VITAMIN D3

Vitamin D3 deficiency is very common at diagnosis in most cancer types, lung, liver, kidney, triple negative breast cancer, prostate and more. The suggested reasons include cancer related systemic inflammation and even direct dysfunctions in vitamin D3 metabolism linked to the tumor microenvironment. And, often accompanied by low magnesium levels, which affect vitamin D3 metabolism and also need to be corrected and sustained. Both vitamin D3 and magnesium are strongly depleted by inflammation and by many drugs including those used in oncology.

Clinical trials can show mixed results, as with any trials. Nevertheless, there is a clear weight of evidence that higher levels mean lowered risks progression during treatment including in prostate, breast, colorectal, ovarian cancer and others. The VITAL trial is perhaps the most significant so far across many cancer types. At 2000IU daily the results report a 17% reduced progression to metastatic cancer. Importantly, at this dose the effects were 38% in those of low BMI and become insignificant as BMI increases. Researchers suggest higher doses might be considered. In colorectal cancer, there are similar 1/3 or so risk reductions (see References)

Analyses sometimes miss the need for regular and sufficient doses at daily sustained levels to reach significance. And least in breast, colorectal and ovarian cancer treatment, the larger effects are seen at 4000IU and beyond, where meta-analysis across 6000 patients shows significant and increasing relative survival benefits with dose (see Examples). Immunotherapy results for lung, kidney cancer and melanoma, even low supplementation programs have been reported to reduce risk levels very significantly, risk reductions almost a half (see References, PROVIDENCE trial). Very recent research into a variety of immunotherapy drug response rates shows that winter time deficiency in Vitamin D3 has major negative effects, whilst supplementation gave risk reductions 30 percent plus range. (see References) Possibly related, in metastatic clear cell kidney cancer, immunotherapy treatments have very recently been shown to be more effective in the morning.

Vitamin D3 deficiency is associated in several studies with increased metastatic spread. Mainly from research in other diseases, having sufficient levels of vitamin D3 are reported to decrease abnormally high platelet levels, aggregation and adhesion levels with obvious similarity to aspirin or statin actions. All of which are frequently reported mechanisms involved in metastatic spread (click icon for references)

Also taken as Calcitrol, Vitamin D3 is a great opportunity for many. If a dose of 2000, 4000 or 10000IU sounds like a lot, remember that it would be a few minutes of sunshine on a bright summers day. In fact, the aptly named 2019 SUNSHINE trial in advanced colorectal cancer showed doses of 4000IU provided 34% improved survival rates vs 400IU. The “Madden” breast cancer intervention trial confims up to double the relative survival rates for immediate post-diagnosis use. Detailed clinical studies on 10,000 and 40,000IU doses show increasing suppression of prostate cancer (see References). Some clinicial trials are using 10,000IU daily, some 50,000IU weekly. Its important to increase your levels both before and during treatment. 10,000IU or 250 microgram supplements are safe and readily available

Prevention effects of daily vitamin D3 have been reported as 7% risk reduction across the whole population, and 15%  in adults aged ≥ 70 years due to a 28% lower risk in men.  Probably connected to 12% risk reduction in prostate cancer incidence and 28% in colorectal cancer patients whereas no preventative pre-diagnosis effects were seen in breast and lung cancer patients (see Examples) Similarly in prevention, women in particular see these dose related risk reductions for kidney cancer.

ANTI-METASTATIC ACTIONS

TYPICAL ABSORPTION LEVELS

High

EXAMPLES OF IMPROVED OUTCOMES

YES
ANALYSIS

PRE-DIAGNOSIS OR PREVENTION

YES
ANALYSIS

Highlighted Studies

Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen ..The IPD meta-analysis .confirmed the finding of all trials. we believe that the arguments for an efficacy of daily vitamin D treatment regimens are convincing. Indeed, restricting the IPD meta-analysis to trials with daily dosing regimen yielded a statistically significant 13% cancer mortality reduction and 11% increase...

