CAMIH - User contributions [en]

Ryan et al. (2013): Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients

2024-11-21T14:25:48Z

CHoppe:

{{Reference
|Reference=Publication: Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients
}}
=Brief summary=
In this study, breast cancer patients were examined during radiotherapy, with one half taking curcumin alongside radiotherapy and the other half taking a placebo. In the curcumin arm, the severity of radiodermatitis (a common skin disease associated with radiotherapy) was found to be significantly lower at the end of radiotherapy than in the placebo arm. The two arms showed different courses of radiodermatitis severity. From the fourth week onwards, the intensity in the curcumin arm increased less steeply than in the placebo arm and even decreased slightly from week six to seven. In addition, there were fewer cases of moist skin peeling in the curcumin arm. With regard to the redness of the dermatitis, the pain experienced and other adverse symptoms such as nausea and vomiting, there were virtually no differences between the curcumin and placebo patients. A positive aspect of this study was the double blinding (investigators/patients did not know which arm they belonged to). On the negative side, however, only a very small sample was examined and a large number of individual tests were carried out. This increases the probability that a significant difference will be calculated by chance, even though there is actually no difference.

In dieser Studie wurden Brustkrebspatientinnen während der Radiotherapie untersucht, wobei eine Hälfte parallel zur Radiotherapie Curcumin einnahm und die andere Hälfte ein Placebo. In der Curcumin-Gruppe wurde die Schwere von Radiodermatitis (eine häufige Hautkrankheit, die mit Radiotherapie assoziiert ist) am Ende der Radiotherapie deutlich geringer eingeschätzt als in der Placebo-Gruppe. Die beiden Gruppen wiesen unterschiedlicher Verläufe der Radiodermatitis-Schwere auf. Ab der vierten Woche stieg die Intensität in der Curcumin-Gruppe weniger steil an als in der Placebo-Gruppe und nahm von Woche sechs bis sieben sogar leicht ab. Zudem traten in der Curcumin-Gruppe weniger Fälle von feuchter Hautablösung auf. Hinsichtlich der Röte der Dermatitis, des erlebten Schmerzes und weiterer unerwünschter Symptome wie z.B. Übelkeit und Erbrechen fanden sich so gut wie keine Unterschiede zwischen den Curcumin- und den Placebo-Patienten. Positiv an dieser Studie war die doppelte Verblindung (Untersuchter/Patienten wissen nicht, welcher Gruppe sie angehören). Negativ war jedoch, dass nur eine sehr kleine Stichprobe untersucht wurde und dass sehr viele Einzeltests durchgeführt wurden. Das erhöht die Wahrscheinlichkeit, dass man zufällig einen bedeutsamen Unterschied berechnet, obwohl eigentlich kein Gruppenunterschied vorhanden ist.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Diagnosed with noninflammatory breast cancer or carcinoma in situ and prescribed radiotherapy without concurrent chemotherapy at the University of Rochester Cancer Center
|Exclusion criteria=Patients who: had bilateral breast cancer; previous radiation to the chest or breast area; diagnosis of inflammatory breast cancer; breast reconstruction and/or expanders prior to RT; were taking anti-coagulant therapy (warfarin, coumadin or heparin) or antiepidermal growth factor receptor (EGFR) therapy or were receiving partial breast irradiations
|N randomized=35
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=Assessed at baseline, weekly after every fifth radiotherapy session, at the end of radiotherapy, and at 2 post-radiotherapy appointments (1-month and 6-months post-radiotherapy)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=0 – IV
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=Standard fractionated RT (~1.8–2.4 Gy per session) for four to seven weeks with or without boost for a total radiation dose of ≥ 42 Gy

Prior (n(%)):

* Lumpectomy 27 (90%)

* Mastectomy 3 (10%)

* Chemotherapy before radiation 13 (43.3%)
|Previous cancer therapies=Surgery, Chemotherapy
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) = 58.1 (2.2) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=17
|Drop-out=3
|Drop-out reasons=Patient-initiated n=1, Ineligibility n=1, Non-compliance n=1

Overall reasons for n=5:
* patient-reported hot flashes (1/5)

* undisclosed personal reasons (1/5)

* ineligibility due to concurrent participation in another RT intervention trial (1/5)

* and noncompliance with study procedures (2/5)
|Intervention=Curcumin (Curcumin C3 Complex®)

+ “Standard care” topical agents for radiation dermatitis (i.e., Radiaplex® gel, silvadine, hydrocortisone cream) were allowed
|Dosage and regime=500mg capsules (≥95% curcuminoids), 3 times daily, 4 capsules each time

Duration: 7 weeks (entire radiationtherapy)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=According to information no side effects.
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=18
|Drop-out=2
|Drop-out reasons=Patient-initiated n=1, Non-compliance n=1

Overall reasons for n=5:

* patient-reported hot flashes (1/5)

* undisclosed personal reasons (1/5)

* ineligibility due to concurrent participation in another RT intervention trial (1/5)

* and noncompliance with study procedures (2/5)
|Intervention=Placebo (500 mg calcium hydrogen phosphate and yellow food coloring)

+ “Standard care” topical agents for radiation dermatitis (i.e., Radiaplex® gel, silvadine, hydrocortisone cream) were allowed
|Dosage and regime=3 times daily, 4 capsules each time

Duration: 7 weeks (entire radiationtherapy)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=According to information no side effects.
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Dermatitis
|Outcome specification=Severity of radiodermatitis (skin measurements weekly after the 5th radiationtherapy session)
|Type of measurement=RDS (Radiation Dermatitis Severity)
|Results during intervention=Mean difference:
* Intervention arm – Placebo arm (SD; 95% CI) = -0.8 (0.8, -1.4; -0.2); p = 0.008

Model over time:

* Intervention vs. Placebo (without considering time): p = 0.963, but significant arm/week interaction p = 0.007, i.e., the trend over time is different

* According to the graph, Intervention and Placebo follow a similar trend until week 4, after which the values in the Intervention arm increase less sharply and even decrease slightly in week 7, while the Placebo arm continues to increase
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Dermatitis
|Outcome specification=Moist desquamation
|Type of measurement=Observation
|Results during intervention=Number in %:
* Intervention arm: 28.6%, Placebo arm: 87.5%; p = 0.002
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Dermatitis
|Outcome specification=Redness of skin
|Type of measurement=Observation
|Results during intervention=Intervention vs. placebo (without considering time): p = 0.328

Arm/week interaction: p = 0.588, i.e., no significant differences in the redness trend
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|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=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=NA
|Type of measurement=MPQ-SF (McGill Pain Questionnaire - Short Form), SI (Symptom Inventory questionnaire)
|Results during intervention=Mean change from baseline to end of radiotherapy (95% CI):
* Pain at radiotherapy site: Intervention arm: 1.929 (0.855, 3.002), Placebo arm: 1.313 (0.365, 2.260); p = 0.504

* Other pain: Intervention arm: –0.286 (-1.309, 0.738), Placebo arm: –0.563 (-1.432, 0.307); p = 0.967

MPQ-SF:

* MPQ - total: Intervention arm: 4.643 (2.045, 7.241), Placebo arm: 2.875 (1.543, 4.207); p = 0.144

* Perceived pain: Intervention arm: 0.857 (0.358, 1.356), Placebo arm: 0.813 (0.523, 1.102); p = 0.644

* Sensory pain: Intervention arm: 3.286 (1.217, 5.354), Placebo arm: 1.750 (0.827, 2.673); p = 0.081

* Affective pain: Intervention arm: 0.500 (0.061, 0.939), Placebo arm: 0.375 (-0.008, 0.758); p = 0.550

