low cost) and better gastrointestinal absorption, we recommend using 50,000 IU D3 capsules for community setups.(1, 6, 7) Together, a number of these capsules can be taken as a bolus dose [i.e., single upfront doses such as 100,000 to 400,000 IU]. However, the liver has a limited 25-hydroxylase capacity to convert vitamin D to 25(OH)D: thus, taking 50,000 IU capsules over a few days provides better bioavailability. (1, 6, 7)

Vitamin D2 is manufactured through the ultraviolet irradiation of ergosterol from yeast, while vitamin D3 is synthesized trough the ultraviolet irradiation of 7-dehydrocholesterol from lanolin; both are used in over-the-counter vitamin D supplements. (2) Vitamin D2 has 30% of the biological activity of vitamin D3. It is best to include both Vitamin K2 (Menaquinone [MK7] 100 mcg/day, or 800 mcg/week) and magnesium (250-500 mg/day) when doses of vitamin D > 8 000 IU/day are taken. (8, 9) It should be noted that vitamin K2 itself has anticancer properties and an inverse relationship exists between vitamin K2 (and not K1) intake and cancer mortality. (10-13)

Table 1. Guidance on Upfront Loading Dose Regimens to Replenish Vitamin D Stores in the Body

When serum vitamin D levels are available, the doses provided in this table can be used for the longer-term maintenance of serum 25(OH)D concentration above 50 ng/mL (125 nmol/L). The table provides the initial bolus dose, weekly dose, frequency, and duration of administration of oral vitamin D in non-emergency situations, in a non-obese, 70 kg adult.

Source Nutrients – Special Issue: “Vitamin D – Calciferol and COVID” (6)

More than half of human tissues express the gene for the vitamin D receptor, with vitamin D having pleiotropic functions in pathways of energy metabolism, immunity, and cellular growth and differentiation that clearly extend the control of calcium homeostasis. (14) The biologically active form of vitamin D, 1,25(OH)D3, regulates over 1200 genes within the human genome. (1) The most important extra-skeletal function of vitamin D is its role in the modulation of the immune system. Vitamin D receptors are present on immune cells, with this vitamin playing a critical role in both innate and adaptive host immunity. (15, 16)

Anti-cancer activity of Vitamin D

Vitamin D shows several anticancer effects in cells and animals and is linked to lower cancer mortality. Vitamin D’s active form binds the vitamin D receptor (VDR) and regulates genes that control cell growth and survival.​

Key anticancer actions include:

• Inhibiting cancer cell proliferation and promoting differentiation.​

• Inducing apoptosis and autophagic cell death.​

• Reducing angiogenesis (new tumor blood vessels) and metastatic potential.​

• Modulating inflammation, oxidative stress, DNA damage repair, immune responses, and tumor energy metabolism.​

Evidence from experimental studies

In vitro and animal studies consistently show vitamin D can slow carcinogenesis and tumor progression.​

• Vitamin D reduces inflammatory cytokines (e.g., TNF‑α, IL‑6) in tumor microenvironments and supports DNA repair, which may limit tumor initiation.​

• Supplementation slows growth of xenografted tumors in mice and affects pathways such as PI3K‑Akt, HIF‑1, FoxO, and metabolism of glucose and lipids

Vitamin D has anticancer effects both directly via controlling the differentiation, proliferation, and apoptosis of neoplastic cells as well as indirectly through regulating immune cells that affect the microenvironment of malignant tumors. Evidence from observational and randomized controlled studies indicates that low vitamin D status is associated with higher mortality from life-threatening conditions such as cancer and cardiovascular disease. (17, 18) In a real-world analysis of 445,601 participants, aged 40–73 years, from the UK Biobank cohort, both vitamin D deficiency and insufficiency were strongly associated with all-cause mortality.(19) A Cochrane analysis demonstrated that supplementation with vitamin D3 (cholecalciferol) decreased all-cause mortality (RR 0.94, 95% CI 0.91 to 0.98, p = 0.002); however, supplementation with vitamin D2, calcifediol, and calcitriol did not affect mortality. (20)

