Frankling et al. (2021): ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial

Reference ↗
Title	‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial
Topic	Vitamin D
Author	Frankling, MH, Klasson, C, Sandberg, C, Nordström, M, Warnqvist, A, Bergqvist, J, Bergman, P, Björkhem-Bergman, L
Year	2021
Journal	Cancers
DOI	https://doi.org/10.3390/_cancers13153707

Brief summary

In the study, 244 patients were randomly divided into two arms. The patients suffered from advanced cancer and were receiving palliative care. One arm received 4000 IU vitamin D3 daily for 12 weeks and the other arm a placebo. The change in opioid dose, fatigue, quality of life and amount of antibiotics was recorded. If all patients were included in the analysis, there were no differences in the mean opioid dose. However, when only those who completed the 12 weeks (150) were included, there was an advantage for the vitamin D arm, with lower opioid doses. Calculated with the 150 patients, there were no differences for quality of life or amount of antibiotics. However, there were lower fatigue values in the vitamin D arm. The study is characterized by very detailed reporting. From a methodological point of view, the analysis with all patients who were included in the study at the beginning is the more meaningful, as it is less influenced by bias. Looking only at these results, the study gives no indication of the effectiveness of vitamin D on the need for opioids.

In der Studie wurden 244 Patienten zufällig in zwei Arme eingeteilt. Die Patienten litten unter fortgeschrittenem Krebs und befanden sich in palliativer Versorgung. Der eine Arm erhielt täglich 4000 IU Vitamin D3 für 12 Wochen und der andere Arm ein Placebo. Erhoben wurde die Veränderung der Opioiddosis, Fatigue, Lebensqualität und Menge der Antibiotika. Wurden alle Patienten in die Analyse einbezogen, so zeigten sich keine Unterschiede für die mittlere Opioiddosis. Wurden jedoch nur die Personen eingeschlossen, die die 12 Wochen abgeschlossen hatten (150), so zeigte sich ein Vorteil für den Vitamin D Arm, mit niedrigeren Opioiddosen. Berechnet mit den 150 Patienten zeigten sich keine Unterschiede für Lebensqualität oder Menge der Antibiotika. Es zeigten sich jedoch geringere Fatiguewerte im Vitamin D Arm. Die Studie zeichnet sich durch eine sehr detaillierte Berichterstattung aus. Aus methodischer Sicht ist die Analyse mit allen Patienten die zu Beginn in der Studie aufgenommen wurden die aussagekräftigere, da diese weniger durch Verzerrungen beeinflusst wird. Betrachtet man nur diese Ergebnisse, so gibt die Studie keinen Hinweis auf eine Wirksamkeit von Vitamin D auf den Bedarf an Opioiden.

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	≥18 years old, had advanced and/or metastatic cancer in palliative phase (any type of cancer), a life expectancy of at least three months as assessed by one of the three study physician and 25-OHD ≤50 nmol/L
Exclusion criteria	25-OHD >50 nmol/L, hypercalcemia during the past two months; eGFR<30 mL/h; a medical history of kidney stones, sarcoidosis and/or primary hyperparathyroidism; current medication including vitamin D >400 IU/day, digoxin/digitoxin or thiazides; hypersensitivity to the study drug; participation in other clinical trials involving medication; or other reasons for not being able to complete the planned procedures
N randomized	244
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	A total of 244 patients were included in the ITT analysis, which was based on 769 observations and four time points over 12 weeks; A total of 150 patients completed all 12 weeks of vitamin D (n=67) or placebo (n=83) and constitute the PP population
Countries of data collection	Sweden
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: Baseline T1-T3: every worth week

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.	Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Gastrointestinal Cancers, Gynecologic Cancers, Head and Neck Cancers, Hematologic Cancers, Lung Cancer, Skin Cancer – Melanoma, Prostate Cancer, Unspecified Sarcoma, Genitourinary Cancers - Urethral 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	Advanced and/or metastatic cancer in palliative phase
Comorbidities	NI
Current cancer therapies	No therapy, Chemotherapy, Hormone therapy, Targeted therapy
Specifications on cancer therapies	With no intention to cure
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	n=120 (49%) male and n=124 (51%) female
Age groups	Adults (18+)
Age groups specification	Median (IQR): 68 (61-75)