* No significant differences between intervention and placebo arms

* Considering types of pain: gnawing, aching, splitting (Intervention arm > Placebo arm, p < 0.021), otherwise no significant differences
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Further symptoms of the Symptom Inventory
|Type of measurement=SI (Symptom Inventory questionnaire)
|Results during intervention=No significant differences (nausea, vomiting, depression, shortness of breath, memory, appetite, diarrhea, urination, skin, sleep, fatigue, activity, mood, work, relationships, walking, quality of life)
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding="This study was supported by the FDA IND no. 75,444; NCI PHS grant 1R25CA10618; Dermatology Foundation Research Career Development Award; and URMC CTSI KL2-RR024136. A special thanks to all of the patients with breast cancer who participated in this clinical trial. We thank the Radiation Oncology Red and Yellow Service team members and the Departments of Radiation Oncology and Dermatology for assistance and support of this study."
|Conflicts of Interest=See Funding.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=NI
|Sample size corresponds to power analysis=NI
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NA
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethical approval obtained
* Double-blind with control (Intervention arm: 5/14 (35.7%) of patients think they are in the curcumin arm, placebo arm: 2/16 (12.5%) of patients think they are in the placebo arm).
* High comparable compliance rates (Mean (SD): Intervention arm: 96.6% (6.6%), Placebo arm: 98.4% (3.2%); p = 0.344)
* Assessment of expected and actual pain at baseline

CONTRA:
* Very small sample size
* Dropout rate: Intervention arm: 18%, Placebo arm: 11%
* No intention-to-treat analysis
* No control for multiple testing
}}

Ryan et al. (2013): Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients

2024-11-21T14:25:39Z

CHoppe:

{{Reference
|Reference=Publication: Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients
}}
{{Study Note}}
=Brief summary=
In this study, breast cancer patients were examined during radiotherapy, with one half taking curcumin alongside radiotherapy and the other half taking a placebo. In the curcumin arm, the severity of radiodermatitis (a common skin disease associated with radiotherapy) was found to be significantly lower at the end of radiotherapy than in the placebo arm. The two arms showed different courses of radiodermatitis severity. From the fourth week onwards, the intensity in the curcumin arm increased less steeply than in the placebo arm and even decreased slightly from week six to seven. In addition, there were fewer cases of moist skin peeling in the curcumin arm. With regard to the redness of the dermatitis, the pain experienced and other adverse symptoms such as nausea and vomiting, there were virtually no differences between the curcumin and placebo patients. A positive aspect of this study was the double blinding (investigators/patients did not know which arm they belonged to). On the negative side, however, only a very small sample was examined and a large number of individual tests were carried out. This increases the probability that a significant difference will be calculated by chance, even though there is actually no difference.

In dieser Studie wurden Brustkrebspatientinnen während der Radiotherapie untersucht, wobei eine Hälfte parallel zur Radiotherapie Curcumin einnahm und die andere Hälfte ein Placebo. In der Curcumin-Gruppe wurde die Schwere von Radiodermatitis (eine häufige Hautkrankheit, die mit Radiotherapie assoziiert ist) am Ende der Radiotherapie deutlich geringer eingeschätzt als in der Placebo-Gruppe. Die beiden Gruppen wiesen unterschiedlicher Verläufe der Radiodermatitis-Schwere auf. Ab der vierten Woche stieg die Intensität in der Curcumin-Gruppe weniger steil an als in der Placebo-Gruppe und nahm von Woche sechs bis sieben sogar leicht ab. Zudem traten in der Curcumin-Gruppe weniger Fälle von feuchter Hautablösung auf. Hinsichtlich der Röte der Dermatitis, des erlebten Schmerzes und weiterer unerwünschter Symptome wie z.B. Übelkeit und Erbrechen fanden sich so gut wie keine Unterschiede zwischen den Curcumin- und den Placebo-Patienten. Positiv an dieser Studie war die doppelte Verblindung (Untersuchter/Patienten wissen nicht, welcher Gruppe sie angehören). Negativ war jedoch, dass nur eine sehr kleine Stichprobe untersucht wurde und dass sehr viele Einzeltests durchgeführt wurden. Das erhöht die Wahrscheinlichkeit, dass man zufällig einen bedeutsamen Unterschied berechnet, obwohl eigentlich kein Gruppenunterschied vorhanden ist.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Diagnosed with noninflammatory breast cancer or carcinoma in situ and prescribed radiotherapy without concurrent chemotherapy at the University of Rochester Cancer Center
|Exclusion criteria=Patients who: had bilateral breast cancer; previous radiation to the chest or breast area; diagnosis of inflammatory breast cancer; breast reconstruction and/or expanders prior to RT; were taking anti-coagulant therapy (warfarin, coumadin or heparin) or antiepidermal growth factor receptor (EGFR) therapy or were receiving partial breast irradiations
|N randomized=35
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=Assessed at baseline, weekly after every fifth radiotherapy session, at the end of radiotherapy, and at 2 post-radiotherapy appointments (1-month and 6-months post-radiotherapy)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=0 – IV
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=Standard fractionated RT (~1.8–2.4 Gy per session) for four to seven weeks with or without boost for a total radiation dose of ≥ 42 Gy

Prior (n(%)):

* Lumpectomy 27 (90%)

* Mastectomy 3 (10%)

* Chemotherapy before radiation 13 (43.3%)
|Previous cancer therapies=Surgery, Chemotherapy
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) = 58.1 (2.2) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=17
|Drop-out=3
|Drop-out reasons=Patient-initiated n=1, Ineligibility n=1, Non-compliance n=1

Overall reasons for n=5:
* patient-reported hot flashes (1/5)

* undisclosed personal reasons (1/5)

* ineligibility due to concurrent participation in another RT intervention trial (1/5)

* and noncompliance with study procedures (2/5)
|Intervention=Curcumin (Curcumin C3 Complex®)

+ “Standard care” topical agents for radiation dermatitis (i.e., Radiaplex® gel, silvadine, hydrocortisone cream) were allowed
|Dosage and regime=500mg capsules (≥95% curcuminoids), 3 times daily, 4 capsules each time

Duration: 7 weeks (entire radiationtherapy)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=According to information no side effects.
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=18
|Drop-out=2
|Drop-out reasons=Patient-initiated n=1, Non-compliance n=1

Overall reasons for n=5:

* patient-reported hot flashes (1/5)

* undisclosed personal reasons (1/5)

* ineligibility due to concurrent participation in another RT intervention trial (1/5)

* and noncompliance with study procedures (2/5)
|Intervention=Placebo (500 mg calcium hydrogen phosphate and yellow food coloring)

+ “Standard care” topical agents for radiation dermatitis (i.e., Radiaplex® gel, silvadine, hydrocortisone cream) were allowed
|Dosage and regime=3 times daily, 4 capsules each time

Duration: 7 weeks (entire radiationtherapy)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=According to information no side effects.
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Dermatitis
|Outcome specification=Severity of radiodermatitis (skin measurements weekly after the 5th radiationtherapy session)
|Type of measurement=RDS (Radiation Dermatitis Severity)
|Results during intervention=Mean difference:
* Intervention arm – Placebo arm (SD; 95% CI) = -0.8 (0.8, -1.4; -0.2); p = 0.008

Model over time:

* Intervention vs. Placebo (without considering time): p = 0.963, but significant arm/week interaction p = 0.007, i.e., the trend over time is different

* According to the graph, Intervention and Placebo follow a similar trend until week 4, after which the values in the Intervention arm increase less sharply and even decrease slightly in week 7, while the Placebo arm continues to increase
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Dermatitis
|Outcome specification=Moist desquamation
|Type of measurement=Observation
|Results during intervention=Number in %:
* Intervention arm: 28.6%, Placebo arm: 87.5%; p = 0.002
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Dermatitis
|Outcome specification=Redness of skin
|Type of measurement=Observation
|Results during intervention=Intervention vs. placebo (without considering time): p = 0.328

Arm/week interaction: p = 0.588, i.e., no significant differences in the redness trend
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|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=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=NA
|Type of measurement=MPQ-SF (McGill Pain Questionnaire - Short Form), SI (Symptom Inventory questionnaire)
|Results during intervention=Mean change from baseline to end of radiotherapy (95% CI):
* Pain at radiotherapy site: Intervention arm: 1.929 (0.855, 3.002), Placebo arm: 1.313 (0.365, 2.260); p = 0.504

* Other pain: Intervention arm: –0.286 (-1.309, 0.738), Placebo arm: –0.563 (-1.432, 0.307); p = 0.967

MPQ-SF:

* MPQ - total: Intervention arm: 4.643 (2.045, 7.241), Placebo arm: 2.875 (1.543, 4.207); p = 0.144