Vitamin D deficiency has been demonstrated to increase the risk of breast cancer while supplemental vitamin D intake had an inverse relationship with this outcome. (21) Both prospective and retrospective epidemiologic studies indicate that levels of 25-hydroxyvitamin D below 20 ng per milliliter are associated with a 30 to 50% increased risk of incident colon, prostate, and breast cancer, along with higher mortality from these cancers. (2) People living at higher latitudes are at increased risk for vitamin D deficiency and are reported to have an increased risk of Hodgkin’s lymphoma as well as colon, pancreatic, prostate, ovarian, breast, and other cancers and are more likely to die from these cancers, as compared with people living at lower latitudes. (2, 22) Vitamin D supplementation likely plays an important role in the prevention of cancer, as highlighted in the prospective study by Bischoff-Ferrari et al. (23, 24) Furthermore, in a Meta-Analysis of 50 trials with a total of 74,655 participants, Zhang et al reported that Vitamin D supplementation significantly reduced the risk of cancer death (0.85,0.74 to 0.97, 0%). (25) In subgroup analyses, all-cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation. An analysis of 25(OH)D-cancer incidence rates suggests that achieving a vitamin D level of 80 ng/mL vs. 10 ng/mL would reduce cancer incidence rates by 70 ± 10%. (22)

The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, placebo-controlled, 2X2 factorial trial of vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) for the prevention of cancer and cardiovascular disease. (26) The primary endpoints of this study were total invasive cancer and major cardiovascular events. While the hazard ratios for cancer deaths comparing vitamin D to placebo were HR 0.83 (0.67–1.02) none of the primary or secondary endpoints reached statistical significance. It should be recognized that in this study both the dose of vitamin D and omega 3 fatty acids were low; and it is likely that this study was designed to fail. Nevertheless, the results of the VITAL study differ significantly from the DO-HEALTH trial which used similarly low doses of vitamin D and omega-3 fatty acids. (23, 24) In this study the HR for the prevention of cancer with vitamin D3 and omega 3 fatty acids compared to placebo was 0.53 (0.28-1.0).

Anticancer pathways and mechanisms

Experimental evidence indicates that vitamin D has diverse antineoplastic activity (see Figure 1). Binding of vitamin D to its target, the vitamin D receptor, leads to transcriptional activation and repression of target genes and results in induction of differentiation and apoptosis, inhibition of cancer stem cells, and decreased proliferation, angiogenesis, and metastatic potential. (27) Vitamin D induces apoptosis of cancer cells, (28) counteracts aberrant WNT-β catenin signaling, (29) and has broad anti-inflammatory effects via downregulation of nuclear factor-Κβ and inhibition of cyclooxygenase expression. (30) In colon, prostate, and breast carcinoma cells, 1,25-(OH)2D3 upregulates several pro-apoptotic proteins (BAX, BAK, BAG, BAD, G0S2) and suppresses survival and anti-apoptotic proteins (thymidylate synthase, survivin, BCL-2, BCL-XL). (31) In this way, it favors the release of cytochrome C from mitochondria and the activation of caspases 3 and 9 that lead to apoptosis. 1,25-(OH)2D3 and metformin have additive/synergistic antiproliferative and proapoptotic effects in colon carcinoma and other types of cells. (32)

In many cancer cell types, 1,25-(OH)2 D3 directly arrests the cell cycle in the G0/G1 phase by downregulating cyclin-dependent kinases and repressing genes that encode cyclins D1 and C. (33) 1,25-(OH)2D3 decreases the expression of epidermal growth factor receptor (EGFR) and interferes with the insulin-like growth factor (IGF)-I/II pathway. (22) Vitamin D has activity against human breast cancer cell lines by targeting Ras/MEK/ERK pathway. (31) In addition, 1,25-(OH)2D3 diminishes the proliferation of breast cancer cells by inhibiting estrogen synthesis and signaling through estrogen receptor (ER)α. (34) In colon carcinoma cells, 1,25-(OH)2 D3 upregulates an array of intercellular adhesion molecules that are constituents of adherens junctions and tight junctions, including E-cadherin, occludin, claudin-2 and -12, and ZO-1 and -2. (35) The Wnt/β-catenin pathway plays an important role in cancer. Antagonism of the Wnt/β-catenin pathway by 1,25-(OH)2 D3 was reported in colon carcinoma cells by a double mechanism: (a) liganded VDR binds nuclear β-catenin, which hampers the formation of transcriptionally active β-catenin/TCF complexes, and (b) induction E-cadherin expression that attracts newly synthesized β-catenin protein to the plasma membrane adherens junctions. In that way, it decreases β-catenin nuclear accumulation. (36)

