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Vitamin D deficiency has clearly been shown to be a risk factor in the development of multiple forms of cancer. There also are considerable data to suggest maintaining high levels of vitamin D can prevent the progression of cancer and increase survival rates.
However, the traditional prospective placebo controlled trials have not yet been conducted. Neither are they likely to be conducted any time soon. Vitamin D3 is non patentable and, therefore, of little interest to the pharmaceutical industry. It is only the industry that has the funds and resources necessary to run such trials. Physicians and patients will have to make decisions based on the data available.
The data presented below shows some very strong signals suggesting that maintaining high levels of vitamin D may provide significant benefit to cancer patients.
Summary of Findings:
- For each 10ng/ml increase in the blood level of vitamin D, the death rate from cancer would be reduced by 29%. The relationship between vitamin D and colorectal cancer is particularly strong. The death rate for colorectal cancer would be reduced by 49% (30)
- A Norwegian study showed that cancer patients diagnosed in the summer when vitamin D levels are highest had up to 40% better survival rates than patients diagnosed in the winter when vitamin D levels are at their lowest. (56)
- Breast cancer patients with low levels of vitamin D followed over eleven years had a 70% greater chance of dying and twice the rate of developing metastasis than patients with high levels of vitamin D.(90)
- Early stage lung cancer patients who were diagnosed in the summer and had the highest levels of vitamin D had a five-year survival of 73% compared to 30% for those diagnosed in the winter with low vitamin D levels. (60)
- High vitamin D levels (based on latitude and UV exposure) also correlate with a decreased risk of developing lung cancer, a 45% and 65% reduction in men and women respectively. Similar effects have been demonstrated in colon, prostate, renal and endometrial cancer. (33)
- The risk of death for colorectal cancer patients with advanced disease but with high levels of vitamin D was reduced by over 60% compared to patients with low vitamin D levels. (64)
- Prostate Cancer Patients with Vitamin D levels in the mid and high range had a 60% and 85% respectively reduced risk of death from the condition compared to patients with low levels of Vitamin D. This is almost a seven fold increase in the risk of death in those with low vis high vitamin D levels.(152)
Effects of Vitamin D on Cancer Progression and Survival
In a study conducted in Norway, almost 250,000 cancer patients were followed and their progress compared based on whether they were diagnosed in the summer or winter months. The aim was to determine if being diagnosed in the summer when vitamin D levels are higher would confer any survival benefit compared to being diagnosed in the winter when levels are lower.
Seven types of cancer were investigated which included the four commonest: lung, colon, breast and prostate cancer. The analysis showed that patients diagnosed in the summer had a 15-25% better survival (over the first 36 months after diagnosis) than those who presented during the winter months. (56)
It is also well know that Black Americans have lower vitamin D levels than white Americans. This potentially explains why Afro Americans suffer from higher rates of cancer and have a worse prognosis than white Americans.
Afro American women have a 25% higher mortality from cancer that white American in a state-by state comparison.
Afro American men have been shown to have an incidence of cancer 30% higher than while Americans and their rate of death is almost twice that of white Americans.
Two studies have proposed that low levels of vitamin D in the afro American male account for these differences.
Dr Giovannucci of Harvard Medical School also published a review on the incidence and death rates from cancer in 47,800 men followed up as part of the Health Professionals Follow-up Study. In this population there were 4286 cases of cancer and 2015 deaths from cancer. After estimating the vitamin D levels of these participants, they able to correlate both the incidence of cancer and the death rate from cancer with vitamin D levels.
They concluded that for every increase in vitamin D levels of 25nmol/L (10ng/ml) there was a 17% reduction in the incidence of cancer and 29% reduction in death from cancer. In particular, there was a strong correlation with vitamin D and colorectal cancer showing a 49% reduction in the death rate from digestive system cancers.