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Utilizing a dose-response meta-analysis, the pooled HR [Hazard Ratio] for overall survival in breast cancer patients was 0.994 (per 1 nmol/L) [ie level of Vitamin D3 in blood]. At or above a 23.3 nmol/L threshold, for a 10 nmol/L, 20 nmol/L, or 25 nmol/L increment in circulating 25-OH-D levels, the risk of breast cancer overall mortality decreased by 6%, 12%, and 14%, respectively. There was no significant nonlinearity in the relationship between overall survival and circulating 25-OH-D level...

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Stratifying by the time of vitamin D assessment, the HR [Hazard Ratio] of prostate cancer-specific mortality was 0.91 for prediagnosis studies and 0.84 for post-diagnosis ones. The HR of all-cause mortality was 0.94 in pre-diagnosis subgroup. Restricting the analysis among more than 10-year follow-up yielded a HR of 0.92 and 0.94 for prostate cancer-specific mortality and all-cause mortality respectively, which was slightly higher than the overall results. Moreover, there was no evidence of s...

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..this randomized clinical trial of daily high-dose vitamin D supplementation for 5 years reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort of adults without a diagnosis of cancer at baseline, with strongest risk reduction in individuals with normal weight. Additional randomized trials focusing on cancer patients should be considered, as well as investigations of differential benefit by BMI. Even if vitamin D effects were modest, vitamin D supplementation at...

