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

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Title	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
Topic	Vitamin D
Author	Ng, K, Nimeiri, HS, McCleary, NJ, Abrams, TA, Yurgelun, MB, Cleary, JM, Rubinson, DA, Schrag, D, Miksad, R, Bullock, AJ, Allen, J, Zuckerman, D, Chan, E, Chan, JA, Wolpin, BM, Constantine, M, Weckstein, DJ, Faggen, MA, Thomas, CA, Kournioti, C, Yuan, C, Ganser, C, Wilkinson, B, Mackintosh, C, Zheng, H, Hollis, BW, Meyerhardt, JA, Fuchs, CS
Year	2019
Journal	JAMA
DOI	https://doi.org/10.1001/jama.2019.2402

Study Note

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Brief summary

The study included 139 patients. Randomly divided into two arms, half received chemotherapy and additional high-dose vitamin D3 and the other half received additional standard-dose vitamin D3. The aim of the study was to investigate whether high-dose vitamin D therapy could improve the success of chemotherapy in patients with advanced or metastatic colorectal cancer and achieve a longer tumor-free period. There was no significant difference in the time without disease progression. The objective tumor response rate and overall survival time also did not differ between the arms. When calculating the risk of death or disease progression of patients, there was an advantage for the high-dose arm. The study has some weaknesses in the statistics and it should be noted that the authors have numerous conflicts of interest and the study was supported by a pharmaceutical industry.

Die Studie schloss 139 Patienten ein. Zufällig in zwei Arme eingeteilt, erhielt die Hälfte die Chemotherapie und zusätzlich Vitamin D3 in hoher Dosis und die andere Hälfte zusätzlich Vitamin D3 in Standarddosis. Ziel der Studie war es, der Frage nachzugehen, ob eine Hochdosis Vitamin D Therapie die Erfolge einer Chemotherapie bei Patienten mit fortgeschrittenem oder metastasiertem Darmkrebs verbessern und eine länger andauernde tumorfreie Zeit erzielt werden könnte. In Bezug auf die Zeit ohne Krankheitsfortschritt zeigte sich kein bedeutsamer Unterschied. Die objektive Ansprechrate des Tumors und die Gesamtüberlebenszeit unterschieden sich ebenfalls nicht zwischen den Armen. In der Berechnung des Risikos für Versterben oder Krankheitsfortschritt der Patienten, zeigte sich ein Vorteil für den Arm mit hoher Dosierung. Die Studie weist einige Schwächen in der Statistik auf und es sollte beachtet werden, dass Die Autoren zahlreiche Interessenskonflikte haben und die Studie von einer Pharmaindustrie unterstützt wurde.

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
Countries of data collection	United States
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: basline T1: 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	?
Specifications on cancer stages	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
Comorbidities	?
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	?
Previous cancer therapies	?
Gender	?
Gender specifications	?
Age groups
Age groups specification	?

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	NA
Drop-out reasons	NA
Intervention	Vitamin D3
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	Most common adverse events: neutropenia (24 patients (35%)) and hypertension (9 patients (13%)), diarrhea (1 patient (1%)), the only adverse events that were reported as possibly related to vitamin D3 were hyperphosphatemia (1 patient in intervention arm) and kidney stones (1 patient in the placebo arm)

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	NA
Drop-out reasons	NA
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	Most common adverse events: neutropenia (21 patients (31%)) and hypertension (11 patients (16%)), diarrhea (8 patient (12%))

Outcomes

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Time from the start of chemotherapy and vitamin D3 to first occurrence of documented disease progression or death
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: No significant differences; Supporting analysis: multivariable HR for progression-free survival or death was 0.64 (95% CI, 0-0.90; p=.02) Subgroupanalysis: High-dose vitamin D3 on progression-free survival appeared to be greater among patients with a lower body mass index (p=.04 for interaction), more metastatic sites (p=.02 for interaction), and KRAS wild-type tumors (p=.04 for interaction) Post-Hoc-Analysis: Comparison between the both arms: ECOG performance status was statistically significant (p=.03); No effects for adjustment by enrollment sites or tumor location

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)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	high 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	high risk

Tumor response

Outcome type As specificed by the authors	Secondary
Outcome specification	Proportion of patients with complete or partial tumor response
Type of measurement	NI
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".	NA

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	?

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	Time from the start of treatment to any cause of death
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: No significant differences

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	?

Vitamin D level

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
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".	Only 9% of the total study population had sufficient levels (≥30 ng/mL) of 25-hydroxyvitamin D at baseline; Plasma 25-hydroxyvitamin D levels increased into the sufficient range at the time of the first restaging (T1) among patients in intervention arm (median level, 32.0 ng/mL (IQR, 25.7-39.5 ng/mL)), whereas patients in control arm had no substantial change in their 25-hydroxyvitamin D level (median level, 18.7 ng/mL (IQR, 16.1-22.5 ng/mL)) (difference, 12.8 ng/mL (95% CI, 9.0- 16.6 ng/mL); p<.001); T2 (second restaging): intervention arm: median 25-hydroxyvitamin D level of 35.2 ng/mL (IQR, 25.0-45.4 ng/mL) vs. control arm: 18.5 ng/mL (IQR, 16.0-22.6 ng/mL) (difference, 16.7 ng/mL (95% CI, 10.9-22.5 ng/mL); p<.001); At treatment discontinuation: intervention arm: maintained vitamin D sufficiency and median 25-hydroxyvitamin D level of 34.8 ng/mL (IQR, 24.9- 44.7 ng/mL) vs. control arm: still deficient in vitamin D (18.7 ng/mL (IQR, 13.9-23.0 ng/mL)) (difference, 16.2 ng/mL [95% CI, 9.9-22.4 ng/mL]; p<.001)
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".	NA

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	?
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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