Tretli S, Hernes E, Berg JP, Hestvik UE, Robsahm TE. Association between serum 25(OH)D and death from prostate cancer. Br J Cancer. 2009;100:450-454.
Prospective case-cohort association study
One hundred sixty patients with histologically verified prostate cancer diagnosed during the period of 1984 to 2004 who donated serum samples to the JANUS serum bank of Norway participated. The samples were tested for circulating 25(OH)D using competitive radioimmunoassay. The patients’ serum 25(OH)D was categorized as follows: low (below 50 nmol/L or 20 ng/mL), medium (50-80 nmol/L or 20-32 ng/mL), and high (above 80 nmol/L or 32 ng/mL). The patients were split into 2 groups. Group 1 consisted of 37 patients who had been treated with hormonal treatment of androgen inhibitors, luteinizing hormone-releasing hormone (LHRH), or castration, prior to measurement of 25(OH)D measurement. Group 2 consisted of 123 patients who were treatment-naïve at the time of 25(OH)D measurement. After 25(OH)D levels were measured in group 2 participants, they underwent varied treatments for their prostate cancer: 20 of 123 patients received radio therapy, 29 of 123 received surgery, 60 of 123 received hormonal therapy, and 14 of 123 received an unspecified treatment. When combining groups 1 and 2, a total of 97 patients received hormonal therapy of androgen inhibitors, LHRH, or castration at some point before or during the study. Participants were followed from the date of 25(OH)D measurement until date of death, migration, or the end of the study (December 31, 2005), whichever occurred first. Participant’s death and cause of death were identified using the National Death Registry.
Serum 25(OH)D at medium to high levels were significantly related to better prognosis and reduced mortality from prostate cancer when compared to patients with a low level. The hazard ratio for patients with medium and high levels of serum 25(OH)D were 0.48 and 0.35 respectively, with a 95% confidence interval. When the analysis was further restricted to only patients receiving hormone therapy, an even stronger association was noted. When the analysis was adjusted for age, tumor differentiation, and functional status a nonsignificant lower risk of death from prostate cancer was observed for patients with high 25(OH)D values.
In the United States, vitamin D is commonly measured in ng/mL, but the Standard International (SI) measures in nmol/L. The conversion factor to SI units is 1 ng/mL=2.496 nmol/L. Evidence is accumulating that shows the importance of vitamin D in other disease states and cancer types. There was already a causal relationship between the season of prostate cancer diagnosis and prognosis, which was thought to be related to serum 25(OH)D levels.1 From a preventive medicine perspective, this study shows the potential benefits of having sufficient vitamin D levels prior to a cancer diagnosis.
The study authors noted that the majority of patients accrued had adequate levels of 25(OH)D for bone health. A meta-analysis looking at optimal serum levels of vitamin D indicated that the optimal level may vary according to the underlying disease or condition.2 Ongoing research in this area continues. Interestingly, a study published in 2008 showed that high circulating 25(OH)D may increase the risk of aggressive prostate cancer,3 which suggests there may be a “sweet spot” in the desired serum range. Corroborating this, another study showed an increased risk of prostate cancer when serum 25(OH)D was below 19 nmol/L (8 ng/mL) or above 80 nmol/L (32 ng/mL). Therefore, it is recommended to supplement deficient levels of vitamin D with caution towards the upper limit above 80 nmol/L (32 ng/mL).4
It is interesting to note that the men being treated with hormonal therapy had a stronger association between vitamin D levels and prognosis. Men receiving androgen-suppressive therapies are also at higher risk for osteoporosis and fractures.5 This would be an excellent indication for serum 25(OH)D level testing in addition to DEXA scans and other bone density markers.
While it is unknown whether supplementing with vitamin D after diagnosis affects prognosis or outcome, vitamin D is currently being studied in combination with chemotherapy to increase the effectiveness of treatment for metastatic prostate cancer. Using high-dose calcitriol has shown promise in increasing response when combined with docetaxel6 and paclitaxel.7 Further clinical trials are needed to confirm these results, and the dose cited is for use within research settings.
While this study is compelling, it has several limitations that prevent immediate changes to best practices for prostate cancer. One of the main limitations is sample size. A study of 160 patients is not large enough to draw broad conclusions about the population at large. Due to the small sample size, a majority of the patients included in this trial were treated with hormonal therapy and relatively few were treated with surgery or radiation therapy. A larger sample size may help reduce treatment bias in the mortality outcomes.
Another weakness was the amount of time that participants were followed, which averaged 44 months. The global 5-year survival rate for prostate cancer ranges from 40% to 80% and time of progress from prostate cancer diagnosis to death from prostate cancer can be upwards of 10 years.8 This suggests that 44 months is not an adequate monitoring period for progression to death from prostate cancer and a longer follow-up period is necessary.
Additionally, some patients included in this trial had already received hormonal treatment prior to sampling. It is unknown whether hormonal treatment can affect serum 25(OH)D levels. This patient subgroup was more likely to have metastatic disease when compared to the group not previously treated. A better trial design would have excluded patients that had previously been treated with hormonal manipulation, surgery, chemotherapy, or radiation therapy.
While this study shows a strong association between prostate cancer mortality and serum 25(OH)D levels, association studies do not prove causality or the need for treatment intervention with supplementation of vitamin D. Larger studies are needed to confirm the relationship between serum 25(OH)D and prostate cancer death. Once this association has been established, further trials using randomization to receive vitamin D with standard cancer treatment would help elucidate the role of vitamin D supplementation in patients diagnosed with prostate cancer.
- Lagunova Z, Porojnicu AC, Dahlback A, Berg JP, Beer TM, Moan J. Prostate cancer survival is dependent on season of diagnosis. Prostate. 2007;67(12):1362-1370.
- Bischoff-Ferrari HA, Giovannucci E, Willet WC, Dietrich T, Watson-Hughes B. Estimation of optimal serum concentration of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin. 2006;84:18-28.
- Ahn J, Peters U, Albanes D, et al. Serum vitamin D concentration and prostate cancer risk: A nested case-control study. J Natl Cancer Inst. 2008;100:796-804.
- Tuohimaa P, Tenkanen L, Ahonen M, et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer. 2004;108 (1):104-108.
- Diamond TH, Bucci J, Kersley JH, Aslan P, Lynch WB, Bryant C. Osteoperosis and spinal fractures in men with prostate cancer: risk factors and effects of androgen deprivation therapy. J Urol. 2004;172(2):529-532.
- Beer TM, Ryan, CW, Venner PM, et al. Double-blinded randomized study of calcitriol plus docetaxel compared with placebo plus docetaxek in androgen-independent cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007;25(6):669-674.
- Hershberger PA, Yu WD, Modzelewski RA, Rueger RM, Johnson CS, Trump DL. Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis. Clin Cancer Res. 2001;7(4):1043-1051.
- American Cancer Society. Global Facts and Figures. 2007.