They concluded that low levels of vitamin D are associated with increased cancer rates and mortality from cancer. To achieve an increase in plasma levels of 25nmol/L (10ng/ml), a dose of at least 1500IU would be needed. (30)
There also are data in the following tumor types that suggest that vitamin D levels have a pronounced effect on progression and survival rates:
The mechanisms by which vitamin D is thought to affect cancer outcome are applicable to most if not all tumor types. The absence of data on a specific tumor type is no reason not to ensure that vitamin D levels are kept optimal.
The mechanisms by which vitamin D is thought to affect cancer outcome are applicable to most if not all tumor types. The absence of data on a specific tumor type is no reason not to ensure that vitamin D levels are kept optimal.
Vitamin D in the treatment of Breast Cancer
Summary of the Findings in Breast Cancer
- A Norwegian study showed that breast cancer patients diagnosed in the summer when vitamin D levels are highest had up to 25% better survival rates than patients diagnosed in the winter when vitamin D levels are lower. (57)
- Breast cancer patients with low levels of vitamin D and followed for up to eleven years had a 70% greater chance of dying and twice the rate of developing metastasis than did patients with high levels of vitamin D (90)
Data On Breast Cancer and Vitamin D
One of the highlights ASCO 2008, the world’s largest cancer conference was a presentation by Dr. Pamela Goodwin from Mount Sinai Hospital, Toronto Canada. She presented data showing that low vitamin D levels correlated with a poor outcome in breast cancer patients.
Here is a summary of Dr Goodwin’s findings in a media video covering the presentation:
While many epidemiological studies had previously predicted this effect, this study was considered to be of great interest because its design was prospective. (Patients had their vitamin D levels measured at diagnosis and then followed for outcome.)
The following is a summary of the data presented:
Patients who were newly diagnosed with breast cancer presenting between 1989 and 1995 had their vitamin D levels checked at the time of diagnosis and then followed until 2006.
512 patients were entered into the study. At baseline 37.5% of women were considered to have deficient levels of vitamin D (< 50nmol/L), 38.5% had insufficient levels (50-72nmol/L) and 24% were considered adequate.(>72nmol/L).
During the follow up period of 11 years, 22.7% of patients developed metastasis and 20.7% died.
The outcome of patients was compared between those who had deficient levels of vitamin D versus those with adequate levels.
Both distant disease free survival, (DDFS-refers to patients who did not develop metastasis and survived) and overall survival (OS) was significantly worse in those with deficient levels of vitamin D. The magnitude of the effect was quite remarkable.
Patients with deficient levels of vitamin D were almost twice as likely to develop metastasis as those patients with adequate levels. (Presented as a Hazard Ratio of 1.94)
In addition the risk of death was more than 70% greater in the deficient group compared to the adequate group. (Presented as a Hazard Ratio of 1.73)
Survival According to Vitamin D Level at Diagnosis Table 1
Deficient Vitamin D Sufficient Vitamin D Hazard Ratio P value Distant disease-free69% (31% mets) 83% (17% mets) 1.94 .02 Overall Survival 74% (26% dead) 85% (15% dead) 1.73 .02
First, this study demonstrated how many patients have low levels of vitamin D, 76% had levels considered less than adequate.
It is also noteworthy that these results, showing a halving of the rate of metastasis and death over an eleven year period are predicted by a single vitamin D level taken as much as eleven years prior to the clinical event.
It is remarkable that a single level can predict events so far in the future and may suggest that breast cancer may be exquisitely sensitive to variations in vitamin D levels. These results also correlate with similar findings in lung and colon cancer studies.
Another study published a year earlier predicted this effect . Although the study did not examine actual vitamin D levels the effects are still highly interesting.
Changes in risk of death from breast cancer with season and latitude: sun exposure and breast cancer survival in Norway
Breast Cancer Res Treat 2007 May;102(3):323-8 Porojnicu AC (57)
In this study, the investigator divided Norway into three regions depending on the amount of sunlight and resulting annual UV exposure. They then compared the outcome of breast cancer patients diagnosed in summer or winter in these three regions. (This was done with the assumption that vitamin D levels are higher in the summer.)
When they looked at all age groups of patients combined they found that the risk of death for patients diagnosed in the summer was 15-25% less than those diagnosed in the winter.
