Brown et al. (2019): Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial

Reference ↗
Title	Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial
Topic	Vitamin D
Author	Brown, JC, Rosenthal, MH, Ma, C, Zhang, S, Nimeiri, HS, McCleary, NJ, Abrams, TA, Yurgelun, MB, Cleary, JM, Rubinson, DA, Schrag, D, Bullock, AJ, Allen, J, Zuckerman, D, Chan, E, Chan, JA, Wolpin, BM, Constantine, M, Weckstein, DJ, Faggen, MA, Thomas, CA, Kournioti, C, Yuan, C, Zheng, H, Hollis, BW, Fuchs, CS, Ng, K, Meyerhardt, JA
Year	2019
Journal	Cancers
DOI	https://doi.org/10.3390/cancers12113451

Study Note

This study is a further analysis of the study by Ng et al. (2019): Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial.

Brief summary

A total of 105 patients with advanced or metastatic adenoma carcinomas were included, with the intervention arm receiving high-dose vitamin D3 daily during chemotherapy (1st cycle: 8000 IU, cycle 2-8: 4000 IU) and the control arm receiving only a standard dose of vitamin D3 daily (cycle 1-8: 400 IU). The aim of the study was to investigate the effect of high-dose vitamin D3 on important body measurements such as skeletal muscle development and adipose tissue after the 8th chemotherapy cycle. In addition, the authors hypothesized that the positive association between high-dose vitamin D3 on progression-free survival may be explained by a potential positive effect of high-dose vitamin D3 on these body measures. However, the results showed no significant differences between the intervention and control arms in terms of body weight, BMI, muscle area, muscle atrophy and adipose tissue. Positive aspects of this study included the blinding, the monitoring of vitamin D levels before and after treatment and the high treatment compliance of the participants. However, it was unclear whether the two arms were comparable at the start of treatment because the differences were not tested.

Insgesamt wurden 105 Patienten mit fortgeschrittenen oder metastasierten Adenomkarzinomen eingeschlossen, wobei der Interventionsarm während der Chemotherapie täglich hochdosiertes Vitamin D3 (1. Zyklus: 8000 IU, Zyklus 2-8: 4000 IU) und der Kontrollarm täglich nur eine Standarddosis Vitamin D3 (Zyklus 1-8: 400 IU) erhielt. Ziel der Studie war es, die Wirkung des hochdosierten Vitamin D3 auf wichtige Körpermaße wie den Aufbau der Skelettmuskulatur und das Fettgewebe nach dem 8. Chemotherapiezyklus zu untersuchen. Zudem vermuteten die Autoren, dass der positive Zusammenhang zwischen hochdosierten Vitamin D3 auf das progressionsfreie Überleben durch eine potenzielle positive Wirkung von hochdosiertem Vitamin D3 auf diese Körpermaße erklärt werden kann. In den Ergebnissen zeigten sich jedoch keine bedeutsamen Unterschiede zwischen Interventions- und Kontrollarm hinsichtlich Körpergewichts, BMI, Muskelbereich, Muskelschwächung und Fettgewebe. Positiv an dieser Studie war die u.a. die Verblindung, die Überprüfung des Vitamin D-Spiegels vor und nach der Behandlung und die hohe Therapietreue der Teilnehmer. Es war jedoch unklar, ob die beiden Gruppen zu Beginn der Behandlung vergleichbar waren, weil die Unterschiede nicht getestet wurden.

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	Pathologically confirmed, unresectable locally advanced or metastatic adenocarcinoma of the colon or rectum with measurable disease per version 1.1 of the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines; patients were eligible if they received prior neoadjuvant or adjuvant chemotherapy or chemoradiation as long as the last dose of treatment was more than 12 months prior to cancer recurrence; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, normal baseline organ function, and no evidence of hypercalcemia or conditions predisposing to hypercalcemia (ie, hyperparathyroidism).
Exclusion criteria	Receiving prior treatment for advanced or metastatic disease; taking 2000 IU/d or greater of vitamin D3, had symptomatic genitourinary stones within the past year, or were taking thiazide diuretics.
N randomized	139
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
Specifications on analyses	Exploratory analysis using data from the SUNSHINE trial
Countries of data collection	United States
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: basline T1: after cycle 4 of chemotherapy (8 weeks) T2: after cycle 8 of chemotherapy (16 weeks) Follow-Up

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	Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal 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	Advanced Stage
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Continuous infusion of 2400 mg/m2 of 5-fluorouracil (5-FU) over 46 to 48 hours, a bolus of 400 mg/m2 of 5-FU, 400 mg/m2 of leucovorin, and 85 mg/m2 of oxaliplatin (mFOLFOX6) plus 5 mg/kg of bevacizumab administered intravenously every 14 days per institutional standard of care (1 cycle=14 days), bevacizumab was allowed to be omitted during the first cycle and started with cycle 2 at the investigator’s discretion
Previous cancer therapies	Diverse
Gender	Mixed
Gender specifications	Intervention arm: n=32 (64%) male, n=18 (36%) female; placebo arm: n=27 (49%) male, n=28 (51%) female
Age groups	Adults (18+)
Age groups specification	Intervention arm: median=54 (interquartile range: 47-65); placebo arm: median: 56 (interquartile range: 49-65)

Arms

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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	69
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	19
Drop-out reasons	11 CT images unusable, 8 CT images not available
Intervention	Vitamin D
Dosage and regime	A loading dose of 8000 IU/d of vitamin D3 (two 4000 IU capsules) for cycle 1 followed by 4000 IU/d for subsequent cycles
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	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	70
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	15
Drop-out reasons	11 CT images unusable, 4 CT images not available
Intervention	Placebo
Dosage and regime	400 IU/d of vitamin D3 during all cycles (one 400 IU capsule plus 1 placebo capsule during cycle 1)
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	NI

Outcomes

Body composition

Outcome type As specificed by the authors	NI
Outcome specification	Body weight, body mass index, muscle area, muscle attenuation, visceral adipose tissue area and subcutaneous adipose tissue area
Type of measurement	Scale, Measuring tape, SPECT (Single Photon Emission Computed Tomography)
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
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)	low risk
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	NA
Overall RoB judgment	some concerns

Vitamin D level

Outcome type As specificed by the authors	Others
Outcome specification	Change in Plasma 25(OH)D
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".	Change in plasma 25(OH)D concentration from baseline to cycle 8 was not significantly associated with change in body weight, body mass index, muscle area, muscle attenuation, visceral adipose tissue area and subcutaneous adipose tissue area
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	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

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	NI
Outcome specification	NA
Type of measurement	Observation
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".	NA
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".	Overall: In the subgroup of 105 participants randomization to high-dose vitamin D3 was associated with a lower risk of disease progression or death as compared with low-dose vitamin D3 [HR: 0.67; (95% CI: 0.42, 1.07)]; the magnitude of risk reduction was similar to that observed in the full analysis set of 139 participants as previously reported; Change in body composition over the first 8 cycles of chemotherapy did not mediate the association between randomized arm and progression-free survival

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)	low risk
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	low risk
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	?
Conflicts of Interest	?

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

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