* Perceived pain: Intervention arm: 0.857 (0.358, 1.356), Placebo arm: 0.813 (0.523, 1.102); p = 0.644

* Sensory pain: Intervention arm: 3.286 (1.217, 5.354), Placebo arm: 1.750 (0.827, 2.673); p = 0.081

* Affective pain: Intervention arm: 0.500 (0.061, 0.939), Placebo arm: 0.375 (-0.008, 0.758); p = 0.550

* No significant differences between intervention and placebo arms

* Considering types of pain: gnawing, aching, splitting (Intervention arm > Placebo arm, p < 0.021), otherwise no significant differences
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Further symptoms of the Symptom Inventory
|Type of measurement=SI (Symptom Inventory questionnaire)
|Results during intervention=No significant differences (nausea, vomiting, depression, shortness of breath, memory, appetite, diarrhea, urination, skin, sleep, fatigue, activity, mood, work, relationships, walking, quality of life)
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding="This study was supported by the FDA IND no. 75,444; NCI PHS grant 1R25CA10618; Dermatology Foundation Research Career Development Award; and URMC CTSI KL2-RR024136. A special thanks to all of the patients with breast cancer who participated in this clinical trial. We thank the Radiation Oncology Red and Yellow Service team members and the Departments of Radiation Oncology and Dermatology for assistance and support of this study."
|Conflicts of Interest=See Funding.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=NI
|Sample size corresponds to power analysis=NI
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NA
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethical approval obtained
* Double-blind with control (Intervention arm: 5/14 (35.7%) of patients think they are in the curcumin arm, placebo arm: 2/16 (12.5%) of patients think they are in the placebo arm).
* High comparable compliance rates (Mean (SD): Intervention arm: 96.6% (6.6%), Placebo arm: 98.4% (3.2%); p = 0.344)
* Assessment of expected and actual pain at baseline

CONTRA:
* Very small sample size
* Dropout rate: Intervention arm: 18%, Placebo arm: 11%
* No intention-to-treat analysis
* No control for multiple testing
}}

Rao et al. (2014): The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study

2024-11-21T14:24:44Z

CHoppe:

{{Reference
|Reference=Publication: The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study
}}
=Brief summary=
This study investigated the efficacy of a curcumin mouth rinse compared to a povidone-iodine mouth rinse in patients with head and neck cancer during radiotherapy. Throughout radiotherapy, mucositis (an inflammation of the mucosa, a common adverse side effect of radiotherapy) was less severe in the curcumin arm than in the other arm. There were also fewer overall cases of intolerable mucositis in the curcumin arm. In addition, curcumin patients lost less weight on average than the others. No differences were found with regard to the number of patients who had to interrupt treatment and the average duration of the interruption.

In dieser Studie wurden die Wirksamkeit einer Curcumin-Mundspülung im Vergleich zu einer Povidon-Iod-Mundspülung bei Patienten mit Kopf-Hals-Tumor während der Radiotherapie untersucht. Über die gesamte Radiotherapie hinweg war Mukositis (eine Entzündung der Schleimhaut, eine häufige unerwünschte Nebenwirkung von Radiotherapie) in der Curcumin-Gruppe weniger schwerwiegend als in der anderen Gruppe. In der Curcumin-Gruppe gab es auch insgesamt weniger Fälle von unerträglicher Mukositis. Zudem verloren Curcumin-Patienten im Durchschnitt weniger Gewicht als die anderen. Keine Gruppenunterschiede fanden sich hinsichtlich der Anzahl an Patienten, bei denen eine Therapieunterbrechung nötig war und hinsichtlich der durchschnittlichen Dauer der Unterbrechung.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=NI
|Exclusion criteria=Infected tooth, ulcers, or mucositis of the oral cavity
|N randomized=80
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=India
|LoE=1b Oxford 2009
|Outcome timeline=Mucositis was assessed before the start of the radiation treatment and at weekly intervals
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers
|Stage cancer=Early Stage
|Cancer stage specification=T1-TX, N0-NX, M0-MX
|Comorbidity=NI
|Current cancer therapy=Surgery, Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Only radiation therapy, radiation therapy + chemotherapy or radiation therapy + chemotherapy + surgery
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=20% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD, range) = 55.96 (12.25, 26-85) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=40
|Drop-out=1
|Drop-out reasons=Personal reasons
|Intervention=Curcumin solution

+ Standard oral, dental, medical, and supportive care was provided to all subjects of both cohorts by a qualified dental physician. The patients were also instructed to clean their teeth with a soft toothbrush 4 times a day
|Dosage and regime=Curcumin solution; 1 capsule with 400g curcumin powder dissolved in approximately 80ml water (prepared by the nurse), 10ml as a mouthwash (4 times for 2 minutes each)

Start: Day 1 radiotherapy, 6 times daily

Duration: 7 weeks
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=40
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Povidone-iodine solution

+ Standard oral, dental, medical, and supportive care was provided to all subjects of both cohorts by a qualified dental physician. The patients were also instructed to clean their teeth with a soft toothbrush 4 times a day
|Dosage and regime=Povidone-iodine solution (diluted 1:100; 1ml Betadine, 100ml water), Mouthwash, 10ml twice daily

Duration: 6 weeks
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Oral Mucositis
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=Weeks 1-7:
* Curcumin arm < Povidone-iodine arm; p < 0.001, derived from graph only, no values provided

Cases of intolerable mucositis:

* Curcumin arm: 14/39, Povidone-iodine arm: 34/40; p < 0.0001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=Number (%) of patients requiring therapy interruption:
* Curcumin arm: 7 (17.95%), Povidone-iodine arm: 9 (24%) ns.

Number of days lost: mean (SD)

* Curcumin arm: 7 (0), Povidone-iodine arm: 7.25 (0.56) ns.

Weight loss: mean (SD)

* Curcumin arm: 3.92 (2.13), Povidone-iodine arm: 4.45 (2.15); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=According to information none.
|Conflicts of Interest=According to authors no conflict of interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* Intervention arm has to rinse its mouth much more often than comparison arm, and this increased rinsing frequency could potentially affect the results
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NA
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained
* Active control
* Large sample size according to power analysis calculation
* Low dropout (Curcumin arm: 2.5%, Povidone-iodine arm: 0%)

CONTRA:
* Curcumin arm must rinse mouth much more frequently than Povidone-iodine arm
* Poor reporting quality (e.g., some numbers can only be derived from graphs)
}}

Rao et al. (2014): The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study

2024-11-21T14:24:34Z

CHoppe:

{{Reference
|Reference=Publication: The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of a curcumin mouth rinse compared to a povidone-iodine mouth rinse in patients with head and neck cancer during radiotherapy. Throughout radiotherapy, mucositis (an inflammation of the mucosa, a common adverse side effect of radiotherapy) was less severe in the curcumin arm than in the other arm. There were also fewer overall cases of intolerable mucositis in the curcumin arm. In addition, curcumin patients lost less weight on average than the others. No differences were found with regard to the number of patients who had to interrupt treatment and the average duration of the interruption.