1,25-(OH)2 D3 is an important modulator of the immune system, as reflected by the expression of vitamin D receptors by almost all types of immune cells. 1,25-(OH)2D 3 is an enhancer of innate immune reactions against tumor cells by activating macrophages, natural killer (NK) cells, and neutrophils. (22) An important mechanism of 1,25-(OH)2D3 is the inhibition of the NF-ΚB pathway. In turn, this causes the downregulation of multiple cytokines and their effects. 1,25(OH)2 D3 reduces the pro-tumorigenic effect of PG E2 in prostate cancer cells by inhibiting COX-2 and so decreasing the levels of PG E2 and two PG receptors (EP2 and FP). (37)

Autophagy is a process of elimination of cytoplasmic waste materials and dysfunctional organelles that serves as a cytoprotective mechanism but that, when excessive, leads to cell death. (22) In cancer, VDR ligands trigger autophagic death by inducing crucial genes in several cancer cell types. Thus, 1,25-(OH)2 D3 de-represses the key autophagic MAP1LC3B (LC3B) gene and activates 50-AMP-activated protein kinase (AMPK). In Kaposi’s sarcoma cells and myeloid leukemia cells, vitamin D compounds inhibit PI3K/AKT/mTOR signaling and activate Beclin-1-dependent autophagy. 1,25-(OH)2D3 has a pro-differentiation effect on several types of carcinoma cells either by direct upregulation of epithelial genes and/or the repression of key epithelial mesenchymal transcription factors (EMT-TFs). (38)

In diverse types of carcinoma cells (colon, prostate, and breast), the antiangiogenic action of 1,25-(OH)2 D3 relies to a great extent on its ability to inhibit two major angiogenesis promoters: it suppresses the expression and activity of hypoxia-inducible factor (HIF)-1α, a key transcription factor in hypoxia-induced angiogenesis, and of vascular endothelial growth factor (VEGF). (22) 1,25-(OH)2D3 also has inhibitory effects on tumor-derived endothelial cells. It reduces their proliferation and sprouting in vitro and diminishes the blood vessel density in cancer models. (39)

Clinical studies

Data suggest that the majority of patients with cancer are vitamin D deficient (level < 20 ng/ml).(18, 27, 40, 41) Several prospective observational studies have shown that higher levels of plasma 25-hydroxyvitamin D were associated with improved survival among patients with colorectal cancer. (40, 42-44) Similarly, elevated 25-OH D levels were associated with better overall survival in patients with breast and gastric cancer and lymphoma. (45) In a population-based study of patients with cancer of the breast, colon, lung, and lymphoma a 25-OHD level below 18 ng/ml at diagnosis experienced shorter survival. (46) In a Meta-Analysis of 19 studies Robsahm et al reported an inverse relationship between 25-Hydroxyvitamin D and cancer survival. (47)

Chen performed a Meta-Analysis of observational cohort studies and randomized trials which assessed the role of post-diagnosis vitamin D supplement intake on survival among cancer patients. (48) The Meta-Analysis included 11 publications consisting of 5 RCTs and 6 observational cohort studies. The summary relative risk (SRR) for overall survival of vitamin D supplement use vs. non-use, pooling cohort studies and randomized trials, was 0.87 (95% CI, 0.78–0.98; p = 0.02). Vaughan-Shaw et al performed a Meta-Analysis of 7 studies evaluating the use of supplemental vitamin D in patients with colorectal cancer. (49) The study reported a 30% reduction in adverse outcomes and a beneficial effect on progression-free survival (HR = 0.65; 95% CI: 0.36–0.94). In a Meta-Analysis by Kuznia et al, subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %. (50) It should be recognized that a daily dose of between 800 IU and 4000 IU was administered in the studies included in this Meta-Analysis and that vitamin D levels were not monitored. A more dramatic reduction in mortality would likely be realized if patients were dosed more appropriately.