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TABLE OF REFERENCES

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214278/5Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86–1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78–0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91–1.24]; p-value for interaction: 0.042).The conclusion of the main meta-analysis of all RCTs is that vitamin D3 supplementation did not reduce cancer mortality because the 6% reduction of cancer mortality was not statistically significant: HR 0.94 (95% CI: 0.86; 1.02). However, we believe that the arguments for an efficacy of daily (as compared to bolus) vitamin D treatment regimens are convincing. Indeed, restricting the IPD meta-analysis to trials with daily dosing regimen yielded a statistically significant 13% cancer mortality reduction and 11% increased cancer-specific survival.
https://journals.sagepub.com/doi/full/10.1177/15347354177120075In conclusion, our findings suggest that there is a highly significant linear dose-response relationship between circulating 25-OH-D levels and overall survival in patients with breast cancer. At, or above, a 23.3 nmol/L threshold, for a 10 nmol/L, 20 nmol/L, 25 nmol/L increment in circulating 25-OH-D levels, the risk of breast cancer overall mortality decreased by 6%, 12%, and 14%, respectively.The two-stage fixed-effects dose-response model showed that the pooled HR for overall survival in breast cancer patients was 0.994 per 1 nmol/L (Z = −4.95, Pfor linear trend < .001). At or above a 23.3nmol/L threshold, the pooled HR for overall survival in breast cancer patients was 0.94 (95% CI = 0.92-0.96, P < .001) per 10 nmol/L increment in circulating 25-OH-D levels, 0.88 (95% CI = 0.84-0.93, P < .001) per 20 nmol/L and 0.86 (95% CI = 0.81-0.91, P < .001) per 25 nmol/L increment in circulating 25-OH-D levels. There is no significant nonlinearity in the relationship between overall survival and circulating 25-OH-D levels Screenshot from 2025-06-17 14-52-18
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240137/5Seven eligible cohort studies with 7808 participants were included. The results indicated that higher vitamin D level could reduce the risk of death among prostate cancer patients. The summary HR [Hazard Ratio] of prostate cancer-specific mortality correlated with an increment of every 20 nmol/L in circulating vitamin D level was 0.91, The HR for all-cause mortality with the increase of 20 nmol/L vitamin D was 0.91There is also some evidence from clinical trials on the roles of vitamin D in prostate cancer. In a clinical trial, low-grade prostate cancer patients took 4000 IU of vitamin D3 every day for a whole year and had a biopsy after the supplementation. Results of biopsy revealed a decreased number of positive cores and no increase in Gleason score . Several randomized clinical trials showed that oral vitamin D3 modestly decreased the level of PSA and reduced the PSA rise rate . However, a vitamin D supplementation trial showed no influence on free or total PSA level in African American population
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/27730745This [VITAL] randomized clinical trial of daily high-dose vitamin D supplementation for 5 years reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort of adults without a diagnosis of cancer at baseline, with strongest risk reduction in individuals with normal weight. Additional randomized trials focusing on cancer patients should be considered, as well as investigations of differential benefit by BMI. Even if vitamin D effects were modest, vitamin D supplementation at the studied levels are much less toxic and lower cost than many current cancer therapiesHowever, a significant reduction [17%] in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12 927 assigned to vitamin D [1.7%] and 274 of 12 944 assigned to placebo [2.1%]..When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI ...but not among those with overweight or obesity; BMI ≥30:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911644/5In conclusion, we observed a particularly high prevalence of vitamin D deficiency among patients with advanced or metastatic CRC. In light of our findings that higher 25(OH)D levels are associated with improved OS and PFS, randomized trials are warranted to assess the benefit of vitamin D supplementation in CRC patients. These findings, followed by the promising results of our SUNSHINE randomized phase II trial (7), have now paved the way for an Alliance-led randomized phase III trial of vitamin D supplementation in combination with standard chemotherapy plus biologic therapy among previously untreated metastatic CRC patientsAbundant preclinical evidence supports the hypothesis that vitamin D may possess antineoplastic activity against CRC. VDR and 1-α-hydroxylase, which converts 25(OH)D into 1,25(OH)2D, are present in colon cancer cells (27–29). The binding of VDR by 1,25(OH)2D promotes differentiation (30,31), activates apoptotic pathways (32), and inhibits angiogenesis (33,34), proliferation (35), and metastasis (36) of colon cancer. In the genetically engineered mouse model of intestinal carcinogenesis (APCmin), tumor burden was significantly increased by inactivation of the VDR gene (37) and decreased by treatment with vitamin D or its synthetic analogue (38). Other mechanisms through which vitamin D may influence colorectal carcinogenesis include modulation of cellular immunity and systematic inflammation
