Inglis et al. (2020): Effects of High-Dose Vitamin D Supplementation on Phase Angle and Physical Function in Patients with Prostate Cancer on ADT

Reference ↗
Title	Effects of High-Dose Vitamin D Supplementation on Phase Angle and Physical Function in Patients with Prostate Cancer on ADT
Topic	Vitamin D
Author	Inglis, JE, Fernandez, ID, Van Wijngaarden, E, Culakova, E, Reschke, JE, Kleckner, AS, Lin, P-J, Mustian, KS, Peppone, LJ
Year	2020
Journal	Nutrition and cancer
DOI	https://doi.org/10.1080/01635581.2020.1819348

Brief summary

The 59 patients suffering from prostate cancer and treated with androgen deprivation therapy were randomly divided into two arms. 29 patients received daily high-dose vitamin D and 30 patients received a placebo, and both arms received a multivitamin (low dose of vitamin D and calcium). After 24 weeks, there were small indications that the patients who received high-dose vitamin D might have healthier muscle cells. Over time, androgen deprivation therapy may result in a reduction in lean body mass, which is the lean body mass associated with muscle mass. However, for most tests (e.g. grip strength, leg extension and walking) there were no benefits for the vitamin D arm. The study has a small sample size and gives little information about the patients, which may mean that factors such as cancer stage are not taken into account in the analysis. Also, vitamin D levels are not measured at the end of the study, so it is unclear whether patients remained in deficit.

Die 59, an Prostatakrebs leidenden und mit Androgendeprivationstherapie behandelten Patienten, wurden zufällig in zwei Arme eingeteilt. 29 Patienten erhielten täglich hochdosiertes Vitamin D und 30 Patienten ein Placebo, sowie beide Arme ein Multivitamin (geringe Dosis Vitamin D und Kalzium). Nach 24 Wochen zeigen sich kleine Hinweise darauf, dass die Patienten, die hochdosiertes Vitamin D erhielten, gesündere Muskelzellen haben könnten. Unter der Androgendeprivationstherapie kann im Laufe der Zeit eine Reduktion der Lean body mass auftreten, also der der fettfreien Körpermasse, welche mit der Muskelmasse in Verbindung steht. Jedoch zeigten sich für die meisten Tests (zB. Griffstärke, Beinstreckung und Gehen) keine Vorteile für der Vitamin D Arm. Die Studie hat eine kleine Stichprobe und gibt wenig Informationen über die Patienten, wodurch möglicherweise Faktoren wie Krebsstadium in der Analyse nicht berücksichtigt werden. Auch werden am Ende der Studie keine Vitamin D Spiegel gemessen, so dass unklar ist, ob die Patienten im Defizit verblieben sind.

Study Design

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	Double
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	No
Number of arms	2

Study characteristics

Inclusion criteria	A confirmed diagnosis of prostate cancer (stage I-IV) with no bone metastases; being within six months of starting androgen deprivation therapy (ADT) with an additional six more months planned; suboptimal vitamin D levels (<32 ng/ml); total serum calcium ≤10.5 mg/dl; no contraindications for fitness testing and 5) ≥60 years old
Exclusion criteria	Adequate vitamin D levels; hypercalcemia, osteoporosis, stage IV kidney disease or myocardial infarction within the past year
N randomized	59
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.	ITT Analysis
Specifications on analyses	The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
Countries of data collection	United States
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: basline T1: week 12 T2: week 24

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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Prostate 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, Advanced Stage
Specifications on cancer stages	Stage I-IV
Comorbidities	NI
Current cancer therapies	Hormone therapy
Specifications on cancer therapies	Androgen deprivation therapy
Previous cancer therapies	NI
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	67.6 (5.4)

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	29
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NA
Drop-out reasons	NA
Intervention	High-dose vitamin D3
Dosage and regime	50,000 IU/ week, over 24 weeks + all participants: daily multivitamin containing the RDA for vitamin D: 600 IU/day + 210 mg/day calcium and calcium supplements (800 mg/day)
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.	168
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	30
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NA
Drop-out reasons	NA
Intervention	Placebo (Low-dose vitamin D3)
Dosage and regime	Placebo vitamin D weekly, over 24 weeks + all participants: daily multivitamin containing the RDA for vitamin D: 600 IU/day + 210 mg/day calcium and calcium supplements (800 mg/day)
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.	168
Side effects / Interactions	NI

Outcomes

Body composition

Outcome type As specificed by the authors	NI
Outcome specification	Phase angle and lean mass
Type of measurement	BIA (Bioelectrical impedance analysis)
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".	Phase angle: significantly wider phase angle values in intervention arm at week 12 (p=0.014;95% CI -0.824, -0.098) and at week 24 (p=0.018; 95% CI -0.922, -0.090) Lean mass: significantly higher in intervention arm at week 12 (p=0.036; 95% C.I. 0.229, 6.556) but no significant differences between arms at any other time point
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	some concerns
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	low risk
Other sources of bias	?
Overall RoB judgment	high risk

Physical functioning

Outcome type As specificed by the authors	NI
Outcome specification	Hand grip, lower body strength, physical performance
Type of measurement	Dynamometer, SPPB (Short Physical Performance Battery), Physical examination
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".	No significant differences between arms at any time point
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	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	Funded by grants NIH NCI CA175793, NIH NCI T32CA102618 and NIH NCI UG1CA189961
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

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	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• Ethics vote
• Comparability of the groups to the baseline
• Adherence controlled with tablets count at T1 and T2

CONTRA:

• Small sample size
• Lack of data for factors such as cancer stage that may have further influenced the effect of the intervention
• No indication of a power analysis
• No data on vitamin D levels at the end of the study
• Very low dose of vitamin D
• Simultaneous automatic calcium administration