Jacot et al. (2016): 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

Reference ↗
Title	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
Topic	Vitamin D
Author	Jacot, W, Firmin, N, Roca, L, Topart, D, Gallet, S, Durigova, A, Mirr, S, Abach, L, Pouderoux, S, D'Hondt, V, Bleuse, J, Lamy, P, Romieu, G
Year	2016
Journal	Annals of Oncology
DOI	https://doi.org/10.1093/annonc/mdw145

Brief summary

n this study, two arms of breast cancer patients with vitamin D deficiency were examined who either received high doses of vitamin D (arm A) or standard vitamin D therapy (arm B) 7 to 12 months after the start of their chemotherapy. After 6 months, a higher rate of patients with normalized levels was found in arm A (30%) than in arm B (12.6%). This was also found taking into account the vitamin D level at the beginning of the study. In a further subgroup analysis, patients were divided according to the season in which they were included. In this case, the arm differences were only found in the patients from fall and winter. In arm A, patients reported a deterioration in quality of life in many areas, while in arm B, quality of life remained largely stable over 6 months. Positive aspects of this study were the large sample size and the low drop-out rate. On the negative side, however, many patients did not take the medication as prescribed and the arm difference in quality of life was not statistically analyzed.

In dieser Studie wurden zwei Arme von Brustkrebspatientinnen mit Vitamin D Mangel untersucht, die 7 bis 12 Monate nach dem Beginn ihrer Chemotherapie entweder jeweils hohe Dosen Vitamin D erhielten (Arm A) oder eine Vitamin D-Standardtherapie bekamen (Arm B). Nach 6 Monaten wurde in Arm A eine höhere Rate an Patienten mit normalisierten Spiegeln gefunden (30%) als in Arm B (12.6%). Das fand sich auch unter Berücksichtigung des Vitamin D Spiegels zum Beginn der Studie. In einer weiteren Subgruppenanalyse wurden die Patienten nach der Jahreszeit aufgeteilt, in der sie eingeschlossen wurden. In diesem Fall fanden sich die Gruppenunterschiede nur bei den Patienten vom Herbst und Winter. In Arm A berichteten die Patientinnen in vielen Bereichen eine Verschlechterung der Lebensqualität, während in Arm B die Lebensqualität über 6 Monaten größtenteils stabil blieb. Positiv an dieser Studie waren die große Stichprobe und die geringe Ausfallrate. Negativ ist jedoch, dass viele Patientinnen die Medikation nicht so eingenommen haben, wie es vorgegeben war und dass bei der Untersuchung der Lebensqualität der Gruppenunterschied statistisch nicht untersucht wurde.

Study Design

Crossover to the intervention arm was allowed after 6 months of conventional treatment if the serum vitamin D level had not normalized.

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	No
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	Yes
Number of arms	2

Study characteristics

Inclusion criteria	Female patients with histologically confirmed primary early-stage breast cancer, treated in the last 12 months with adjuvant or neoadjuvant chemotherapy, and with an ECOG performance status of <2, vitamin D deficiency
Exclusion criteria	Known hypersensitivity reaction to vitamin D or calcium com-pounds, known comorbidities affecting the vitamin D/calcium balance or bone health, concomitant vitamin D supplementation
N randomized	195
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis, ITT Analysis
Specifications on analyses	All randomized patients were analyzed for efficacy, and 182 patients (93%) were evaluable for toxicity.
Countries of data collection	France
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline At 6, 12, 18 and 24 months