In dieser Studie wurden die Wirksamkeit einer Curcumin-Mundspülung im Vergleich zu einer Povidon-Iod-Mundspülung bei Patienten mit Kopf-Hals-Tumor während der Radiotherapie untersucht. Über die gesamte Radiotherapie hinweg war Mukositis (eine Entzündung der Schleimhaut, eine häufige unerwünschte Nebenwirkung von Radiotherapie) in der Curcumin-Gruppe weniger schwerwiegend als in der anderen Gruppe. In der Curcumin-Gruppe gab es auch insgesamt weniger Fälle von unerträglicher Mukositis. Zudem verloren Curcumin-Patienten im Durchschnitt weniger Gewicht als die anderen. Keine Gruppenunterschiede fanden sich hinsichtlich der Anzahl an Patienten, bei denen eine Therapieunterbrechung nötig war und hinsichtlich der durchschnittlichen Dauer der Unterbrechung.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=NI
|Exclusion criteria=Infected tooth, ulcers, or mucositis of the oral cavity
|N randomized=80
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=India
|LoE=1b Oxford 2009
|Outcome timeline=Mucositis was assessed before the start of the radiation treatment and at weekly intervals
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers
|Stage cancer=Early Stage
|Cancer stage specification=T1-TX, N0-NX, M0-MX
|Comorbidity=NI
|Current cancer therapy=Surgery, Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Only radiation therapy, radiation therapy + chemotherapy or radiation therapy + chemotherapy + surgery
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=20% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD, range) = 55.96 (12.25, 26-85) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=40
|Drop-out=1
|Drop-out reasons=Personal reasons
|Intervention=Curcumin solution

+ Standard oral, dental, medical, and supportive care was provided to all subjects of both cohorts by a qualified dental physician. The patients were also instructed to clean their teeth with a soft toothbrush 4 times a day
|Dosage and regime=Curcumin solution; 1 capsule with 400g curcumin powder dissolved in approximately 80ml water (prepared by the nurse), 10ml as a mouthwash (4 times for 2 minutes each)

Start: Day 1 radiotherapy, 6 times daily

Duration: 7 weeks
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=40
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Povidone-iodine solution

+ Standard oral, dental, medical, and supportive care was provided to all subjects of both cohorts by a qualified dental physician. The patients were also instructed to clean their teeth with a soft toothbrush 4 times a day
|Dosage and regime=Povidone-iodine solution (diluted 1:100; 1ml Betadine, 100ml water), Mouthwash, 10ml twice daily

Duration: 6 weeks
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Oral Mucositis
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=Weeks 1-7:
* Curcumin arm < Povidone-iodine arm; p < 0.001, derived from graph only, no values provided

Cases of intolerable mucositis:

* Curcumin arm: 14/39, Povidone-iodine arm: 34/40; p < 0.0001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=Number (%) of patients requiring therapy interruption:
* Curcumin arm: 7 (17.95%), Povidone-iodine arm: 9 (24%) ns.

Number of days lost: mean (SD)

* Curcumin arm: 7 (0), Povidone-iodine arm: 7.25 (0.56) ns.

Weight loss: mean (SD)

* Curcumin arm: 3.92 (2.13), Povidone-iodine arm: 4.45 (2.15); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=According to information none.
|Conflicts of Interest=According to authors no conflict of interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* Intervention arm has to rinse its mouth much more often than comparison arm, and this increased rinsing frequency could potentially affect the results
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NA
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained
* Active control
* Large sample size according to power analysis calculation
* Low dropout (Curcumin arm: 2.5%, Povidone-iodine arm: 0%)

CONTRA:
* Curcumin arm must rinse mouth much more frequently than Povidone-iodine arm
* Poor reporting quality (e.g., some numbers can only be derived from graphs)
}}

Mansourian et al. (2015): The effect of "curcuma Longa" topical gel on radiation -induced oral mucositis in patients with head and neck cancer

2024-11-21T14:21:35Z

CHoppe:

{{Reference
|Reference=Publication: The effect of "curcuma Longa" topical gel on radiation -induced oral mucositis in patients with head and neck cancer
}}
=Brief summary=
In this study, patients with head and neck tumors were examined during radiotherapy. The patients were instructed to apply a gel to the entire oral cavity 3 times a day, with half receiving a curcumin gel and the other half a placebo gel. There were more cases of severe mucositis (an inflammation of the mucous membrane, a common adverse side effect of radiotherapy) in the curcumin arm than in the placebo arm. In addition, patients in the curcumin arm reported less burning in the mouth and had less redness of the oral mucosa and minor mouth ulcers. There are some criticisms of this study. Only a very small sample was examined and it cannot be ruled out that the two arms differed at the beginning of the study because very few characteristics of the patients were reported at the beginning of the study. In addition, the quality of reporting in the study was generally poor; for example, there was no information on the extent to which the patients used the gels as instructed.

In dieser Studie wurden Patienten mit Kopf-Hals-Tumor während der Radiotherapie untersucht. Die Patienten bekamen die Anweisung 3 Mal täglich den gesamten Mundraum mit einem Gel zu bestreichen, wobei die eine Hälfte ein Curcumin-Gel bekam und die andere Hälfte ein Placebo-Gel. In der Curcumin-Gruppe gab es mehr Fälle von schwerer Mukositis (eine Entzündung der Schleimhaut, eine häufige unerwünschte Nebenwirkung von Radiotherapie) als in der Placebo-Gruppe. Zudem berichteten die Patienten der Curcumin-Gruppe geringeres Brennen im Mund und hatten kleinere Hautrötungen der Mundschleimhaut und kleinere Geschwüre im Mund. An dieser Studie gibt es einige Kritikpunkte. Es wurde nur eine sehr kleine Stichprobe untersucht und es ist nicht ausgeschlossen, dass sich die beiden Gruppen zur Beginn der Studie unterschieden haben, weil nur sehr wenige Charakteristiken der Patienten zu Beginn der Studie berichtet wurden. Zudem hat die Studie allgemein eine schlechte Berichtqualität, es fehlt zum Beispiel die Angabe, inwiefern die Patienten die Gels so verwendet haben, wie es vorgegeben war.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Minimum age of 18 years, presence of head and neck cancer, minimum radiation dose of 50 Gy (the least dose resulting in mucositis), the ability of patient to use topical gel (by his/her or examiner’s report), minimally 50% of patient’s oral cavity in radiation field (according to the radiotherapist’s opinion)
|Exclusion criteria=History of radiation therapy or chemotherapy in previous year, chemotherapy protocol in addition to radiotherapy, any allergy to condiments, especially "Turmeric root", any complications due to the use of topical gel during the study, suffering from any kind of oral disease such as active oral infection, ulcer, having any systemic disease or taking any medication
|N randomized=37
|Analysis=ITT Analysis
|Specifications on analyses=ITT not specified, but no drop-out reported.
|Countries of data collection=Iran
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline
T1-T3: Tag 7, 14, 21
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=16% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 51.34 (12.08) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=19
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Curcumin
|Dosage and regime=Topical turmeric gel (0.5%); Coat entire mouth with gel 3 times a day

Start: day 0 radiotherapy

Duration: entire radiotherapy (21 days)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=18
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo Gel
|Dosage and regime=Coat entire mouth with gel 3 times a day

Start: day 0 radiotherapy

Duration: entire radiotherapy (21 days)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=NA
|Type of measurement=Observation, WHO-Scale (World Health Organisation)
|Results during intervention=Max. degree of mucositis (number (%) of patients):
* Grade 1: Intervention arm: 15 (78.9%), Placebo arm: 3 (16.7%)

* Grade 2: Intervention arm: 4 (21.1%), Placebo arm: 8 (44.4%)

* Grade 3: Intervention arm: 0 (0%), Placebo arm: 7 (38.9%)

* Grade 4: Intervention arm and Placebo arm: 0

* Difference between arms in distribution of grades: p < 0.001

* Time between T0 and onset of max. mucositis: no numbers given; p = 0.315

Incidence of max. mucositis (number (%)):
* 7 days: Intervention arm: 4 (21.1%), Placebo arm: 8 (44.4%)

* 14 days: Intervention arm: 6 (31.6%), Placebo arm: 4 (22.2%)

* 21 days: Intervention arm: 9 (47.4%), Placebo arm: 6 (33.3%)
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Burning Sensation in the mouth
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=Mean (SD)
* Intervention arm: 3.7 (2.1), Placebo arm: 7.9 (2.0); p < 0.001
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Erythema
|Outcome specification=Oral mucosal erythema
|Type of measurement=Observation
|Results during intervention=Max. size in mm (Mean (SD)):
* Intervention arm: 4.9 (2.2), Placebo arm: 8.9 (2.7); p < 0.001
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Oral ulcus
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=Max. size in mm (Mean [SD]):
* Intervention arm: 1.3 (2.7), Placebo arm: 6.4 (4.2); p < 0.001
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=According to authors no conflict of interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* Possible baseline differences cannot be excluded, hardly any information on baseline characteristics (only gender, age and radiotherapy dose)

* Poor report quality (e.g. no information on how cancer types are distributed between the arms, no information on dropout and compliance)
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=NI
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NA
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained
* Double-blinding

CONTRA:
* Small sample size
* No power analysis
* Possible baseline differences cannot be ruled out
* Limited information on baseline characteristics (only gender, age, and radiotherapy dose)
* Poor reporting quality (e.g., no information on cancer types distribution between arms, no data on dropout and compliance)
}}