https://www.mdpi.com/2072-6643/15/20/43615In the subgroup of CRC [colorectal cancer] patients with the highest tertile of sCD40L, the 5-year RFS [regression free survivial] rate in the vitamin D group was 77.9%, which was significantly higher than 33.2% in the placebo group... In conclusion, elevated sCD40L might be a biomarker of poor prognosis in patients with CRC, but vitamin D supplementation might improve RFS in patients with high sCD40L.Specifically, we observed that the lowest tertile of sCD40L levels exhibited a substantially reduced risk of relapse or mortality, amounting to less than one-third of the risk observed in the middle and highest sCD40L tertiles. This risk reduction persisted even after adjustment for various factors, including age, sex, BMI, 25(OH)D levels, vitamin D supplementation or placebo administration, cancer stage, and adjuvant chemotherapy. These findings underscore the potential of reduced sCD40L levels as a superior prognostic biomarker specifically in CRC patients.
https://jamanetwork.com/journals/jama/fullarticle/27301125 In this [SUNSHINE] phase 2 randomized clinical trial that included 139 patients with advanced or metastatic colorectal cancer, treatment with chemotherapy plus high-dose vitamin D3 supplementation vs chemotherapy plus standard-dose vitamin D3 resulted in a median progression-free survival of 13 months vs 11 months, respectively, that was not statistically significant, but a multivariable hazard ratio of 0.64 for progression-free survival or death that was statistically significant.There were no statistically significant differences in the effects of high-dose vitamin D3 between patients with baseline plasma 25-hydroxyvitamin D levels of 20 ng/mL or less vs levels greater than 20 ng/mL (P = .40 for interaction). The effect of high-dose vitamin D3 on progression-free survival appeared to be greater among patients with a lower body mass index (P = .04 for interaction), more metastatic sites (P = .02 for interaction), and KRAS wild-type tumors (P = .04 for interaction)
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/28085745This important new observation by Kanno et al2 requires confirmation. It would be prudent, based on all available evidence, that patients with cancer consider improving their vitamin D status with 2000 IU daily to reduce morbidity and mortality associated with their cancer, except for those patients who have a hypersensitivity to vitamin D, including patients with granulomatous disorders and some lymphomas. Patients who had detectable serum anti-p53 antibody and received 2000 IU daily had a significant, more than 2.5-fold improvement in relapse or death compared with the placebo group that had detectable p53 immunoreactivity. The observed 27% absolute risk reduction translates to a number needed to treat of 4. In those patients who had no p53 immunoreactivity, 2000 IU of vitamin D3 daily provided insignificant benefit for 5-year relapse-free survival.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459116/5Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% . In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46)In the current study, vitamin D was effective only in a subgroup of patients with middle (20-40 ng/mL) serum 25(OH)D levels at baseline. However, this finding must be considered exploratory and interpreted with caution in the context of the null findings for the primary outcome measures in the total population, as well as the potential for type I error due to multiple comparisons. It was hypothesized that vitamin D would be effective in the subgroup with low 25(OH)D at baseline, as was observed in an RCT for a subgroup of patients with lung cancer (although with a nonsignificant interaction test).24 It is possible that the optimal range of serum 25(OH)D levels with respect to survival may be quite different among types of cancers. In addition, the supplement dosage of 2000 IU/d in the trial may have been insufficient to increase vitamin D levels sufficiently in the subgroup with low 25(OH)D levels.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387395/5No adverse events associated with vitamin D3 supplementation were observed. No significant changes in PSA levels were observed. However, 24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score.Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D3 supplementation at 4000 IU/d.
https://www.sciencedirect.com/science/article/pii/S0002916523277527?via%3Dihub5In our cohort, higher serum 25(OH)D concentrations at diagnosis were associated with longer survival among women with ovarian cancer. If confirmed in other studies, this suggests that vitamin D status at diagnosis may be an independent predictor of prognosis. Furthermore, if the association is found to be causal, improving vitamin D status may improve ovarian cancer survival rates.Based on the results mentioned earlier, we can draw the conclusion that higher vitamin D level is significantly associated with a risk reduction of all-cause mortality and prostate cancer-specific mortality, indicating vitamin D may exert a protective effect in the progression and prognosis of prostate cancer. More cohort studies and randomized clinical trial are needed to further illustrate the role of vitamin D in the pathogenesis and prognosis of prostate cancer.
