Vitamin D has been hypothesized to have an association with cancer risk and survival, and several studies in the literature document a high prevalence of vitamin D deficiency in cancer patients [35
]. Although vitamin D deficiency is now more recognized in the oncology population, relatively less is known about patients' response to supplementation, dosing regimens, and overall benefits other than bone health. The current study was undertaken to investigate the effectiveness of oral vitamin D supplementation to restore suboptimal serum 25(OH)D levels in a large heterogeneous population of patients with cancer.
The response to supplementation (in terms of restoration from suboptimal levels to optimal levels) was most pronounced in patients with lung and prostate cancer and least in those with colorectal and pancreatic cancer. Consistent with the above findings, we also observed that vitamin D supplementation resulted in a significant absolute increase in patients with lung and prostate cancer while those with colorectal cancer recorded the lowest absolute improvement. One potential explanation on why patients with colorectal cancer showed less benefit as compared to those with lung cancer could be the more severe gastrointestinal toxicity (stomatitis and diarrhea) associated with chemotherapy regimens for colorectal cancer [36
]. Severe stomatitis could have an effect on compliance or ability to take an oral supplement, while severe diarrhea could impact intake as well as absorption. This explanation seems to be consistent with the findings from a study which observed an association between chemotherapy and a significant increase in the risk of severe vitamin D deficiency in colorectal cancer patients [36
]. The study hypothesized that chemotherapy administration in colorectal cancer might result in dietary modifications such as reduction or elimination of milk products as part of the management of chemotherapy- induced diarrhea. It also surmised that patients undergoing chemotherapy might not absorb dietary vitamin D well due to subclinical mucositis [36
]. As a result, these patients may need higher amounts of supplementation for a longer period of time in order to achieve adequate serum 25(OH)D status. Future studies should evaluate response to supplementation in relation to different chemotherapy regimens.
The response to supplementation from suboptimal to optimal levels was greatest in patients with baseline 25(OH)D levels between 20-32 ng/ml as compared to those below 20 ng/ml. Also, vitamin D supplementation resulted in a significant absolute increase in serum 25(OH)D levels particularly in patients with lower levels at baseline. This is not surprising because patients with lower baseline levels have to cover a greater ground to convert from suboptimal to optimal levels. On the other hand, those with higher baseline levels are more likely to convert. The observation of highest absolute improvement in serum 25(OH)D in those with lowest baseline levels is also corroborated by previous research conducted in different patient populations including elderly, premenopausal and healthy individuals which found that participants with lower baseline serum 25(OH)D concentrations had a stronger serum 25(OH)D response to supplementation [40
]. It has been hypothesized that hydroxylation of vitamin D3 to 25(OH)D is likely a saturable process, causing an attenuated response to supplementation in individuals with higher baseline serum 25(OH)D concentrations [45
In order to put our study in context, we review here 3 studies in breast cancer that have evaluated the impact of vitamin D supplementation on serum 25(OH)D levels. Crew et al. examined the effects of standard-dose vitamin D supplementation on serum 25(OH)D levels in breast cancer patients. They observed that cholecalciferol 400 IU daily for 1 year raised serum 25(OH)D levels only modestly, by less than 3 ng/mL in only a small percentage of premenopausal women (< 15%). Although the RDA of vitamin D in premenopausal women is only 200 IU daily, their study suggested that a dose of 400 IU daily was inadequate in breast cancer patients, even to maintain skeletal health, and was probably too low for meaningful anticancer effects [28
The other study conducted on breast cancer patients by Khan et al. reported the safety and efficacy of vitamin D supplementation using 50,000 IU weekly on postmenopausal women. They studied the effect of vitamin D-ss (standard supplementation) and vitamin D-HD (high dose) supplementation on serum 25(OH)D levels. According to them vitamin D-HD for 12 weeks is extremely effective in optimizing 25(OH)D levels and results in a predictable increase in 25(OH)D levels. Comparing women who received vitamin D-HD versus vitamin D-ss, the former displayed statistically significant higher values. Moreover, vitamin D-HD was safe in this population, with no cases of hypercalcemia or renal stones. Their results also suggested that 50,000 IU of vitamin D3, when given weekly to post-menopausal women starting adjuvant letrozole, resulted in clinically significant improvement in disability from joint symptoms [29
A more recent data published by Nogues et al. reported a prevalence of 85-92% of vitamin D deficiency (defined as < 30 ng/ml) in breast cancer patients as compared to 74% reported by Crew et al. (defined as < 20 ng/ml) and 63% by Khan et al (defined as < 20 ng/ml). In this study, treatment with 16,000 IU of vitamin D every 2 weeks increased vitamin D plasma levels significantly in about 76.52% of subjects with baseline vitamin D deficiency (plasma levels < 30 ng/ml) over 3 months follow up. However, few subjects had baseline 25(OH)D levels ≥ 30 ng/ml and were prescribed the normal daily calcium and vitamin D supplements (800 IU) and their 25(OH)D levels did not increase significantly [30
