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: Difference between revisions
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Change in body composition over the first 8 cycles of chemotherapy did not mediate the association between randomized arm and progression-free survival | Change in body composition over the first 8 cycles of chemotherapy did not mediate the association between randomized arm and progression-free survival | ||
|Bias arising from the randomization process= | |Bias arising from the randomization process=some concerns | ||
|Bias due to deviation from intended intervention (assignment to intervention)= | |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 deviation from intended intervention (adhering to intervention)=NA | ||
|Bias due to missing outcome data= | |Bias due to missing outcome data=low risk | ||
|Bias in measurement of the outcome= | |Bias in measurement of the outcome=low risk | ||
|Bias in selection of the reported result= | |Bias in selection of the reported result=low risk | ||
|Other sources of bias= | |Other sources of bias=low risk | ||
|Overall RoB judgment= | |Overall RoB judgment=some concerns | ||
|Order number=3 | |Order number=3 | ||
}} | }} | ||
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{{Further points for assessing the study | {{Further points for assessing the study | ||
|power analysis performed= | |power analysis performed=Yes | ||
|Sample size corresponds to power analysis= | |Sample size corresponds to power analysis=Yes | ||
|Reasons given for samples being too small according to power analysis= | |Reasons given for samples being too small according to power analysis=NA | ||
|Samples sufficiently large= | |Samples sufficiently large=NA | ||
|Ethnicity mentioned= | |Ethnicity mentioned=Yes | ||
|Other explanations for an effect besides the investigated intervention= | |Other explanations for an effect besides the investigated intervention=No | ||
|Possibility of attention effects= | |Possibility of attention effects=NA | ||
|Possibility of placebo effects= | |Possibility of placebo effects=NA | ||
|Other reasons= | |Other reasons=NA | ||
|Correct use of parametric and non-parametric tests= | |Correct use of parametric and non-parametric tests=Yes | ||
|Correction for multiple testing= | |Correction for multiple testing=NA | ||
|Measurement of compliance= | |Measurement of compliance=Yes | ||
|Consistent reporting in numbers= | |Consistent reporting in numbers=Yes | ||
|Comprehensive and coherent reporting= | |Comprehensive and coherent reporting=No | ||
|Cross-over= | |Cross-over=No | ||
|sufficient washout period= | |sufficient washout period=NA | ||
|Tested for carry-over effects= | |Tested for carry-over effects=NA | ||
|Were sequence effects tested= | |Were sequence effects tested=NA | ||
|Effect sizes reported= | |Effect sizes reported=No | ||
|Were side effects systematically recorded= | |Were side effects systematically recorded=No | ||
|Side effects taken into account in the interpretation of the results= | |Side effects taken into account in the interpretation of the results=No | ||
|Ethics / CoI / Funding= | |Ethics / CoI / Funding=Yes | ||
}} | }} | ||
{{Additional Notes | {{Additional Notes | ||
Revision as of 10:35, 5 November 2024
| Reference ↗ | |
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| 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. | ITT Analysis |
| Specifications on analyses | All analyses adhered to the modified intention-to-treat principle. |
| 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
| 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;
|
| 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 | Supported by grants R00-CA218603, R25-CA203650, P50CA127003, R01CA205406, R01CA118553 from the National Cancer Institute of the National Institutes of Health, grant U54-GM104940 from the National Institute of General Medicine Sciences of the National Institutes of Health, and grant P30-DK072476 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health;
additional funding was provided by the Gloria Spivak Faculty Advancement Award, Friends of Dana-Farber Cancer Institute Award, Project P Fund, Douglas Gray Woodruff Chair fund, Consano, Pharmavite LLC, and Genentech; pharmavite provided the vitamin D3 and placebo capsules for the study
|
|---|---|
| Conflicts of Interest | J.C.B. reported receiving grants from the National Institutes of Health the American Institute for Cancer Research, and the Susan G. Komen Foundation. H.S.N. reported being employed at AbbVie. T.A.A. reported receiving grants from Eli Lilly and Bristol-Myers Squibb; and receiving personal fees from Bristol-Myers Squibb and Genentech. M.B.Y. reported consulting fees from Janssen Pharmaceuticals and receiving personal fees for peer review services from UpToDate. J.M.C. received research funding to his institution from Abbvie, Merus, Roche, and Bristol Myers Squib; received research funding from Merck, Astrazeneca, Esperas Pharma, and Tesaro; received consulting fees from Bristol Myers Squibb; and received travel funding from Bristol Myers Squib. D.S. reported receiving personal fees from JAMA; receiving grants from Pfizer, the Alliance for Clinical Trials in Oncology, the American Association for Cancer Research, the National Cancer Institute, the Patient-Centered Outcomes Research Institute, and the American Cancer Society; and receiving nonfinancial support from Epic Systems Corporation. A.J.B. reported receiving personal fees from Taiho Oncology, Bayer, Eisai, Exelixis, and Celgene. E.C. reported being employed at Amgen; and receiving funding from Dana-Farber Cancer Institute and owning shares of Amgen stock. J.A.C. reported receiving personal fees from Novartis, Ipsen, Lexicon, AAA, and Exelixis; and receiving support from Novartis, Merck, Sanofi, and Lilly. B.W. reported receiving grants from Celgene; and receiving personal fees from BioLineRx and Grail. C.A.T. reported receiving personal fees from Genetech/ Roche, Bristol-Myers Squibb, and Aztra Zeneca. H.Z. reported receiving grants from the National Institutes of Health. C.S.F. reported receiving personal fees from Eli Lilly, Entrinsic Health, Pfizer, Merck, Sanofi, Roche, Genentech, Merrimack Pharma, Dicerna, Bayer, Celgene, Agios, Gilead Sciences, Five Prime Therapeutics, Taiho, KEW, and CytomX Therapeutics; and receiving support from CytomX Therapeutics. K.N. reported receiving grants from the National Cancer Institute, Genentech, Consano, Gilead Sciences, Tarrex Biopharma, Trovagene, Celgene, and Pharmavite; and receiving personal fees from Genentech, Lilly, Tarrex Biopharma, Bayer, and Seattle Genetics. J.A.M. has received institutional research funding from Boston Biomedical, has served as an advisor/consultant to Ignyta and COTA Healthcare, and served on a grant review panel for the National Comprehensive Cancer Network funded by Taiho Pharmaceutical. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. |
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 | NA |
| 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 | No |
|---|---|
| - Possibility of attention effects | NA |
| - Possibility of placebo effects | NA |
| - Other reasons | NA |
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 | Yes |
|---|---|
| Correction for multiple testing | NA |
| Measurement of compliance | Yes |
| Consistent reporting in numbers (figures, flowchart, abstract, results) | Yes |
| Comprehensive and coherent reporting | No |
| Cross-over | No |
| - Sufficient washout period | NA |
| - Tested for carry-over effects | NA |
| - Tested for sequence effects | NA |
Interpretation of results
| Effect sizes reported (clinical vs. statistical significance) | No |
|---|---|
| Side effects systematically recorded | No |
| Side effects considered in result interpretation | No |
| Ethics votum | Yes |
Additional Notes
PRO
- Ethics vote
- Study protocol
- Blinding
- Randomization
- Pre/post level control of vitamin D (mean increase 25 (OH) D level over 1. 8 CTX cycles in intervention arm vs.placebo arm: mean difference 20.0 ng/mL; (95% CI: 14.7, 25.2); p<0.001)
- High treatment adherence with regard to vitamin D3: median: 98%
- Intention-to-treat analysis
CONTRA
- No indication of p-values for baseline differences