https://link.springer.com/article/10.1007/s10549-018-4896-65There was a 20% reduction in breast cancer-specific mortality in de novo vitamin D users (modelled as a time-varying variable) compared to non-users (HR 0.80; 95% CI 0.64–0.99, p = 0.048) and the reduction was greater at 49% (HR 0.51), if vitamin D was initiated soon after the breast cancer diagnosis (within 6 months)de novo vitamin D use post-diagnosis was found to be associated with a reduction in breast cancer-specific mortality. Vitamin D, therefore, has the potential as a non-toxic and inexpensive agent to improve survival in breast cancer patients. Findings support the need for RCTs exploring the effect of vitamin D supplementation on breast cancer survival.
https://www.nature.com/articles/bjc2017445This is the first systematic review with meta-analysis that examines the relationship between cancer outcomes and variation in vitamin D pathway genes, and also by far the largest review on vitamin D status and cancer outcome. Our review suggests that higher circulating vitamin D in cancer patients is associated with a 26% lower rate of death and a 16% lower rate of disease progression. The clear association with survival was also observed in site-specific analyses of breast, haematological and colorectal cancers, while an association with reduction in disease progression was also found in those diagnosed with breast, haematological and skin cancer.However, evidence that genetic factors linked to vitamin D metabolism and pathways impact upon cancer survival may be used to counter such concerns and support a causal link. In our meta-analysis, we found evidence of an association between the VDR gene variants with functionally characterised effects and cancer outcome. Forty percent higher rate of death was observed in TT 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.
https://www.mdpi.com/2072-6694/16/24/42065To the best of our knowledge, this is the first study that specifically reports the effect of baseline VD levels in this BC setting. The present meta-analysis reveals that adequate baseline VD levels are associated with a 22% reduction in the risk of non-response to NACT and a 35% reduction in the risk of disease progression. These findings highlight the significant role of adequate levels of VD in enhancing both NACT [chemo] response and PFS in BC patients. Forest plots depicting the influence of VD on OR and PFS are presented.... The pooled data analysis revealed a 22% decrease in the risk of non-response to NACT associated with adequate baseline VD [vitamin D3] levels, based on data from 722 patients and analyzed using random-effects models (HR: 0.78, 95% CI: 0.30–1.25; p = 0.001). In terms of progression risk, the analysis of 1033 patients showed a 35% reduction in the risk of progression, with consistent findings across both fixed- and random-effects models (HR: 0.65).
https://pmc.ncbi.nlm.nih.gov/articles/PMC3387395/5..active surveillance and vitamin D3 supplementation at 4000 IU/d resulted in a decreased number of positive cores at repeat biopsy in more than half of patients diagnosed with low-risk prostate cancer. These subjects (responders) are all eligible to remain on active surveillance and do not require definitive treatment (e.g. surgery or radiation therapy). Therefore, this regimen may decrease the chances of overtreatment for patients with low-risk prostate cancer who, based on the results of the repeat biopsy, respond to the combination and remain stable or improve.this suggests that vitamin D action on prostate tissue is through an autocrine/paracrine mechanism, rather than the classic renal endocrine pathway. The mechanism of action is likely to be mediated through the delivery of cholecalciferol and 25(OH)D to prostatic cells, with subsequent activation to 25(OH)D and 1,25(OH)2D by CYP2R1 and CYP27B1, respectively (9, 10). A similar mechanism has been described for the control of cathelicidin production by human monocytes and macrophages, for which circulating calcitriol levels are of little consequence (32). The increased circulating levels of cholecalciferol may be of considerable importance because its free concentration would be high enough to enter the cell at an accelerated rate