Figure 1. Anticancer pathways of Vitamin D3

Figure 2. Anticancer effects of Vitamin D3

SUNSHINE was a double-blind, multicenter, randomized clinical trial designed to evaluate the efficacy of “high dose” vitamin D3 compared with standard-dose vitamin D3 given in combination with standard chemotherapy in patients with metastatic colorectal cancer. (27) The high-dose group received a loading dose of 8,000 IU per day of vitamin D3 (two 4,000 IU capsules) for cycle 1 followed by 4,000 IU/d for subsequent cycles. The standard dose group received 400 IU/d of vitamin D3 during all cycles. In this underpowered (n=139) RCT, multivariable HR for progression-free survival or death was 0.64 (95% CI, 0-0.90; p = .02) in favor of the high dose group. Comparison of progression-free survival between the high-dose and standard-dose vitamin D3 groups using a log-rank test stratified by ECOG performance status was statistically significant (p = .03). At baseline, median plasma 25-hydroxyvitamin D levels were deficient in both the high-dose vitamin D3 group (16.1 ng/mL [IQR, 10.1 to 23.0 ng/mL]) and in the standard-dose vitamin D3 group (18.7 ng/mL [IQR, 13.5 to 22.7 ng/mL]). Only 9% of the total study population had sufficient levels (≥30 ng/mL) of 25-hydroxyvitamin D at baseline. At treatment discontinuation, patients in the high-dose vitamin D3 group had a median 25-hydroxyvitamin D level of 34.8 ng/mL (IQR, 24.9-44.7 ng/mL), whereas those in the standard-dose vitamin D3 group were still deficient in vitamin D and had a median 25-hydroxyvitamin D level of 18.7 ng/mL(IQR, 13.9-23.0ng/mL) (difference, 16.2 ng/mL [95% CI, 9.9-22.4 ng/mL]; P < .001). It is important to note that based on these levels the “high dose” group was profoundly underdosed. As indicated above, vitamin D dosing should be based on a serum level aiming for a level of > 70 ng/ml (target 70-90 ng/ml). Based on the data from this study we would suggest a daily dose of vitamin D3 of 20,000 to 50,000 IU/day until an adequate vitamin D3 level is obtained. It is possible that patients with cancer may require an even higher level, approximating 150 ug/dl.

Wang et al demonstrated that postoperative vitamin D supplementation in esophageal cancer patients undergoing esophagectomy was associated with improved quality of life and with improved disease-free survival. (51) Similarly, vitamin D use post-diagnosis was found to be associated with a reduction in breast cancer-specific mortality. (52) Two recent clinical trials in prostate cancer patients suggest that vitamin D supplementation may prevent prostate cancer progression. (53, 54) Vitamin D has additive or synergistic effects when combined with conventional chemotherapy. (32) Zeichner et al demonstrated that use of vitamin D during neoadjuvant chemotherapy in HER2-positive nonmetastatic breast cancer was associated with improved disease-free survival (HR, 0.36; 95% CI, 0.15-0.88; p=0.026). (55)

Types of cancers that Vitamin D may be beneficial for

Vitamin D supplementation is likely beneficial in most cancers, but particularly in patients with breast, colorectal, gastric, esophagus, lung, and prostate cancer as well as those with lymphomas and melanoma.

Figure 3. Treatment with Vitamin D and cancer types

Dosing and cautions

Vitamin D is generally safe when used appropriately, but there are clear contraindications and important cautions where supplementation can cause harm—primarily through hypercalcemia and related complications.

