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Jacot W, Firmin N, Roca L, et al. Effects of tailored oral vitamin D supplementation therapy on serum 25-hydroxyvitamin D levels in early-stage breast cancer patients: a randomized phase III trial.Ann Oncol. 2016;27:1235-1241.
Goals
To compare the safety and effectiveness of high-dose vitamin D supplementation tailored to baseline levels of deficiency with conventional vitamin D supplementation in women with early breast cancer. Secondary objectives included assessment of compliance and quality of life (QoL).
Draft
Multicenter, open-label, randomized phase III study
Participant
The study included 195 women; All women included in the study had vitamin D deficiency (<30 ng/mL), had been treated with adjuvant or neoadjuvant chemotherapy for histologically confirmed primary early breast cancer (EBC) in the past 12 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status of <2. Women with known hypersensitivity reactions 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 randomly assigned to either a vitamin D supplementation regimen tailored to the baseline level of deficiency [tailored (T) poor; 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).
intervention
All patients in the T arm received 100,000 IU vitamin D3on the following schedule: days 1, 15, 28, 43, and 58 and after 3 months for baseline vitamin D levels <10 ng/mL; Days 1, 15, 28 and 43 and after 3 months for baseline values of 10-20 ng/ml; and on days 1 and 15 and after 3 months for baseline values of 20-30 ng/ml. All patients in the C arm received 400 IU of vitamin D daily3.
Study parameters assessed
Serum calcium and vitamin D levels were assessed 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)D3to provide total circulating 25(OH)D levels.
Overall, vitamin and antioxidant deficiencies should be considered in the treatment of cancer, including individually tailored assessment and replenishment strategies.
A 24-hour urinary calcium test was performed the week before follow-up visits. QoL was measured using the European Organization of Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and at the end of the treatment period.
Safety of oral doses of vitamin D3and calcium (unspecified form) given in the study were evaluated 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 reported vials taken divided by the number of vials prescribed (3, 5, or 6 vials, depending on vitamin D deficiency), reported as a percentage.
Target parameters
The primary endpoint was the percentage increase in normalization of serum 25(OH)D levels, defined as a minimum target blood 25(OH)D level of 30 ng/mL. Secondary measurements included the percentage of patients with normal vitamin D at 12, 18, and 24 months and the percentage of serum 25(OH)D normalization at 6 months of crossover in the C-arm population per arm. Additional endpoints included results of safety and QOL assessments.
Key insights
At 6 months, significantly more patients in the T arm had normalized serum vitamin D levels compared to the C arm (30% vs. 12.6%;P=0.003); the 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, 6-month normalization was reported in 38.5% (n = 30) of the T arm and 16% (n = 12) of the C arm.
52 patients (55%) without vitamin D normalization from the C arm switched to the T arm after 6 months. After 12 months, 44% of these patients (n=23) showed normalization. The median values at 6 and 12 months 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 supplement. Vitamin D and calcium supplementation were well tolerated, with no difference in treatment-related toxicity between arms (1 case of asymptomatic hypercalciuria was reported in each arm).
No statistically significant difference in quality of life was observed between treatment and control arms at 6 months. At 6 months, there was no significant difference in overall quality of life between the normalized and deficient populations. However, a worsening of QoL was observed in the normalized group during exercise (P=0.006) and cognitive functions (P=0.002), pain (P=0.051) and dyspnea (P=0.014) between baseline and after 6 months.
Practice implications
This study suggests that baseline vitamin D deficiency is common in breast cancer patients (91.6%), which is supported by extensive data and consistent with what many of us observe in clinical practice.1.2This study also suggests that high doses of oral liquid vitamin D3Improving the normalization of serum vitamin D levels in patients who do not achieve normalization with conventional dosage (400 IU/day).
There is little controversy that vitamin D supplementation can improve outcomes in patients with a history of breast cancer. In a systematic review and meta-analysis of patients with breast cancer by Maalmi et al3Pooled estimates comparing the highest (weighted average 88 nmol/L) to the lowest (weighted average 41 nmol/L) quantiles of serum 25(OH)D showed a 38% reduced risk of all-cause mortality in 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 all-cause mortality (HR: 0.82; 95% CI: 0.75-0.88).
These data imply that it is not administration of vitamin D but rather satiation of patients that is therapeutic.
Pooled estimates comparing the highest (weighted average 88 nmol/L) to the lowest (weighted average 41 nmol/L) quantiles of serum 25(OH)D showed a 43% reduced risk of breast cancer-specific mortality in patients with high levels (HR: 0.57; 95% CI: 0.38-0.84). These data imply that it is not administration of vitamin D but rather satiation of patients that is therapeutic.
Intermittent high-bolus dosing of vitamin D is a complex dosing schedule compared to the oral daily dosing often recommended to patients by naturopathic and integrative providers for vitamin D supplementation. This has been used in previous vitamin D studies and was shown to be safe and effective in the short term.4However, several studies suggest that rare high doses or high-normal serum levels of 25-hydroxycholicalciferol may lead to an increased risk of falls in the elderly.5.6The question remains: Does this more complex type of dosing regimen offer enough advantages over lower, safer dosing regimens?
It was surprising that the study found no improvement in quality of life, physical and cognitive functions, pain or shortness of breath after 6 months of normalization. Previous non-randomized studies have described a decrease in arthralgia and an increase in QoL in breast cancer patients who achieved vitamin D normalization on aromatase inhibitors.7.8
The majority of patients in the study received neoadjuvant/adjuvant chemotherapy. Therefore, persistent side effects of treatment may have influenced the results. In addition, almost half of the women were postmenopausal and 72% of the T group were estrogen receptor positive, so the number of women taking aromatase inhibitors was limited in this study.
Finally, attention should be paid to an actual deterioration in the quality of life - physical (P=0.006) and cognitive functions (P=0.002), pain (P=0.051) and dyspnea (P=0.014) – between baseline and 6 months in those who normalized their circulating vitamin D levels. Future studies will need to determine whether this is actually a valid result of high-dose, intermittent vitamin D supplementation.
restrictions
The authors do not report the type of oral vitamin D3and calcium used in the study. They report “cholecalciferol” in the supplementary method information (provided via an online link, separate from the published article). In the discussion of the paper they state that “vials” were given for oral administration with the intention of using a very high dosage to possibly achieve normal serum values after 6 months. And for perspective, these results are similar to those reported by Crew et al. were reported in their study evaluating zoledronate.9
The study didn't look at daily sun exposure or dietary vitamin D intake, two potential confounding factors.
Finally, Traub et al. in a well-designed comparative analysis of vitamin D available on the market, that there are significant differences between the vitamin D dosage stated on the label3Content in dietary supplements and provides a comparison of the effectiveness of capsule, liquid and tablet forms of vitamin D3in achieving increases and normalization of serum vitamin D in humans.10While the bolus dosage of liquid D3appeared to be superior to daily dosing of low-dose oral forms (400 IU), we cannot be sure that it is not just the form but the dose itself.
Overall, all vitamin and mineral deficiencies should always be considered when treating cancer, including individually tailored assessment and replenishment strategies. Vitamin D has the great advantage of being easy to assess through blood tests. The optimal dosage regimen has not yet been decided. This study suggests that we should be open to infrequent, large doses as a possible option for those who are unable or unwilling to take daily doses.