Mansourian et al. (2015): The effect of "curcuma Longa" topical gel on radiation -induced oral mucositis in patients with head and neck cancer

2024-11-21T14:21:23Z

CHoppe:

{{Reference
|Reference=Publication: The effect of "curcuma Longa" topical gel on radiation -induced oral mucositis in patients with head and neck cancer
}}
{{Study Note}}
=Brief summary=
In this study, patients with head and neck tumors were examined during radiotherapy. The patients were instructed to apply a gel to the entire oral cavity 3 times a day, with half receiving a curcumin gel and the other half a placebo gel. There were more cases of severe mucositis (an inflammation of the mucous membrane, a common adverse side effect of radiotherapy) in the curcumin arm than in the placebo arm. In addition, patients in the curcumin arm reported less burning in the mouth and had less redness of the oral mucosa and minor mouth ulcers. There are some criticisms of this study. Only a very small sample was examined and it cannot be ruled out that the two arms differed at the beginning of the study because very few characteristics of the patients were reported at the beginning of the study. In addition, the quality of reporting in the study was generally poor; for example, there was no information on the extent to which the patients used the gels as instructed.

In dieser Studie wurden Patienten mit Kopf-Hals-Tumor während der Radiotherapie untersucht. Die Patienten bekamen die Anweisung 3 Mal täglich den gesamten Mundraum mit einem Gel zu bestreichen, wobei die eine Hälfte ein Curcumin-Gel bekam und die andere Hälfte ein Placebo-Gel. In der Curcumin-Gruppe gab es mehr Fälle von schwerer Mukositis (eine Entzündung der Schleimhaut, eine häufige unerwünschte Nebenwirkung von Radiotherapie) als in der Placebo-Gruppe. Zudem berichteten die Patienten der Curcumin-Gruppe geringeres Brennen im Mund und hatten kleinere Hautrötungen der Mundschleimhaut und kleinere Geschwüre im Mund. An dieser Studie gibt es einige Kritikpunkte. Es wurde nur eine sehr kleine Stichprobe untersucht und es ist nicht ausgeschlossen, dass sich die beiden Gruppen zur Beginn der Studie unterschieden haben, weil nur sehr wenige Charakteristiken der Patienten zu Beginn der Studie berichtet wurden. Zudem hat die Studie allgemein eine schlechte Berichtqualität, es fehlt zum Beispiel die Angabe, inwiefern die Patienten die Gels so verwendet haben, wie es vorgegeben war.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Minimum age of 18 years, presence of head and neck cancer, minimum radiation dose of 50 Gy (the least dose resulting in mucositis), the ability of patient to use topical gel (by his/her or examiner’s report), minimally 50% of patient’s oral cavity in radiation field (according to the radiotherapist’s opinion)
|Exclusion criteria=History of radiation therapy or chemotherapy in previous year, chemotherapy protocol in addition to radiotherapy, any allergy to condiments, especially "Turmeric root", any complications due to the use of topical gel during the study, suffering from any kind of oral disease such as active oral infection, ulcer, having any systemic disease or taking any medication
|N randomized=37
|Analysis=ITT Analysis
|Specifications on analyses=ITT not specified, but no drop-out reported.
|Countries of data collection=Iran
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline
T1-T3: Tag 7, 14, 21
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=16% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 51.34 (12.08) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=19
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Curcumin
|Dosage and regime=Topical turmeric gel (0.5%); Coat entire mouth with gel 3 times a day

Start: day 0 radiotherapy

Duration: entire radiotherapy (21 days)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=18
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo Gel
|Dosage and regime=Coat entire mouth with gel 3 times a day

Start: day 0 radiotherapy

Duration: entire radiotherapy (21 days)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=NA
|Type of measurement=Observation, WHO-Scale (World Health Organisation)
|Results during intervention=Max. degree of mucositis (number (%) of patients):
* Grade 1: Intervention arm: 15 (78.9%), Placebo arm: 3 (16.7%)

* Grade 2: Intervention arm: 4 (21.1%), Placebo arm: 8 (44.4%)

* Grade 3: Intervention arm: 0 (0%), Placebo arm: 7 (38.9%)

* Grade 4: Intervention arm and Placebo arm: 0

* Difference between arms in distribution of grades: p < 0.001

* Time between T0 and onset of max. mucositis: no numbers given; p = 0.315

Incidence of max. mucositis (number (%)):
* 7 days: Intervention arm: 4 (21.1%), Placebo arm: 8 (44.4%)

* 14 days: Intervention arm: 6 (31.6%), Placebo arm: 4 (22.2%)

* 21 days: Intervention arm: 9 (47.4%), Placebo arm: 6 (33.3%)
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Burning Sensation in the mouth
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=Mean (SD)
* Intervention arm: 3.7 (2.1), Placebo arm: 7.9 (2.0); p < 0.001
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Erythema
|Outcome specification=Oral mucosal erythema
|Type of measurement=Observation
|Results during intervention=Max. size in mm (Mean (SD)):
* Intervention arm: 4.9 (2.2), Placebo arm: 8.9 (2.7); p < 0.001
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Oral ulcus
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=Max. size in mm (Mean [SD]):
* Intervention arm: 1.3 (2.7), Placebo arm: 6.4 (4.2); p < 0.001
|Results after intervention=NA
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=According to authors no conflict of interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* Possible baseline differences cannot be excluded, hardly any information on baseline characteristics (only gender, age and radiotherapy dose)

* Poor report quality (e.g. no information on how cancer types are distributed between the arms, no information on dropout and compliance)
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=NI
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NA
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained
* Double-blinding

CONTRA:
* Small sample size
* No power analysis
* Possible baseline differences cannot be ruled out
* Limited information on baseline characteristics (only gender, age, and radiotherapy dose)
* Poor reporting quality (e.g., no information on cancer types distribution between arms, no data on dropout and compliance)
}}

Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study

2024-11-21T14:20:29Z

CHoppe:

{{Reference
|Reference=Publication: Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study
}}
{{Study Note
|Study Note=One study in two publications. Further endpoints are reported in [[Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer]].
}}
=Brief summary=
Prostate cancer patients were examined in this study. One half took curcumin capsules three times a day during radiotherapy and the other half took placebo capsules instead. In the first study of [[Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer]], the quality of life of the patients was examined. The curcumin arm reported fewer urinary-related symptoms that limited quality of life. No differences were found with regard to bladder-related and treatment-related symptoms or sexual activity. In the second study of [[Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study]], there were no significant differences between the arms in the development of prostate specific antigen (PSA; an important marker in prostate cancer) in the blood over the course of the study. Positive aspects of these studies were the double blinding (patients/investigators do not know which arm they belong to), the low drop-out rate and that the majority of patients took the curcumin/placebo as prescribed. Overall, however, it was a very small sample and the two arms differed slightly even at the beginning of the study. In addition, other endpoints were reported than described in the study protocol.