For women under the age of 50 their prognosis depended upon in which of the three regions of Norway they resided. Those living in the South and, therefore, receiving higher annual UV exposure had a 40% reduction in their risk of death. The southern regions receive 1.5 times the UV exposure of the Northern regions.
For women over the age of 50, no significant difference was found based on the region in which they lived.(see comments below)
Comment: Actual vitamin D levels were not measured in the study but it can be assumed that the population as a whole would be deficient since Norway is at a high latitude and, therefore, has low exposure to strong sunlight.
The difference in survival seen between the North and Southern regions is remarkable especially when one takes into account that people living in the Northern regions of Norway have a higher intake of dietary Vitamin D due to their higher rate of consumption of fatty fish. This difference is diet would have worked against a positive outcome of the investigation as the high fish diet could have made the difference in the vitamin D levels of those in the north versus the south less pronounced. Yet still a significant difference in survival was seen.
The lack of effect in the patients over 50 years of age may be explained by the fact that older people are much less efficient at making vitamin D when exposed to sunlight which highlights the even greater need for supplementation in older age groups.
Similar improvements in survival of breast and lung cancer patients, dependent upon the season of diagnosis have been observed in the UK. (58)
Vitamin D in the treatment of Lung Cancer
Significant effects of Vitamin D on lung cancer patients have been demonstrated in a number of studies published since 2005. The following is a review of the most recent and important literature.
Summary of Findings in Lung Cancer.
- Patients operated on (for removal of early stage lung tumors) in the summer and who had the highest dietary intake of vitamin D compared to those who were operated on in the winter and had the lowest intake of vitamin D had a fourfold improvement in their risk of death. (59)
- The five year relapse free survival rates for the two groups were 56% versus 23% respectively. (summer diagnosis and highest vitamin D consumption versus winter diagnosis and lowest vitamin D consumption) (59)
- Five-year survival figures for the two groups were 73% versus 30%. (59)
- Patients with the highest versus the lowest levels of vitamin D demonstrated a 55% reduction in the risk of death. (60).
- High vitamin D levels (based on latitude and UV exposure) also correlate with a decreased risk of developing lung cancer, a 45% and 65% reduction in men and women respectively. (33)
Data On Lung Cancer and Vitamin D
This study began in 1992 and documented the progress of 456 cases of early stage (IA-IIB) lung cancer. 321 of these patients were able to supply dietary information from which their level of vitamin D consumption could be estimated. The patients were followed up and their outcome determined.
All patients had surgical resections of their tumor as their initial treatment. The investigators planned to investigate the effects of surgery season, vitamin D intake and the combination of both on patient outcome. Both season of diagnosis and dietary intake are indicators of vitamin D levels.
The investigators planned to measure the recurrence-free survival (RFS-is the time until the first signs of a recurrence or death occurred) and overall survival in three different analyses:
1) the combined effect of both season of diagnosis and intake of vitamin D
2) the effect of season of diagnosis on outcome
3) the effect of dietary intake of vitamin D
The mean follow up time was 71 months. During that time there were 161 recurrences and 231 deaths.
1) Combined effect of season and dietary intake
Patients diagnosed in the summer who had the highest intake of vitamin D were compared to those diagnosed in the winter who had the lowest intake of vitamin D. Those diagnosed in the summer had a 66% reduction in their relapse free survival (RFS) (expressed as an adjusted hazard ratio of 0.33) and a 75% reduction in their risk of death (expressed as an adjusted hazard ratio of 0.25).
The five-year RFS rates for the two groups were 56% vs 23% respectively.
The five-year overall survival rates were significantly 72% vis 30%.
All of these findings on the combined effect of season and dietary intake were highly statistically significant.
2) The effect of season of diagnosis on patient outcome
Patients who were diagnosed and operated on in the summer had a 25% reduction in RFS compared to those diagnosed and operated on in the winter.
The five-year relapse free survival (RFS) rates were 53% vis 43% and
the five-year overall survival was 59% versus 50% for summer versus winter diagnosis. Neither of these results reached statistical significance.