https://www.nature.com/articles/s41416-020-01060-85This is the first systematic review with meta-analysis of randomised controlled trials to examine the effect of vitamin D supplementation on survival outcomes in patients with CRC. We found that supplementation imparts a 30% reduction in adverse survival outcomes overall, with a 24% reduction in CRC-specific death and a 33% in disease progression or death. The effect on survival was consistently observed in sub-group analyses both in trials specifically including CRC patients and in population trials reporting outcomes in incident CRC cases.While trials varied in inclusion criteria, intervention dose and outcomes, meta-analysis found a 30% reduction in adverse CRC outcomes with supplementation (n = 815, HR = 0.70). A beneficial effect was seen in trials of CRC patients (progression-free survival, HR = 0.65), with suggestive effect in incident CRC cases from population trials (CRC-specific survival, HR = 0.76). No heterogeneity or publication bias was noted.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10576732/5Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS), time to treatment failure (TTF), and higher disease control rate (DCR). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55) and treatment discontinuation (HR 0.61) for patients from PROVIDENCE cohort 1 in comparison to the control cohort.The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs...In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16)
https://link.springer.com/article/10.1007/s00262-023-03522-3#Abs15Our study provides for the first-time practice informing evidence about the high prevalence of hypovitaminosis D in patients with solid tumors treated with ICI and on the efficacy of systematic supplementation to timely restore adequate vitamin D levels in most patients. Our explorative comparative analysis offers provocative insights about the putative multifaceted immune-modulating effects of vitamin D systematic supplementation, which could potentially improve clinical outcomes and prevent thyroid irAEs in patients receiving ICI-based treatmentsIn comparison to the control cohort, whilst increased DCR for the PROVIDENCE cohort 1 found further confirmation (OR 1.99). IPTW-fitted multivariable Cox regression, including ECOG-PS, number of metastatic sites, and primary tumor, showed that patients from the PROVIDENCE cohort 1 experienced a significantly decreased risk of death (HR 0.55) and treatment discontinuation (HR 0.61) ...when compared to the non-repleted control cohort.
https://academic.oup.com/jcem/article/98/4/1498/25368415In conclusion, our clinical trial data support the hypothesis that prostatic in vivo vitamin D metabolism can be modulated by high oral vitamin D dosing. Furthermore, the decrease in Ki67 labeling and modest declines in serum PSA and PTH with higher prostate calcitriol achieved with vitamin D doses (10 000 and 40 000 IU/d) suggest a potential clinical benefit. Lastly, the vitamin D doses (400–40 000 IU/d) were well tolerated by PCa patients without signs of toxicity. Further studies are needed to validate the potential utility of moderate-dose vitamin D3 supplementation in PCa prevention and of higher doses of vitamin D as part of the treatment for PCa.Prostate tissue and serum levels of vitamin D metabolites, including calcitriol, increased dose dependently (P < .03) and were significantly higher in the 40 000-IU/d group than in every other dose group (P < .03). Prostate vitamin D metabolites correlated positively with serum levels (P < .0001). Ki67 measures did not differ significantly among vitamin D dose groups. However, cross-sectional analysis indicated that the calcitriol level attained in prostate was inversely associated with Ki67 intensity and Ki67 (3+) percent positive nuclei in PCa and benign tissue (P < .05). Safety measures did not change adversely with dosing. Compared with the 400-IU/d group, serum PTH and PSA were lower in the combined higher-dose groups at the end of the study (P < .02)
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-04889-25Moreover, in one study, although the concentration of VD was measured before the initiation of therapy and oral supplementation, and the authors referenced scientific literature demonstrating the ability of supplementation to maintain VD levels consistently above 30 ng/ml in patients with metastatic colon cancer, formal monitoring of VD in their case series was lacking [31]. VD has demonstrated clear anti-carcinogenic properties and the ability to modulate immune responses, which can potentially enhance the efficacy of chemotherapy. Based on the results of our meta-analysis, it is imperative for future studies to investigate whether VD supplementation in this clinical setting could serve as an innovative approach to improve clinical outcomes.The effect size of VD levels on prognosis was determined by HR. Forest plots illustrating the effect of VD on OS and PFS can be seen in Fig. 3A and B, respectively. The pooled analysis showed a 47% increased risk of death in 1712 patients using fixed-effects models (HR: 1.47, 95% CI: 1.21–1.79). The pooled analysis for progression risk in 1264 patients resulted in a 38% increase (HR: 1.38; 95% CI: 1.13–1.70). Our findings suggest that inadequate VD concentration before initiating chemotherapy has a significant negative impact on OS and PFS in stage IV CRC patients.
