Jacot W, Firmin N, Roca L, et al. Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study. Ann Oncol. 2016;27:1235-1241.
To compare the safety and efficacy of high-dose vitamin D supplementation tailored to baseline deficiency levels with conventional vitamin D supplementation in women with early breast cancer. Secondary objectives included assessment of compliance and quality of life (QoL).
Multicenter, open-label, randomized, phase III trial
The trial included 195 women; all women included in the study were vitamin D-deficient (<30 ng/mL), had been treated in the last 12 months with adjuvant or neoadjuvant chemotherapy for histologically confirmed primary early breast cancer (EBC), and had an Eastern Cooperative Oncology Group (ECOG) performance status of <2. Women with known hypersensitivity reaction to vitamin D or calcium compounds, known comorbidities affecting vitamin D-calcium balance or bone health, or concomitant vitamin D supplementation were excluded from the study. Participants were randomized to either a vitamin D supplementation regimen tailored to baseline level of deficiency [tailored (T) arm; n=100; median age=51] or a conventional regimen [control (C) arm; n=95; median age=49].
Participants were stratified into 3 baseline vitamin D deficiency levels (<10, 10-20, or 20-30 ng/mL), hormone receptor positivity (yes or no), and menopausal status (perimenopausal/premenopausal or menopausal).
All patients in the T arm received 100,000 IU of vitamin D3 on the following schedule: days 1, 15, 28, 43, and 58 and at 3 months for baseline vitamin D levels <10 ng/mL; days 1, 15, 28, and 43 and at 3 months for baseline levels 10-20 ng/mL; and days 1 and 15 and at 3 months for baseline levels 20-30 ng/mL. All patients in the C arm received daily 400 IU vitamin D3.
Study Parameters Assessed
Calcium and vitamin D serum levels were obtained at baseline and during follow-up (6, 12, 18, and 24 months). Vitamin D levels were measured as circulating 25-hydroxyvitamin D2 (25[OH]D2) and 25(OH)D3 to provide total circulating 25(OH)D levels.
Overall, vitamin and antioxidant deficiency should be considered in the management of cancer, including individually tailored assessment and repletion strategies.
A 24-hour urinary calcium study was performed the week before the follow-up visits. QoL was assessed using the European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) measured at baseline and at the end of the treatment period.
Safety of oral doses of vitamin D3 and calcium (unspecified form) given in the study was assessed by descriptive analysis. Adverse events were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
Compliance with high-dose discontinuous vitamin D supplementation (T arm) was measured as the number of vials reported taken divided by the prescribed number of vials (3, 5, or 6 vials, according to the vitamin D deficiency), reported as a percentage.
The primary outcome measure was percentage increase of normalization of serum 25(OH)D, defined as a 25(OH)D blood level minimum target of 30 ng/mL. Secondary measures included percentage by arm of patients with a normal vitamin D value at 12, 18, and 24 months and percentage of 25(OH)D serum normalization after 6 months of crossover in the C arm population. Additional endpoints included results of safety and QOL assessments.
After 6 months, compared to the C arm, significantly more patients in the T arm had normalized serum vitamin D levels (30% vs 12.6%; P=0.003); median 6-month vitamin D levels were 28.1 ng/mL (T arm) and 24.2 ng/mL (C arm; P<0.001). In the compliant population, a 6-month normalization was reported in 38.5% (n=30) of the T arm and 16% (n=12) of the C arm.
Fifty-two patients (55%) without vitamin D normalization from the C arm switched to the T arm after 6 months. At 12 months, 44% of these patients (n=23) showed normalization. Median 6- and 12-month levels were 23.9 ng/mL (8.1-29.6) and 28.6 ng/mL (16.3-53.0) respectively (P<0.001).
Compliance was similar in both arms; 67% of the T arm and 68.4% of the C arm reported taking at least 80% of the planned daily oral calcium supplementation. Vitamin D and calcium supplementation was well-tolerated, with no difference in treatment-related toxicity between the arms (1 case of asymptomatic hypercalciuria was reported in each arm).
No statistically significant difference in QoL was observed between treatment and control arms at 6 months. There was no significant difference in overall QoL between the normalized and deficient populations at 6 months. However, worsening QoL was observed in the normalized group in physical (P=0.006) and cognitive functions (P=0.002), pain (P=0.051), and dyspnea (P=0.014) between baseline and after 6 months.
This study suggests a baseline vitamin D deficiency in breast cancer patients is common (91.6%), which is supported by ample data and is consistent with what many of us observe in clinical practice.1,2 This study also suggests that high doses of oral liquid vitamin D3 improve normalization of serum vitamin D levels in those who do not achieve normalization with conventional (400 IU/d) dosing.
There is little dispute that repletion of vitamin D in those with a history of breast cancer may improve outcomes. In a systematic review and meta-analysis of patients with breast cancer by Maalmi et al3 pooled estimates comparing highest (weighted average 88 nmol/L) with lowest (weighted average 41 nmol/L) quantiles of serum 25(OH)D showed a 38% reduced risk of overall mortality among patients with high vitamin D levels (hazard ration [HR]: 0.62; 95% confidence interval [CI]: 0.49-0.78). Further analysis showed that a 20 nmol/L increase in serum 25(OH)D level was associated with an 18% decrease in overall mortality (HR:0.82; 95% CI: 0.75-0.88).