3) The effect of dietary intake of vitamin D
There was no difference in outcome between those with high and low vitamin D intake (see comments below).
Comment: Dietary intake of vitamin D can only provide a small fraction of what is needed. It is note worthy that the difference in intake between the low and high intake groups was listed in the publication as <239IU versus >596IU per day. It is now known that patients with low vitamin D levels need to take 1000-4000IU per day to have a major impact on blood levels.
This very small difference in dietary intake between the two groups could only have resulted in a similarly small effect on blood levels. This would account for why no difference was seen between the two groups in RFS or overall survival based on vitamin D consumption alone.
Also this study was conducted in Boston, Massachusetts where previous studies have shown that few patients have optimal levels of vitamin D.
However, the combined effect of higher sunlight exposure in the summer and higher intake produced a dramatic improvement in patient’s outcome. The difference in five-year survival (72% vis 30%) is impressive.
In this next study which is a continuation of the above study, the researchers studied the effect of actual vitamin D levels on outcome in early stage lung cancer patients.
This study was conducted in 447 patients with early stage lung cancer. Vitamin D levels were determined at the time of diagnosis and the patients were followed for a median of 72 months.
The effect of dietary vitamin D was also taken into account in 309 patients who were able to supply dietary information, and the patients were stratified into four groups depending on their baseline vitamin D levels.
The four groups of patients were defined by vitamin D levels of < 10nl/ml, 10.2-15.5ng/ml, 184.108.40.206 ng/l and > 21ng/ml. (see note in comments on these levels.)
The outcome of these patients was determined by their recurrence free survival (RFS) and overall survival (OS).
In these 447 patients, there were 161 recurrences and 234 deaths during the follow up period.
For overall survival in the patients who where stage IB-IIB (excluding the IA group) the adjusted hazard ratio for the patients with the highest versus the lowest vitamin D level was 0.45 which translates in a 55% reduction in the risk of death. No difference was seen in the very early stage patients, stage IA.
For overall survival in the whole patient cohort of 447 patients, the adjusted hazard ratio for the patients with the highest versus the lowest vitamin D level was 0.74 which translates in to a 26% reduction in the risk of death.
The results were also analyzed for the effect of high and low dietary intake of vitamin D in those patients for whom dietary information was available (309 patients).
Patients were stratified by whether their dietary intake of vitamin D was less than, or greater than, 371IU per day. Patients whose serum level was < 15.7 ng/ml and who also had dietary intakes of < 371IU per day were the reference group.
For patients with high vitamin D levels and high dietary intake, the adjusted hazard ratio for overall survival was 0.64 which translates into a reduction in the risk of death by 46%.
For RFS the reduction in risk was 43% as expressed by an adjusted hazard ratio of 0.67.
In patients with stage IB-IIB the reduction in risk of death was 50% for the group with high vitamin D and high intake. The stage IA patients showed a smaller benefit.
For RFS the reduction in risk was 45% for this group of patients and again the stage IA patients showed a smaller benefit.
Comment: This study was conducted in Boston, Massachusetts where the majority of patients have vitamin D levels that are well below what are considered to be optimal. Patients with levels > 21 ng/ml formed the ‘high vitamin D’ group. This is still well below the optimal range. Various experts in this area now consider optimal to mean >50ng/ml.
Despite the fact that even the group of patients, considered to have a high level, were still way below the optimal level of vitamin D, a striking improvement on overall survival and relapse free survival was seen. One can only wonder what improvements in survival would have been seen if patients could have had their levels elevated to >50ng/ml.
Another study by Giovannucci published in 2006 studied vitamin D levels as a predictor of death in male cancer patients and concluded that every increment of 10ng/ml in the level of vitamin D would result in a 29% reduction in mortality.
An additional study from Norway also confirmed that increased exposure to sunlight and the resulting improved vitamin D levels increased the chances of survival in lung cancer patients. The paper is summarized below.
