Frankling et al. (2021): ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial: Difference between revisions
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|Reference=Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial | |Reference=Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial | ||
}} | }} | ||
=Brief summary= | =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 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. | ||
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|Side Effects / Interactions=n=2 mild hypercalcemia, n=2 gastrointestinal symptoms (mild diarrhea, nausea and abdominal pain), n=1 elevated creatine level | |Side Effects / Interactions=n=2 mild hypercalcemia, n=2 gastrointestinal symptoms (mild diarrhea, nausea and abdominal pain), n=1 elevated creatine level | ||
|Order number=1 | |Order number=1 | ||
|Arm topic=Vitamin D | |||
}} | }} | ||
{{Arm | {{Arm | ||
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|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 | |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 | ||
|Order number=2 | |Order number=2 | ||
|Arm topic=Vitamin D | |||
}} | }} | ||
{{Arm Overview}} | {{Arm Overview}} | ||
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|Overall RoB judgment=low risk | |Overall RoB judgment=low risk | ||
|Order number=1 | |Order number=1 | ||
|Outcome topic=Vitamin D | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
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|Overall RoB judgment=low risk | |Overall RoB judgment=low risk | ||
|Order number=2 | |Order number=2 | ||
|Outcome topic=Vitamin D | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
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|Overall RoB judgment=high risk | |Overall RoB judgment=high risk | ||
|Order number=3 | |Order number=3 | ||
|Outcome topic=Vitamin D | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
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|Bias due to missing outcome data=low risk | |Bias due to missing outcome data=low risk | ||
|Bias in measurement of the outcome=high risk | |Bias in measurement of the outcome=high risk | ||
|Bias in selection of the reported result= | |Bias in selection of the reported result=high risk | ||
|Other sources of bias=NA | |Other sources of bias=NA | ||
|Overall RoB judgment=high risk | |Overall RoB judgment=high risk | ||
|Order number=4 | |Order number=4 | ||
|Outcome topic=Vitamin D | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
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|Overall RoB judgment=NA | |Overall RoB judgment=NA | ||
|Order number=5 | |Order number=5 | ||
|Outcome topic=Vitamin D | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
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|Results during intervention=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 during intervention=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=NA | |Results after intervention=NA | ||
|Bias arising from the randomization process= | |Bias arising from the randomization process=low risk | ||
|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=some concerns | ||
|Other sources of bias= | |Other sources of bias=NA | ||
|Overall RoB judgment= | |Overall RoB judgment=some concerns | ||
|Order number=6 | |Order number=6 | ||
|Outcome topic=Vitamin D | |||
}} | }} | ||
{{Outcome Overview}} | {{Outcome Overview}} | ||
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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=No | ||
|Reasons given for samples being too small according to power analysis= | |Reasons given for samples being too small according to power analysis=NI | ||
|Samples sufficiently large= | |Samples sufficiently large=NA | ||
|Ethnicity mentioned= | |Ethnicity mentioned=No | ||
|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=No | ||
|Measurement of compliance= | |Measurement of compliance=Yes | ||
|Consistent reporting in numbers= | |Consistent reporting in numbers=Yes | ||
|Comprehensive and coherent reporting= | |Comprehensive and coherent reporting=Yes | ||
|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=Yes | ||
|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 | ||
|Blinding reliable=? | |Blinding reliable=? | ||
|Check whether blinding was successful=? | |Check whether blinding was successful=? | ||
Latest revision as of 12:53, 29 November 2024
| 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 | Yes |
|---|---|
| - Sample size corresponds to power analysis | No |
| - Reasons for insufficient sample size based on power analysis | NI |
| If no power analysis performed: at least moderate sample size (n >= 30 per arm) | NA |
| Ethnicity mentioned | No |
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 | No |
| Measurement of compliance | Yes |
| Consistent reporting in numbers (figures, flowchart, abstract, results) | Yes |
| Comprehensive and coherent reporting | Yes |
| 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 | Yes |
| Side effects considered in result interpretation | No |
| Ethics votum | Yes |
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
- Vitamin D level 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