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative, Neo-adjuvant, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) i.v. on day 1 every 21 days for three cycles, followed by docetaxel 100 mg/m2 i.v. on day 1 every 21 days for three cycles; Docetaxel - 2 cyclophosphamide, methotrexate, 5-fluorouracile; Trastuzumab
Previous cancer therapies	NI
Gender	Female
Gender specifications	100% Kemal
Age groups	Adults (18+)
Age groups specification	Intervention arm: median (range): 51 (27-74) Control arm: median (range): 49 (25-71)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	100
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	4
Drop-out reasons	Did not receive allocated intervention (Withdrew from study, adverse event)
Intervention	Vitamin D3
Dosage and regime	Baseline vitamin D deficiency level: <10 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43, 58 and at 3 months, Baseline vitamin D deficiency level: 10-20 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43 and at 3 months, Baseline vitamin D deficiency level: 20-30 ng/ml 100 000 IU vitamin D3 on day 1, 15 and at 3 months
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	n=1 hypercalciuria

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Active control
Number of participants (arm) N randomized	95
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	9
Drop-out reasons	Did not received allocated intervention (Withdrew from study, adverse event, other)
Intervention	Vitamin D3
Dosage and regime	Daily 400 IU vitamin D3
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	n=1 hypercalciuria

Outcomes

Vitamin D level

Outcome type As specificed by the authors	Primary
Outcome specification	Increase of normalization of serum 25OHD, defined as a 25OHD blood-level minimum target of 30 ng/ml
Type of measurement	Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 6 months, significantly more patients in the intervention arm had a normalized serum vitamin D level compared with the control arm patients (30% versus 12.6%; p = 0.003), the median 6 month-vitamin D level was 24.2 ng/ml (8.1–39.2) and 28.1 ng/ml (7.3–51.8) respectively in the control and intervention arms (p < 0.001); Percentage of correction was significantly higher in the intervention arm for patients included during fall (28% vs. 3%; p = 0.006), there was a trend in favor of intervention arm for patients included during winter (52% vs. 28%; p = 0.083), while there was no significant difference for patients included in spring and summer;
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	52 patients without vitamin D normalization from the control arm switched to the intervention arm after 6 months: at 12 months, 44% of these patients (n = 23) showed vitamin D normalization, median 6- and 12–month vitamin D levels were 23.9 ng/ml (8.1–29.6) and 28.6 ng/ml (16.3–53.0) respectively (p < 0.001)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	NA
Bias due to deviation from intended intervention (assignment to intervention)	NA
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	NA
Bias in measurement of the outcome	NA
Bias in selection of the reported result	NA
Other sources of bias	NA
Overall RoB judgment	NA

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Difference in baseline Quality of Life for the physical function (p = 0.028), higher in the intervention arm and diarrhea, more severe in the control arm (p = 0.093); no statistically significant difference was observed between intervention and control arms at 6 months, there was no significant difference in overall Quality of Life between the normalized and deficient populations at 6 months
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	high risk
Bias due to deviation from intended intervention (assignment to intervention)	some concerns
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

Funding and Conflicts of Interest

Funding	There was no specific funding for this study.
Conflicts of Interest	The authors have declared no conflicts of interest.

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	Yes
- Reasons for insufficient sample size based on power analysis	Sample size was sufficient to detect differences between intervention and placebo arm. At the same time there were not enough patients for having the right prevalence of vitamin D deficiency in the target population.
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	NA
Ethnicity mentioned	Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	There were baseline differences in in QoL and diarrhea

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	NI
Correction for multiple testing	No
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	No
Cross-over	Yes
- Sufficient washout period	Yes
- Tested for carry-over effects	No
- Tested for sequence effects	No

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	Yes
Side effects considered in result interpretation	No
Ethics votum	Yes

Additional Notes

PRO

• Ethics vote
• Large sample, number sufficient according to power analysis
• Low dropout: Arm A: 4%, Arm B: 9%, intention-to-treat analysis (except for side effect analysis)

CONTRA

• Compliance rate: A: 67%, B: 68.4%
• Baseline differences in QoL (physical performance (A > B) and diarrhea (A < B))
• No real group comparison in QoL between arm A and B
• Possibly selective reporting of endpoints (more endpoints described in the methods section than reported in the results section, e.g. vitamin D levels after 12, 18 and 24 months)
• Multiple testing