https://www.mdpi.com/2072-6694/12/3/6754.5Vitamin D insufficiency is common among lung cancer patients. Although vitamin D has been shown to exert anti-tumor activity in multiple pre-clinical tumor models, its role in advanced lung cancer remains controversial. Here, for the first time, we investigated the prognostic value of vitamin D sufficiency in genotype-specific cohorts of advanced LUAD. Our results indicate that vitamin D has LUAD subtype-selective effects on clinical outcomes: EGFR-mutant patients derive a survival benefit from higher vitamin D levels, while KRAS-mutant patients do not. Mechanistically, vitamin D signaling promotes the expression of epithelial markers in EGFR-mutant cells and improves the efficacy of EGFR TKI treatment in vitro. Hence, vitamin D supplementation may be a safe and cost-effective tailored treatment approach for improving clinical outcomes in EGFR-mutant LUAD patients.A recently conducted prospective, double-blind placebo-controlled trial of vitamin D supplementation in unselected NSCLC patients demonstrated that supplementation provided no significant survival benefit in the overall cohort [18]. However, the vitamin D deficient subgroup of patients with early-stage LUAD that received vitamin D3 (1200 IU per day) versus placebo had significantly longer progression-free survival (PFS) and overall survival (OS). Notably, this trial was conducted in Japan, where EGFR mutations are the predominant oncogenic driver of LUAD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387395/4.5Therefore, our working hypothesis is that vitamin D3 supplementation at 4000 IU/d may benefit patients with low-risk prostate cancer by increasing the prostate tissue levels of 1,25(OH)2D3, which in turn will induce apoptosis of cancer cells. We also propose to use positive cores at repeat biopsy as a progression biomarker to assess the potential benefit of treatment options that specifically target early-stage, low-risk prostate cancer.We also compared the number of positive cores and Gleason grade at baseline and repeat biopsy in the supplemented group and the control group (Fig. 3). Using the same criteria, 63% of the subjects in the control group progressed (because of an increase in the number of positive cores or in Gleason score), compared with 34% in the supplementation group (P = 0.05), as seen in Fig. 3A. Furthermore, in the historical control group, four patients (21%) had improvements in biopsy results, three showed no differences (16%), and 12 (63%) progressed. Comparing the proportions who responded in each group , a significant difference was found
https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e14684https://www.ajmc.com/view/study-finds-link-between-vitamin-d-levels-at-start-of-immunotherapy-and-overall-survival4.5Among 209 patients with normal VD [Vitamin D] levels or receiving VD supplements, season of initiation was not associated with OS [Overall Survival] (Nov to Apr vs May to Oct )... However, VD deficiency (n 37) was associated with shorter OS (HR 2.06) and VD supplementation with longer OS (HR 0.69)While VD deficiency and VD supplementation were associated with OS, season of ICI initiation was not. These results provide reassurance the OS benefits of ICIs remain similar irrespective of time of year of initiation despite seasonal factors that may influence the immune system. Research Sponsor: None.
https://www.jstage.jst.go.jp/article/jnsv/67/5/67_273/_article4.5Ten eligible studies were selected for the meta-analysis following specific inclusion and exclusion criteria. Four included studies, covering 5,007 patients, compared the overall survival (OS) and relapse-free survival (RFS) of lung cancer patients among total vitamin D users with non-users. Significantly, the estimated pooled hazard ratio (HR) revealed that vitamin D could improve OS and RFS of lung cancer patients [HR=0.83, 95% CI (0.72–0.95); HR=0.79, 95% CI (0.61–0.97),Vitamin D intake was inversely associated with lung cancer incidence in six studies [OR=0.90, 95% CI (0.83–0.97)]. The present meta-analysis shows vitamin D not only improves the long-term survival of lung cancer patients but has a beneficial effect on the incidence of lung cancer. Notwithstanding, more studies are needed to confirm the study results.
https://www.tandfonline.com/doi/full/10.1080/2162402X.2018.14768174.5Vitamin D serum levels were significantly lower in HNSCC patients compared with healthy controls. Low vitamin D levels were associated with lymphatic metastasis and a negative HPV status and were a significant predictor of poor overall survival. HNSCC patients with severe vitamin D deficiency showed significantly altered intra- and peritumoral immune cell infiltrate levels. After vitamin D substitution, the patients’ NK cells showed a significant rise in cytotoxic activity. Taken together, we could show that Vitamin D deficiency is highly prevalent in HNSCC patients and is a predictor of poor survival. Vitamin D substitution used as an adjuvant in immune therapies such as cetuximab and nivolumab treatment could support antitumorigenic immune responses, thus contributing to the improvement of the patients’ prognosis in the context of a multimodal therapy.Our correlation of vitamin D serum level and clinical patient data revealed a significant association of higher vitamin D serum levels with a negative lymph node status, pointing towards a possible inhibitory effect of vitamin D on tumor cell metastasis. Accordingly, first in vitro studies showed an inhibition of HNSCC cell proliferation by vitamin DCitation28. Apart from cancer cell metastasis, the results mentioned before also raise the question if the beneficial prognostic effect of vitamin D in HNSCC patients could possibly be mediated not only by the immune system but also by a direct effect of vitamin D on cancer cell biology. These are important questions that need to be addressed by future studies.