This data implies that it is not administering vitamin D but repletion of patients that is therapeutic.
Pooled estimates comparing highest (weighted average 88 nmol/L) with lowest (weighted average 41 nmol/L) quantiles of serum 25(OH)D showed a 43% reduced risk of breast cancer-specific mortality among patients with high levels (HR:0.57; 95% CI: 0.38-0.84). This data implies that it is not administering vitamin D but repletion of patients that is therapeutic.
Intermittent high bolus dosing of vitamin D is a complex dosing schedule compared to oral daily dosing, which is commonly recommended to patients by naturopathic and integrative providers for vitamin D repletion. This has been used in previous vitamin D studies and was found to be safe and effective in the short term.4 However, several studies have suggested infrequent high doses or high-normal serum levels of 25-hydroxycholicalciferol may lead to greater risk of falling in the elderly.5,6 The question remains: does this more complex type of dosing schedule offer enough advantage over lower, safer dosing schedules?
It was surprising that the study found no improvement in QoL, physical and cognitive functions, pain, or dyspnea at 6 months with normalization. Previous nonrandomized studies have described a decrease in arthralgia and increase in QoL in breast cancer patients achieving vitamin D normalization while on aromatase inhibitors.7,8
The majority of the patients in the study received neoadjuvant/adjuvant chemotherapy. Therefore, lingering side effects from treatment may have impacted the results. In addition, just under half of the women were postmenopausal and 72% of the T group was estrogen receptor positive, so the number of women taking aromatase inhibitors was limited in this study.
Lastly, attention should be paid to actual worsening of QoL—physical (P=0.006) and cognitive functions (P=0.002), pain (P=0.051) and dyspnea (P=0.014)—between baseline and after 6 months in those who normalized their circulating vitamin D levels. Future studies must determine if this is indeed a valid outcome of high-dose, intermittent vitamin D repletion.
The authors do not report the type of oral vitamin D3 and calcium used in the study. They do specify “cholecalciferol” in the supplementary methods information (provided through an online link, separate from the published article). In the discussion of the paper they state that “vials” were given for oral intake with the intent to use very high dosing to potentially achieve normal serum values by 6 months. And for perspective, these results are similar to those reported by Crew et al in their trial evaluating zoledronate.9
The study did not address daily sun exposure or dietary vitamin D intake, 2 potential confounding factors.
Lastly, in a well-designed comparative analysis of vitamin Ds available on the market, Traub et al report that considerable variability exists between label-claimed dose of vitamin D3 content in supplements and provides a comparison of the efficacy of capsule, liquid, and tablet forms of vitamin D3 in achieving increases in and normalization of serum vitamin D in humans.10 While bolus dosing of liquid D3 appeared to be superior to daily dosing of low-dose (400 IU) oral forms, we cannot be sure it is not simply the form rather than the dose itself.
Overall, all vitamin and mineral deficiencies should always be considered in the management of cancer, including individually tailored assessment and repletion strategies. Vitamin D has one major advantage of lending itself to easy assessment through bloodwork. The optimal dosing schedule has not yet been decided. This study suggests that we should be open to infrequent, large doses as a possible option for those not able or willing to take daily doses.
- Acevedo F, Pérez V, Pérez-Sepúlveda A, et al. High prevalence of vitamin D deficiency in women with breast cancer: The first Chilean study. The Breast. 2016;29:39-43.
- Liu J, Huang W, Zhou R, et al. Serum/plasma 25-hydroxyvitamin D and risk of lung, breast and prostate cancer: a meta-analysis. Int J Clin Exp Med. 2016;9(2):2728-2737.
- Maalmi H, Ord ez-Mena JM, Schottker B, Brenner H. Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: systematic review and meta-analysis of prospective cohort studies. Eur J Cancer. 2014;50(8):1510-1521.
- Kearns MD, Binongo JNG, Watson D, et al. The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr. 2015;69(2):193-197.
- Gallagher JC. Vitamin D and falls—the dosage conundrum. Nat Rev Endocrinol. 2016; 12(11):680-684.
- Välimäki V, Löyttyniemi E, Pekkarinen T, Välimäki MJ. How well are the optimal serum 25OHD concentrations reached in high‐dose intermittent vitamin D therapy? a placebo‐controlled study on comparison between 100 000 IU and 200 000 IU of oral D3 every 3 months in elderly women. Clin Endocrinol (Oxf). 2016;84(6):837-844.
- Khan QJ, Reddy PS, Kimler BF, et al. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat. 2010;119:111-118.
- Prieto-Alhambra D, Javaid MK, Servitja S, et al. Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study. Breast Cancer Res Treat. 2011;125:869-878.
- Crew KD, Shane E, Cremers S, et al. High prevalence of vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy. J Clin Oncol. 2009; 27: 2151-2156.
- Traub ML, Finnell JS, Bhandiwad A, Oberg E, Suhaila L, Bradley R. Impact of vitamin D3 dietary supplement matrix on clinical response. J Clin Endocrinol Metab. 2014;99(8):2720-2728.