Data was reviewed on all lung cancer patients diagnosed between 1964 and 2000 in Norway. This study compared both the effects of living in the North versus the South, where people are exposed to 50% more UV radiation and the effect of the season of diagnosis on the prognosis of lung cancer patients.
They demonstrated that a summer diagnosis of lung cancer rather than a winter diagnosis resulted in a 15% reduced risk of death within 18 months of diagnosis.
In addition, living in a southern region resulted in a further lowering of the risk of death. Men under the age of 50 had a 25% lower rate of mortality if diagnosed in the summer and lived in the South. These effects are believed to be directly due to the increase in vitamin D levels seen in the summer and in patients living in areas with greater UV exposure.
Women with lung cancer did not show the same benefits. It is interesting to note that women had a much smaller variation in vitamin D levels across the seasons compared to men, which may account for this difference in survival between the sexes. Actual vitamin D levels were shown to be between 20-120% higher during the summer season with men showing much greater increases than women in the summer. This same group of researchers demonstrated similar results in prostate, breast and colon cancer as well as Hodgkins Lymphoma.
A similar result was seen in a large study conducted in the UK that demonstrated improved survival for those exposed to high UV radiation. The relationship held true for all major cancer types. (see abstract 4 below).
Comment: Similar results have been seen in colon, prostate, breast and lung cancer patients. As Norway is at high latitude country levels of vitamin D are generally low to begin with and it is unlikely that even those living in the South have anywhere near the optimal levels of vitamin D. What we are comparing here is most likely to be low versus very low levels of vitamin D and yet still a significant reduction in mortality is noted.
Finally, another study published in the Journal of Epidemiology and Community Health in 2008 studied the relationship between latitude and the incidence of lung cancer. (33) Data on the incidence of lung cancer was gathered from 111 countries.
The study demonstrated that the higher the latitude the higher the incidence of lung cancer in both men and women. Living at lower latitudes and thus, being exposed to more sunlight resulted in a reduction in the risk of developing lung cancer by 45% for men and 65% in women.
The lower degree of protection seen in men is believed to be due to their increased rate of smoking compared to women.
Calculating the degree of ultraviolet exposure at each latitude, the relationship with lung cancer was inversely associated with the amount of UV exposure (the higher the exposure to UV the lower the incidence of lung cancer). The correlation with UV exposure at different latitudes was highly statistically significant in men (P=0.003) and even more so in women (P=0.0002).
Also the amount of cloud cover correlated with the incidence of lung cancer. The more cloud cover (hence less UV) the higher the rate of lung cancer.
Vitamin D in the treatment of Colorectal Cancer.
Summary of Findings in Colorectal Cancer
- colorectal cancer patients with high vitamin D levels have 40% less chance of dying of the condition than patients with low levels. (64)
- advanced colorectal cancer patients with high vitamin D levels have 60% less chance of dying of the condition than patients with low levels. (64)
Data on Colorectal Cancer and Vitamin D
Two studies conducted in Norway examined the effect the season of diagnosis on survival in colon cancer patients. The assumption was that those diagnosed in the summer would have higher levels of vitamin D. Both studies demonstrated a significantly better chance of survival for those diagnosed in the summer.(62) (63)
A study published recently (June 2008) and conducted in Boston, Massachusetts, demonstrated a dramatic improvement in survival in colorectal cancer patients with higher levels of vitamin D.
Between 1991 and 2002, 304 participants who developed colorectal cancer in two studies, Nurses' Health Study (NHS) which followed 121,000 nurses between the ages of 30-55, and the Health Professionals Follow-Up Study (HPFS) which followed 51,000 male dentists. All participants were followed until death or mid 2005, which ever came first.
All subjects had had their vitamin D levels measured at baseline. Their outcome was then compared to their baseline level of vitamin D.
During the follow-up period, 304 cases of colorectal cancer occurred. Of these 304, patients 123 deaths occurred of which 96 were due to colorectal cancer. These 304 patients were then divided into four groups depending on their baseline vitamin D levels.
Those with the highest vitamin D levels demonstrated a 50% reduction of mortality from any cause, compared to those with the lowest levels of vitamin D.