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.839816/full4.5We show in this comparative, non-interventional, side-by-side analysis that low vitamin D status is a strong predictor of poor outcome in patients treated for advanced melanoma with BRAFi, MEKi, CTLA-4i, and/or PD-1i. Investigating both “baseline” and “average” 25(OH)D s.c., OS was markedly reduced in severely vitamin D-deficient individuals as compared to patients with 25(OH)D s.c. ≥10 ng/ml. Results of our study are well in line with other investigations that support the concept that vitamin D deficiency may favor poor outcome in cancer patients. Recently, it has been shown that vitamin D regulates via different pathways and independent mechanism functions of many cell types involved in immunologic reactions and in the antitumor responseAlthough the results were not statistically significant, our study indicates that the vitamin D status-associated improved outcome in our patients may be associated with a decreased frequency of AEs. During the complete OP, a trend for slightly reduced AEs (AE ratio -1.01) was documented in patients with average 25(OH)D serum concentrations ≥10 ng/ml as compared to severely vitamin D-deficient individuals [average 25(OH)D serum concentration <10 ng/ml] (p = 0.449). If this trend will be confirmed in future investigations, it can be speculated whether this decrease in the frequency of AEs may be caused by effects of vitamin D compounds on melanoma cells, immune cells, or on other cell types.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7089819/4Vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR]=0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR=0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR=0.79 [0.63-99]) or first 2 years (HR=0.75 [0.59-0.96]) of follow-upPlausible mechanisms by which vitamin D may reduce cancer incidence and/or cancer mortality are shown in Figure 4. Laboratory research suggesting that 1,25(OH)2D, the active vitamin D hormone produced from 25(OH)D, decreases tumor invasiveness, angiogenesis, and metastatic propensity [26, 27]. The cancer mortality findings are also supported by observational studies showing that higher 25(OH)D levels at cancer diagnosis predict longer survival in patients [28–34]. In some [35–45], but not all [46–50], studies,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381363/4This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1–0.9). These results were confirmed in the validation cohort (OR 0.46, 95% CI 0.2–0.9) of 169 patients of whom 49 developed ICI colitis (29%).
https://www.bmj.com/content/340/bmj.b55004 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer. Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 ; 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 ; ≥100.0 nmol/l: 0.77). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintileIn the present study, although cancer risks for 25-(OH)D levels above 75 nmol/l were lower than those in the 50-75 nmol/l mid-range reference, the differences were not statistically significant. This finding suggests that raising very low levels of 25-(OH)D to the mid-range may protect against colorectal cancer, and that levels above 75 nmol/l might not significantly reduce the cancer risks any further, but this needs to be proven in a clinical trial. In light of accumulating evidence for a possible beneficial role of increased circulating vitamin D levels in reducing the risk of a range of different diseases as well as cancer specific and total mortality
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340350/3.5Vitamin D deficiency is significantly widespread in patients with triple-negative tumors. Several studies have observed a possible modulatory effect of vitamin D or its analogues on the expression of different hormone receptors in breast cancer and increased sensitivity to tamoxifen. Vitamin D possesses anti-inflammatory and immunomodulatory effects in patients with breast cancer, and the mechanism of action of vitamin D in patients with breast cancer is discussed. In conclusion, vitamin D appears to have a beneficial role in the prevention and management of breast cancerAs vitamin D downregulates ERα expression via inhibition of NF-κB, it may increase the sensitivity to tamoxifen through induction of functional ERα in ER-negative cancer cells. Vitamin D combined with tamoxifen may be effective in tamoxifen-resistant tumors, and its concurrent use with aromatase inhibitors may be another suitable therapeutic option. Vitamin D analogs that induce ERβ subunits in addition to androgen agonists may be future promising therapeutic interventions to overcome TNBC. Vitamin D appears to possess anti-inflammatory and immunoregulatory effects in patients with breast cancer.

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