In dieser Studie Prostatakarzinompatienten untersucht. Eine Hälfte nahm während der Radiotherapie drei Mal täglich Curcumin-Kapseln ein und die andere Hälfte stattdessen Placebo-Kapseln. In der ersten Studie von [[Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer]] wurde die Lebensqualität der Patienten betrachtet. Die Curcumin-Gruppe berichtete weniger harnbezogenen Symptome, die die Lebensqualität einschränkten. Keine Unterschiede fanden sich hinsichtlich blasenbezogenen und behandlungsbezogenen Symptome sowie hinsichtlich der sexuellen Aktivität. In der zweiten Studie von [[Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study]] zeigten sich zwischen den Gruppen keine bedeutsamen Unterschiede hinsichtlich der Entwicklung des Prostataspezifisches Antigens (PSA; ein wichtiger Marker beim Prostatakrebs) im Blut über die Studie hinweg. Positiv an diesen Studien war die doppelte Verblindung (Patienten/Untersucher wissen nicht, welcher Gruppe sie angehören), die geringe Ausfallrate und dass die Mehrheit der Patienten das Curcumin/Placebo eingenommen hat, wie vorgegeben. Insgesamt war es jedoch nur eine sehr kleine Stichprobe und beiden Gruppen haben sich schon zu Beginn der Studie leicht unterschieden. Zudem wurden andere Endpunkte berichtet, als im Studienprotokoll beschrieben.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Patients referred to local curative radiotherapy with external beam radiotherapy (EBRT), in combination with hormone ablation; Adenocarcinoma of the prostate must be histologically confirmed on biopsy; life expectancy greater than 5 years; no metastatic disease detected during physical examination, standard radiography, bone scan, and magnetic resonance spectroscopy (MRS); no prior hormone therapy, radiotherapy or systemic treatment for prostate cancer and no other malignancy
|Exclusion criteria=Clinical stage T3 or T4, Gleason score ≥ 8, serum PSA ≥ 20 ng/mL, other prior surgery for prostate cancer, concurrent participation in another clinical trial which would require approval upon entry to this trial, gastrointestinal disorders such as inflammatory bowel disease, reflux and peptic ulcers and any adverse reaction to curcumin
|N randomized=45
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=Iran
|LoE=1b Oxford 2009
|Outcome timeline=T0: week -1 radiotherapy
T1: 3 months after radiotherapy (20 weeks after T0)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=Early Stage
|Cancer stage specification=T1-2, M0
|Comorbidity=NI
|Current cancer therapy=Hormone therapy, Radiation therapy
|Specifications on cancer therapies=External beam radiotherapy (EBRT), in combination with hormone ablation
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 70.74 (8.21) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=22
|Drop-out=2
|Drop-out reasons=Withdrew during intervention
|Intervention=Curcumin
|Dosage and regime=BCM95, Biocurcumin (each capsule contained 440mg curcuminoids (347mg curcumin, 84mg desmethoxycurcumin, and 9mg bisdesmethoxycurcumin) and essential oil of turmeric 38mg)

Orally, 2 capsules 3 times a day

Start: week -1 radiotherapy

Duration: until the end of radiotherapy, approx. 9 weeks in total
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=According to information no side effects
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=23
|Drop-out=3
|Drop-out reasons=Withdrew during intervention
|Intervention=Placebo
|Dosage and regime=Orally, 2 capsules 3 times a day (each capsule contained 500mg roasted rice flour)
Start: week -1 radiotherapy

Duration: until the end of radiotherapy, approx. 9 weeks in total
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=According to information no side effect
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=During 1 year
|Type of measurement=Blood Test, Observation
|Results during intervention=NA
|Results after intervention=PSA level (ng/ml) within 3 months:
* Mean change (SD): Intervention arm 0.12 ( 0.16), placebo arm: 0.13 (0.06); p = 0.78

* No information on PFS within one year
|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=some concerns
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding="This study was funded by grants from National Nutrition and Food Technology Research Institute, Iran National Science Foundation, and research deputy of Shahid Beheshti University of Medical Sciences."
|Conflicts of Interest="This study was part of PhD dissertation by the first author and was supported by the research grants from National Nutrition and Food Technology Research Institute, Iran National Science Foundation, and research deputy of Shahid Beheshti University of Medical Sciences. We gratefully acknowledge Arjuna Natural Extracts Ltd for providing the curcumin capsules and placebos."
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=Pilot Trial
|Samples sufficiently large=No
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained
* Double-blinding
* High compliance
* Acceptable dropout (10% & 15%)
* Intention-to-treat analysis conducted
* No baseline differences in Quality of Life

CONTRA:
* Small sample size
* No power analysis calculated
* Baseline differences between arms (total antioxidant capacity; p = 0.045)
* Different endpoints calculated than described in the study protocol; primary endpoints were Progression free survival and PSA after one year, but the studies only reported Quality of life and PSA value after three months
* Poor reporting quality
}}

Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer

2024-11-21T14:19:54Z

CHoppe:

{{Reference
|Reference=Publication: A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer
}}
{{Study Note
|Study Note=One study in two publications. Further endpoints are reported in [[Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study]].
}}
=Brief summary=
Prostate cancer patients were examined in this study. One half took curcumin capsules three times a day during radiotherapy and the other half took placebo capsules instead. In the first study of [[Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer]], the quality of life of the patients was examined. The curcumin arm reported fewer urinary-related symptoms that limited quality of life. No differences were found with regard to bladder-related and treatment-related symptoms or sexual activity. In the second study of [[Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study]], there were no significant differences between the arms in the development of prostate specific antigen (PSA; an important marker in prostate cancer) in the blood over the course of the study. Positive aspects of these studies were the double blinding (patients/investigators do not know which arm they belong to), the low drop-out rate and that the majority of patients took the curcumin/placebo as prescribed. Overall, however, it was a very small sample and the two arms differed slightly even at the beginning of the study. In addition, other endpoints were reported than described in the study protocol.

In dieser Studie Prostatakarzinompatienten untersucht. Eine Hälfte nahm während der Radiotherapie drei Mal täglich Curcumin-Kapseln ein und die andere Hälfte stattdessen Placebo-Kapseln. In der ersten Studie von [[Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer]] wurde die Lebensqualität der Patienten betrachtet. Die Curcumin-Gruppe berichtete weniger harnbezogenen Symptome, die die Lebensqualität einschränkten. Keine Unterschiede fanden sich hinsichtlich blasenbezogenen und behandlungsbezogenen Symptome sowie hinsichtlich der sexuellen Aktivität. In der zweiten Studie von [[Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study]] zeigten sich zwischen den Gruppen keine bedeutsamen Unterschiede hinsichtlich der Entwicklung des Prostataspezifisches Antigens (PSA; ein wichtiger Marker beim Prostatakrebs) im Blut über die Studie hinweg. Positiv an diesen Studien war die doppelte Verblindung (Patienten/Untersucher wissen nicht, welcher Gruppe sie angehören), die geringe Ausfallrate und dass die Mehrheit der Patienten das Curcumin/Placebo eingenommen hat, wie vorgegeben. Insgesamt war es jedoch nur eine sehr kleine Stichprobe und beiden Gruppen haben sich schon zu Beginn der Studie leicht unterschieden. Zudem wurden andere Endpunkte berichtet, als im Studienprotokoll beschrieben.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Patients referred to local curative radiotherapy with external beam radiotherapy (EBRT), in combination with hormone ablation; Adenocarcinoma of the prostate must be histologically confirmed on biopsy; life expectancy greater than 5 years; no metastatic disease detected during physical examination, standard radiography, bone scan, and magnetic resonance spectroscopy (MRS); no prior hormone therapy, radiotherapy or systemic treatment for prostate cancer and no other malignancy
|Exclusion criteria=Clinical stage T3 or T4, Gleason score ≥ 8, serum PSA ≥ 20 ng/mL, other prior surgery for prostate cancer, concurrent participation in another clinical trial which would require approval upon entry to this trial, gastrointestinal disorders such as inflammatory bowel disease, reflux and peptic ulcers and any adverse reaction to curcumin
|N randomized=45
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=Iran
|LoE=1b Oxford 2009
|Outcome timeline=T0: week -1 radiotherapy

T1: 3 months after radiotherapy (20 weeks after T0)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=Early Stage
|Cancer stage specification=T1-2, M0
|Comorbidity=NI
|Current cancer therapy=Hormone therapy, Radiation therapy
|Specifications on cancer therapies=External beam radiotherapy (EBRT), in combination with hormone ablation
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 70.74 (8.21) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=22
|Drop-out=2
|Drop-out reasons=Withdrew during intervention
|Intervention=Curcumin
|Dosage and regime=BCM95, Biocurcumin (each capsule contained 440mg curcuminoids (347mg curcumin, 84mg desmethoxycurcumin, and 9mg bisdesmethoxycurcumin) and essential oil of turmeric 38mg)

Orally, 2 capsules 3 times a day

Start: week -1 radiotherapy

Duration: until the end of radiotherapy, approx. 9 weeks in total
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=According to information no side effects
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=23
|Drop-out=3
|Drop-out reasons=Withdrew during intervention
|Intervention=Placebo
|Dosage and regime=Orally, 2 capsules 3 times a day (each capsule contained 500mg roasted rice flour)