Absolute Contraindications

Vitamin D should not be given (or only under specialist supervision) in the following conditions:

1. Hypercalcemia

• Any cause of elevated serum calcium

• Vitamin D increases intestinal calcium absorption and will worsen hypercalcemia

• Symptoms may include nausea, confusion, arrhythmias, nephrolithiasis

2. Vitamin D Toxicity (Hypervitaminosis D)

• Typically from excessive supplementation

• Defined by elevated 25-hydroxyvitamin D with hypercalcemia

• Further supplementation is contraindicated

---

Strong Relative Contraindications / High-Risk Conditions

Vitamin D may be used only with caution, dose limitation, and monitoring:

3. Granulomatous Diseases

Examples:

• Sarcoidosis

• Tuberculosis

• Certain fungal infections

• Some lymphomas

Why: Activated macrophages express extrarenal 1-α-hydroxylase → uncontrolled conversion to active 1,25-dihydroxyvitamin D → hypercalcemia even at low doses

---

4. Primary Hyperparathyroidism

• Vitamin D may worsen hypercalcemia

• Can be used cautiously if deficient, but only with frequent calcium monitoring

---

5. Severe Chronic Kidney Disease (CKD stage 4–5)

• Reduced ability to regulate calcium/phosphate balance

• Risk of:

  • Hyperphosphatemia

  • Vascular calcification

• Often requires active vitamin D analogs rather than cholecalciferol

---

6. Nephrolithiasis (Calcium Kidney Stones)

• Especially hypercalciuric stone formers

• Vitamin D can increase urinary calcium

• Not absolutely contraindicated, but:

  • Avoid high doses

  • Monitor urine calcium if long-term therapy

---

Important Drug Interactions (Functional Contraindications)

7. Thiazide Diuretics

• Increase renal calcium reabsorption

• Combined with vitamin D → ↑ risk of hypercalcemia

8. Digoxin

• Hypercalcemia increases digoxin toxicity risk

• Requires strict calcium monitoring

---

Key Monitoring Parameters (When Risk Exists)

If any of the above conditions are present, monitor:

• Serum calcium

• 25-hydroxyvitamin D

• ± 24-hour urinary calcium (stone formers)

• Renal function

• PTH

---

Table 2. Dosing suggestions in patients with relative contraindication to Vitamin D

Vitamin D3 levels should be monitored in all patients.

Unless contraindicated (see above) all cancer patients should be treated with vitamin D3. A baseline Vitamin D3, serum calcium and renal functions tests must always be obtained. As almost all patients with cancer are severely vitamin D deficient, a high loading dose of Vitamin D is suggested followed by dose titration according to vitamin D blood levels, aiming for a level of > 70 ng/ml (target 70-90 ng/ml). However, current data suggest that levels up to 150 ng/mL are necessary for certain types of cancer to stop growth and metastasis. Vitamin D intoxication is observed when serum levels of 25-hydroxyvitamin D are greater than 150 ng per milliliter (374 nmol per liter). (2) Hypercalcemia will usually not occur until levels exceed over 250 ng/ml.

In patients with a level < 40 ng/ml we suggest a daily dose of 20,000 to 30 000 IU/day until a vitamin D level is obtained and the dose subsequently titrated to achieve the target level . If measuring vitamin D levels is not feasible/possible, we would suggest a loading dose of 100,000 IU followed by 10,000 IU/day. Doses of 10,000 IU of vitamin D3 per day for up to 5 months were reported to be safe and without toxicity. (2, 5) It should be noted that dosages of vitamin D up to 80,000 IU/day have been reported to be safe. (56, 57) We recommended vitamin D3 over D2 as vitamin D2 is approximately 30% as effective as vitamin D3 in maintaining serum 25-hydroxyvitamin D levels. (2) Furthermore, vitamin D3 should be dosed daily rather than large intermittent bolus dosing. It is best to include both Vitamin K2 (Menaquinone [MK4/MK7] 100 mcg/day, or 800 mcg/week) and magnesium (250-500 mg/day) when doses of vitamin D > 8 000 IU/day are taken. (8, 9) Patients taking coumadin need to be closely monitored and the need to consult with their PCP before taking vitamin K2. Further, we suggest measuring PTH (parathyroid) levels and calcium levels and titrating the dose of Vitamin D according to the PTH levels as follows (Coimbra Protocol): (58, 59) i) if the PTH level is below the lower end of the reference range, reduce the dose of Vitamin D ii) if the PTH level is at (or close too) the lower end of the reference range, maintain dose, iii) if PTH is within the reference range but not near to the low end of the reference range increase the dose of Vitamin D.

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