The dosage used for vitamin D supplementation in our study was 8000 IU/d, consistent with the data from Holick MF of 50,000 IU weekly [33
], which led to an increase in the mean serum 25(OH)D levels from 19.1 ng/ml to 36.2 ng/ml. No safety concerns were reported. When comparing it with the vitamin D dose response in healthy individuals, the literature yielded the following results. Talwar et al. showed that supplementation with 800 IU/d vitamin D3 in postmenopausal African American women raised the mean serum 25(OH)D concentration from a baseline of 18.7+/-8.2 ng/mL to 28.5+/-8.6 ng/mL at a 3 month interval [46
]. In another study, Barger-Lux et al. showed that in a relatively replete group of white subjects, 1000 IU vitamin D3/d resulted in an increase of 5.2 ng/mL from a mean of 26.8 to 32 ng/mL [45
]. Likewise Heaney et al reported a dose response of 0.28 ng/mL per 1 μg/40IU oral vitamin D3 supplemented [47
]. Furthermore, Aloia et al. undertook a dose-finding study in African American and white men and women with the objective of investigating an algorithm for raising 25(OH)D concentrations to between 32 and 56 ng/mL. They suggested a dose of 3800 IU for those above a 25(OH)D threshold of 22 ng/mL and a dose of 5000 IU for those below that threshold [16
Our study has some limitations. This study, because of its retrospective nature, relies on data not primarily meant for research. As a result, we could not adjust for several potential confounding factors that could have influenced serum 25(OH)D levels. For example, we did not adjust for season of blood draw in our analyses. Therefore, increase in serum 25(OH)D levels between baseline and first follow-up could have been influenced by change in season of blood draw, especially since the time between assessments could have put a patient into a different season by the first assessment. Moreover, we did not have information on intake of vitamin D or data regarding their typical sun exposure which could have shed further light on the subjects' vitamin D status. However, our patients reside in all areas of the United States. Other variables such as race, physical activity, BMI and chemotherapy received known to have a significant relationship with 25(OH)D status were not controlled for in the analyses. Without a control group, it is less clear whether vitamin D insufficiency preceded the diagnosis of cancer or whether it was associated with the disease process. We did not collect information about compliance with vitamin D supplementation, which may be an important element to understand the response to vitamin D supplements in certain individuals. For some non-responders that were questioned about compliance, compliance was an issue, as well as the type of vitamin D supplement that was being used. On at least one occasion, a patient taking hard tablets did not respond, and subsequently responded when switched to a capsule. This raises another limitation of our study. In our study, patients were encouraged to use a capsule form of vitamin D3, however, some did choose to use tablets or liquids. The time to first follow-up was not uniform due to differences in medical treatment regimens, and there were several losses to follow-up in the study. This is because many patients decided not to get treated at our hospital after their initial evaluation. Also some patients could not return for follow up due to the advanced nature of their disease or death. A poor follow-up rate of 48.4% introduces selection bias into the study because patients available for first follow-up (n = 799) differed from those not available (n = 852) with regard to several baseline characteristics such as cancer type, stage, gender and treatment history. Since 25(OH)D assays were measured in real-time rather than batches in a central laboratory, this may introduce batch to batch variability in the assays. Most of the literature on vitamin D and cancer (including our study) is largely based upon observational data. Therefore, rigorous clinical trials are needed before we can make broad recommendations about high-dose supplementation to our patients.
There are several clinical implications of this work such as the need to monitor the vitamin D intake and serum 25(OH)D levels in patients with cancer and supplementation of vitamin D in those who are found to have suboptimal levels. Vitamin D insufficiency is prevalent in this population and should be routinely assessed, especially in breast and prostate cancer patients where the treatment for these diseases also has an impact on long-term bone health. There was a significantly lower response to supplementation in individuals with colorectal and pancreatic cancers, suggesting these individuals may need higher doses of supplementation for longer periods of time and/or may have a higher rate of noncompliance. As a result, assessing and monitoring compliance to oral supplementation is critical in colorectal and pancreatic cancer patients where oral intake and absorption may be compromised. Further studies evaluating the higher dose given just once weekly may help answer the question of whether compliance and/or absorption contributes to a less than average response in patients with colorectal cancer. Determining the effects of achieving and maintaining adequate 25(OH)D levels with supplementation on patient outcomes is also an important research avenue.