Start: week -1 radiotherapy

Duration: until the end of radiotherapy, approx. 9 weeks in total
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=According to information no side effect
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Quality of life
|Outcome specification=With EORTC QLQ-PR25
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=NA
|Results after intervention=Three month after radiotherapy mean difference intervention vs. placebo arm (controlled for baseline value) (95% CI):

* Urinary symptoms: -14.1 (-24.7, -3.4); p = 0.011; intervention significantly fewer symptoms than placebo arm

* Bladder symptoms: 5.4 (-4.5, 15.4); p = 0.275

* Treatment-related symptoms: 7.9 (-3.1, 18.9); p = 0.155

* Sexual activity: -3.5 (-19.0, 12.0); p = 0.652
|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=some concerns
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding="This study was funded by grants from National Nutrition and Food Technology Research Institute, Iran National Science Foundation, and research deputy of Shahid Beheshti University of Medical Sciences."
|Conflicts of Interest="This study was part of PhD dissertation by the first author and was supported by the research grants from National Nutrition and Food Technology Research Institute, Iran National Science Foundation, and research deputy of Shahid Beheshti University of Medical Sciences. We gratefully acknowledge Arjuna Natural Extracts Ltd for providing the curcumin capsules and placebos."
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=Pilot trial
|Samples sufficiently large=No
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained
* Double-blinding
* High compliance
* Acceptable dropout (10% & 15%)
* Intention-to-treat analysis conducted
* No baseline differences in quality of life

CONTRA:
* Small sample size
* No power analysis calculated
* Baseline differences between arms (total antioxidant capacity; p = 0.045)
* Different endpoints calculated than described in the study protocol; primary endpoints were Progression free survival and PSA after one year, but the study only reported Quality of life and PSA value after three months
* Poor reporting quality
}}

Niravath et al. (2019): Randomized controlled trial of high‐dose versus standard‐dose vitamin D3 for prevention of aromatase inhibitor‐induced arthralgia

2024-11-07T12:27:12Z

CHoppe:

{{Reference
|Reference=Publication: Randomized controlled trial of high‐dose versus standard‐dose vitamin D3 for prevention of aromatase inhibitor‐induced arthralgia
}}
{{Study Note}}
=Brief summary=
The study included 93 patients with breast cancer who were undergoing aromatase inhibitor therapy. Randomly divided into 2 arms, about half of the patients received high doses of vitamin D3, while the other arm received a standard dose. Symptoms of arthralgia syndrome (mainly joint pain) were recorded. There were no differences between the arms after 12 and 52 weeks. Due to the lack of effect after 12 weeks, no further patients were recruited, which is too small a sample size in view of previous studies in this area. The study also has a lot of missing data from patients, as they did not complete the questionnaires at all times.

In der Studie wurden 93 Patienten mit Brustkrebs eingeschlossen, die einer Aromatasehemmer-Therapie unterzogen wurden. Zufällig in 2 Gruppen eingeteilt erhielt etwa die Hälfte der Patientinnen hochdosiert Vitamin D3, während der andere Arm eine Standarddosis erhielt. Erhoben wurden Symptome eines Arthralgiesyndroms (vorwiegend Gelenkschmerzen). Nach 12 und 52 Wochen zeigten sich keine Unterschiede zwischen den Armen. Aufgrund des Fehlen des Effektes nach 12 Wochen wurden keine weiteren Patienten rekrutiert, was in Anbetracht vorheriger Studien in dem Bereich zu einer zu kleinen Stichprobe führt. Die Studie hat zudem viele fehlende Daten von Patienten, da diese nicht zu jedem Zeitpunkt die Fragebögen ausgefüllt haben.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=≥ 21 years old, with stage I-III hormone receptor-positive breast cancer, who were beginning adjuvant aromatase inhibitor therapy;
post-menopausal, defined as any of the following: age ≥ 60 years old; history of bilateral oophorectomy; or serum estradiol and FSH concentrations in the post-menopausal range, along with either amenorrhea for 12 months or previous hysterectomy; if the patient was < 60 years old at the time of study enrollment and had completed chemo- therapy, post-menopausal status had to have been confirmed prior to chemotherapy
|Exclusion criteria=Aromatase inhibitor therapy in the last 6 weeks, history of kidney stones, hypercalcemia at baseline, history of symptomatic hypercalcemia or hyperparathyroidism, baseline 25-OH Vitamin D level >50 ng/mL, currently taking phenytoin or phenobarbital, currently taking cholestyramine or orlistat, malabsorption syndrome, or chronic granulomata forming disorders, such as sarcoidosis or tuberculosis
|N randomized=93
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=93 patients were evaluable for efficacy analysis;
because six patients did not start treatment with vitamin D, only 87 patients were evaluable for safety
|Countries of data collection=United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline
T1: week 12
T2: week 52
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Stage I-III
|Comorbidity=NI
|Current cancer therapy=Hormone therapy
|Specifications on cancer therapies=Aromatase inhibitor therapy
|Previous cancer therapies=Chemotherapy, Hormone therapy
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Median (range): 64 (44-82)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=46
|Drop-out=5
|Drop-out reasons=n=4 not start treatment (n=3 withdrew consent, n=1 ineligible);
n=1 not complete 12 weeks, found ineligible
|Intervention=High-dose vitamin D
|Dosage and regime=50,000 International Units (IU) oral vitamin D3 per week for 12 weeks followed by 2000 IU daily for 40 weeks

+ all patients: calcium carbonate 600 mg daily
|One-time application=No
|Duration in days=364
|Side Effects / Interactions=No grade 4 or grade 5 adverse events, n=1 renal stones, 4 grade 3 events (deemed to be unrelated to the study drugs)
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=47
|Drop-out=5
|Drop-out reasons=n=2 not start treatment (withdrew consent);
n=3 not complete 12 weeks (n=2 withdrew consent, n=1 non-compliant)
|Intervention=Standard-dose vitamin D
|Dosage and regime=800 IU Vitamin D3 daily for 52 weeks

+ all patients: calcium carbonate 600 mg daily
|One-time application=No
|Duration in days=364
|Side Effects / Interactions=No grade 4 or grade 5 adverse events, n=1 hypercalcemia, 8 grade 3 events (deemed to be unrelated to the study drugs)
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Aromatase inhibitor-induced arthralgia
|Type of measurement=HAQ-DI (Health Assessment Questionnaire-Disability Index), VAS (Visual Analogue Scale)
|Results during intervention=At 12 weeks: no significant differences;
At 52 weeks: no significant differences
|Results after intervention=NI
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Interaction with cancer treatment
|Outcome specification=Compliance with aromatase inhibitor therapy, measured by pill counts
|Type of measurement=Observation
|Results during intervention=No statistical tests because of low numbers of patients (control arm: 96.5% vs. intervention arm: 98.1%)
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Vitamin D level
|Outcome specification=Correlation of low- baseline vitamin D levels with development of aromatase inhibitor-induced arthralgia
|Type of measurement=Blood Test
|Results during intervention=At 12 weeks: mean vitamin D level in control arm was 29.3 ng/mL, compared to 50 ng/mL in intervention arm, increase and the week 12 level were both significantly higher in the intervention arm (p<0.0001 for both comparisons);

No correlation between vitamin D level and development of aromatase inhibitor-induced arthralgia
|Results after intervention=NI
|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
|Order number=3
}}
{{Outcome
|Outcome type=Others
|Outcome name=Hand grip strength
|Outcome specification=Explorative endpoint
|Type of measurement=NI
|Results during intervention=No significant difference between patients who did develop aromatase inhibitor-induced arthralgia and those patients who did not develop aromatase inhibitor-induced arthralgia
|Results after intervention=NI
|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
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=See conflicts of Interests
|Conflicts of Interest=Dr. Nangia has had a consultant/advisory role with Puma, and she has received funding from Paxman Coolers. Dr. Ade- muyiwa has had a consultant/advisory role with Immunomedics, AstraZeneca, Jounce, Eisai, and Best Doctors; she has received funding from Pfizer, Abbvie, Seattle Genetics, Immunomedics, and Polyphor. Dr. Ellis has had a consultant/advisory role with NanoString, Novartis, AstraZeneca, Pfizer, Abbvie, Sermonix, and Puma; he has stock own- ership in Bioclassifier with Royalty income from Prosigna/NanoString. Dr. Osborne has had a consultant/advisory role with Puma, AstraZeneca, and Genentech; stock ownership in GENETEX; and funding from Puma. Dr. Rimawi has had a consultant/advisory role in MacroGenics, Daiichi, and Novartis; he has received funding from Novartis and Pfizer. Dr. Ma has had a consultant/advisory role with Pfizer, Novaris, and Lilly; she has received funding from Eisai, Puma, and Pfizer.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=NI
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=No
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Intention to treat analysis
* Adherence controlled with pill counting
* Power analysis
* Comparability of the groups to the baseline