Deaths from colorectal cancer alone were reduced by 40% in the group with the highest levels of vitamin D.
No matter how the data were analyzed in subgroup analysis, the inverse relationship between blood levels of vitamin D and survival remained constant.
In addition, the reduction in mortality associated with higher levels of vitamin D was even more apparent in patients diagnosed in the summer or autumn when vitamin D levels are higher than at other times of the year. Also, more advanced patients with stage III and IV colorectal cancer showed a greater improvement in survival than did those with stage I and II colorectal cancer. The risk of death for the advanced patients with high levels of vitamin D was reduced by over 60%.
The researchers concluded that higher prediagnosis vitamin D levels were associated with a significant improvement in overall survival. (64)
Comment: It is important to note that vitamin D levels were measured only once, at entry into the study and that this was at least two years prior to developing colorectal cancer. During the course of the study many aspects of the patient's life may have changed that would result in a change in their vitamin D levels, moving to a warmer part of the country, holidays in exotic locations, more leisure time, ete. These factors potentially would have diluted the effect of this study. It is, therefore, remarkable that a single blood level taken years prior to diagnosis could have any predictive value on eventual survival. For the effect to have survived for so many years one may assume that this particular form of cancer is extremely sensitive to vitamin D levels.
Vitamin D as a Potential Treatment for Prostate Cancer
Several ecological studies have suggested that mortality from prostate cancer is favorably influenced by high levels of Vitamin D. (149,58) A small pilot study by Woo et al showed that prostate cancer patients with high serum Vitamin D levels took longer to double their PSA levels than patients with how Vitamin D levels further supporting a therapeutic role for Vitamin D. (53) Despite good preclinical and epidemiology data suggesting a beneficial role of Vitamin D in prostate cancer two studies where then published which suggested that there was no association between vitamin D and the development of prostate cancer in general but that higher levels were associated with an increased risk of aggressive disease. (150,151) The later study by Ahn et al however failed to show any sign of a convincing dose response across the increasing quintiles of vitamin D levels and these results were surprising as a positive effect on progression has now been shown in breast, lung and colon cancer. Calcitriol (the final active form of vitamin D) was combined with docetaxel in a phase II trial reported by investigators at Oregon Health & Science University (Portland, OR).(170) Prostate-specific antigen (PSA) decline of 50% or greater was seen in 81% of patients compared to historical rates of 45% seen with docetaxel alone. This combination was then tried in a larger patient population of 250. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months. While statistical significance was not reached in this study the survival benefit of vitamin D is quite impressive. (171) The British Journal of Cancer in early 2009 published some very positive findings in prostate cancer showing high Vitamin D levels had a very positive effect on the risk of death from prostate cancer. (152)
In this study Vitamin D levels were measured in 160 patients with prostate cancer. The patients were stratified into three groups according to low (<50nmol/l), medium (50-80nmol/l) or high (>80nmol/l) Vitamin D levels.
The patients were followed for a median of 44 months. The risk of death during that time was found to be significantly less for those in the medium and high Vitamin D groups. The risk of death in the mid group was reduced by almost 60% and in the high level group by 85%. This is almost a seven fold increase in the risk of death in those with low vis high vitamin D levels.
These results are very positive and correlate well with the preclinical data on the actions of Vitamin D on prostate cancer cells, the epidemiology data and the effects seen in breast, colon and lung cancer.
In May 2009 preliminary results from a study by Professor Waxman at Imperial College in London were released. After noting that a prostate cancer patient had a notable drop in PSA levels after the patient’s wife had given him Vitamin D, Waxman started a small trial to study the effect. Out of 26 men with recurrent prostate cancer who took approximately 1000IU of Vitamin D daily five responded to the treatment. In two patients the PSA levels fell by more than 50%, in two by 25-50% and in less than 25% in one man. Effects were sustained for as long as 36 months. This result is quite remarkable considering the low dose used. Clinical trials being conducted in Canada are exploring the use of 40,000IU per day in prostate cancer patients.