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	121
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	54
Drop-out reasons	Death due to cancer
Intervention	Vitamin D
Dosage and regime	Vitamin D3 oil drops (color and taste matched) 4000 IU/day, for 12 weeks
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.	84
Side effects / Interactions	n=2 mild hypercalcemia, n=2 gastrointestinal symptoms (mild diarrhea, nausea and abdominal pain), n=1 elevated creatine level

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	123
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	40
Drop-out reasons	Death due to cancer
Intervention	Placebo
Dosage and regime	Placebo (oil drops), for 12 weeks
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.	84
Side effects / Interactions	n=1 renal failure, n=2 mild hypercalcemia, n=1 gastrointestinal symptoms (mild diarrhea, nausea and abdominal pain), n=1 shortness of breath

Outcomes

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Long-acting opioid dose, measured as fentanyl ug/hour during 12 weeks
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".	ITT analysis: no significant differences; PP analysis: mean increase in opioid doses in intervention arm was significantly smaller than in placebo arm, beta coefficient −0.56 (95% CI −1.07; −0.05; p=0.03); Separate non-longitudinal analysis on data after 12 weeks only: significantly lower opioid doses in the vitamin D arm, −7.0 μg /h (p=0.03)
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	low 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	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	low risk

Infection

Outcome type As specificed by the authors	Secondary
Outcome specification	Antibiotic use, measured as the number of days with antibiotics in the previous 30 days
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".	No significant difference
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	low 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	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	low risk

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	ESAS (Edmonton Symptom Assessment Scale), EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
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 difference
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	low 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	low risk
Bias in measurement of the outcome	high risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Fatigue

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	ESAS (Edmonton Symptom Assessment Scale), EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
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".	Significantly lower degree of fatigue assessed with ESAS in intervention arm compared to the placebo arm after 12 weeks; −1.1 point (p<0.01); Assessed with EORTC QLQ-C15-PAL 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	low 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	low risk
Bias in measurement of the outcome	high risk
Bias in selection of the reported result	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

Vitamin D level

Outcome type As specificed by the authors	Others
Outcome specification	NI
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".	Vitamin D treatment increased mean 25-OHD significantly, from 36 (±11) nmol/L to 81 (±26) nmol/L (p<0.001), while mean 25-OHD in the placebo arm remained stable
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	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

OS (Overall Survival)

Outcome type As specificed by the authors	Others
Outcome specification	Post-hoc survival analysis
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".	No difference in survival time between the two treatment arms at any timepoint, after 4 weeks (p=0.36), 8 weeks (p=0.09) or 12 weeks (p=0.08)
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	low 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	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	some concerns
Other sources of bias	NA
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	Financially supported by grants from the Stockholm County Council (SLL20160036 and SLL20180320), Swedish Cancer Society (CAN 2017/233 and CAN2018/316), Stockholms Sjukhems Jubileumsfond, ASIH Stockholm Södra and ASIH Stockholm Norr; The funders of this trial took no part in study design, data collection, data interpretation, writing or reviewing of the manuscript
Conflicts of Interest	According to authors no conflict 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

PRO:

• Ethics vote
• Very detailed descriptions in supplements
• Power analysis
• Control for intra-person correlation
• Comparability of the groups both as ITT and PP sample
• Mirror measurements
• Testing of compliance

CONTRA:

• 4 changes to original design
• Only gastrointestinal tract symptoms, an increase in creatinine levels, hypercalcemia and renal failure had to be reported as side effects according to the protocol
• Fatigue and QoL only assessed by 2 questions each
• According to power analysis, 10 patients too few
• Higher drop-out in A compared to B between T1 and T2 (p=0.02) due to no longer wanting to participate, slightly more drop-outs overall by the end of the study in A (45% vs. 33%); people who dropped out had higher opioid levels at baseline