CONTRA:
* Sample too small in view of the power analysis (about half); early discontinuation of study recruitment as no effect could be found at T1
* No blinding
* Patients who did not complete HAQ-II after 12 weeks were interpreted as having developed AIA
* For compliance, too few complete data sets were available to perform analyses, so general compliance was also unclear
}}

Akiba et al. (2018): Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

2024-11-07T11:15:54Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial
}}
{{Study Note}}
=Brief summary=
FEHLT IN EVIDENZTABELLE

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Histopathologically diagnosed as having NSCLC (adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, or large cell lung carcinoma); with stage IA to IIIA; aged 20 to 75 years at entry; diagnosed and operated at any one of four Jikei University Hospitals at Shimbashi, Kashiwa, Chofu, and Katsushika; with tumor totally resected; discharged without major complications; and could visit the Jikei University Hospitals (Tokyo, Japan) and be followed-up for as long as possible
|Exclusion criteria=Already taking a vitamin D supplement or active vitamin D; had a history of urinary tract stones; and other difficulties as judged by the surgeon in charge
|N randomized=155
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Kaplan–Meier survival curves were drawn and compared using the log-rank test in an intention-to-treat analysis
|Countries of data collection=Japan
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=IA-IIIA
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Oral or injection chemotherapy was administered to the patients according to the stage, except in stage IA and tumor size less than 2 cm
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=38 (25%) female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 68 (9)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=77
|Drop-out=5
|Drop-out reasons=Lost to follow-up
|Intervention=Vitamin D
|Dosage and regime=Two capsules of vitamin D3 (total 1,200 IU/day), for 12 months
|One-time application=No
|Duration in days=365
|Side Effects / Interactions=According to authors no side effects
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=78
|Drop-out=6
|Drop-out reasons=Lost to follow-up
|Intervention=Placebo
|Dosage and regime=Two capsule form and identical in appearance and taste, containing sesame oil, gelatin derived from swine, and glycerin, for 12 months
|One-time application=No
|Duration in days=365
|Side Effects / Interactions=According to authors no side effects
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=RFS (Recurrence-Free Survival)
|Outcome specification=5-year recurrence-free survival: the time from the supplement start date to the earlier date of relapse of cancer or death from any cause
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=''Overall:''
No significant differences (p=0.64)
|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=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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=5-year overall survival: the time from the supplement start date to the date of death from any cause
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=''Overall:''
No significant differences (p=0.63)
|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=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
|Order number=2
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=Intervention arm: mean levels of 25(OH)D increased significantly from 21 to 39 ng/mL (p=0.0001),
placebo arm: no significant change (p=0.14)
|Results after intervention=NA
|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
|Order number=3
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities and by JSPH KAKENHI grant number: 22501060
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=At the midterm analysis in November 2014, 5-year RFS of the vitamin D and placebo groups was much closer than expected. As a result, the reestimated sample size was exploded from 300 to much more than 1,000. Thus, it was decided to stop new enrollment and terminate this trial after further 3-year follow-up. Consequently, a total of 155 patients with NSCLC were randomly assigned.
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=No
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NI
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Groups comparable to baseline
* Double blinding
* Power analysis with planned interim analysis
* Intention-to-treat analysis for overall survival

CONTRA:
* Flowchart: placebo arm n=78, where it was noted n=78 received intervention (placebo), but n=8 did not receive it
* Due to lack of efficacy on RSF at interim analysis, recruitment was stopped, so that neither the previously calculated nor recalculated number of subjects was reached
* No indication of the number of subjects per group for low or high 25(OH)D level
* Low number of subjects for subgroup analyses
}}

Keshavarzi et al. (2019): The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer

2024-11-05T12:25:59Z

CHoppe:

{{Reference
|Reference=Publication: The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer
}}
=Brief summary=
In this study, the influence of vitamin D and E on vaginal atrophy in breast cancer patients undergoing hormone therapy was investigated. Vaginal atrophy includes symptoms such as itching, burning and pain during sexual intercourse, which are caused by a lack of oestrogen. The 96 participants in the study were divided equally into three groups. All subjects in each arm received either a daily vaginal suppository containing vitamin D, vitamin E or a placebo. After 8 weeks, an improvement in symptoms was achieved in both vitamin arms. No comparisons were made between the two vitamin arms in the analysis, so it is unclear whether either was more effective. Many tests were done, which statistically increases the risk of finding an effect that is not there. No measures were taken, so the result should be interpreted with caution.

In dieser Studie wurde der Einfluss von Vitamin D und E auf vaginale Atrophie bei Brustkrebspatientinnen unter Hormontherapie untersucht. Vaginale Atrophie umfasst Symptome wie Juckreiz, Brennen und Schmerzen beim Geschlechtsverkehr, welche durch Östrogenmangel hervorgerufen werden. Die 96 Teilnehmerinnen der Studie wurden zu gleichen Teilen in drei Gruppen eingeteilt. Alle Probandinnen der jeweiligen Arme erhielten entweder täglich ein Vaginalzäpfchen mit Vitamin D, mit Vitamin E oder ein Placebo. Nach 8 Wochen konnte eine Besserung der Symptome in den beiden Vitamin-Armen erzielt werden. In der Analyse werden keine Vergleiche zwischen den beiden Vitaminarme gemacht, so dass unklar ist, ob eine von beiden wirksamer war. Es wurden viele Tests gemacht, wodurch das Risiko einen Effekt zu finden, der nicht da ist statistisch erhöht ist. Es wurden keine Maßnahmen dahingegen unternommen, wodurch das Ergebnis mit Vorsicht zu interpretieren ist.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Triple
|Is randomized=Yes
|Cross-over=No
|Number of arms=3
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Being married, having stage 1 or 2 breast cancer based on the surgery stage, age below 50, receiving tamoxifen, not undergoing chemotherapy or radiotherapy during the study, a normal Pap smear during the last 3 years, no proven malignancies in other parts of the body, being sexually active during the study, meeting at least one of the criteria set in the genitourinary atrophy self-assessment, vaginal pH ≥ 5 according to Chollet et al. study at the time of the study, and a Vaginal Maturation Index (VMI) ≤52 according to Speroff’s study
|Exclusion criteria=Unwillingness to participate in the study, vaginal infection, estrogen therapy in the last 8 weeks, idiopathic vaginal bleeding, and disease recurrence based on the diagnosis recorded in the patient’s file
|N randomized=96
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Iran
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline
T1: week 2
T2: week 4
T3: week 8
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer - Ductal Carcinoma, Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I and II
|Comorbidity=NI
|Current cancer therapy=Hormone therapy
|Specifications on cancer therapies=Tamoxifen
|Previous cancer therapies=Chemotherapy, Radiation therapy
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Vitamin D arm: mean (SD): 43.7 (3.9)

vitamin E arm: mean (SD): 44.1 (4.6)

placebo arm: mean (SD): 42.0 (6.3)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=32
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=Vitamin D
|Dosage and regime=Vaginal suppositories containing 2 g of the base substance plus 1000 IU of vitamin D (0.025 mg), every day before bedtime
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=32
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=Vitamin E
|Dosage and regime=Vaginal suppositories containing 1 mg of vitamin E plus 2 g of the base substance, every day before bedtime
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=32
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Vaginal suppositories containing only 2 g of the base substance, every day before bedtime
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NI
|Order number=3
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Vaginal atrophy
|Outcome specification=Vaginal atrophy, pH, and vaginal maturation index
|Type of measurement=Genitourinary atrophy self-assessment tool, pH-value
|Results during intervention=Controlling the duration of tamoxifen use:
* significant difference of mean vaginal pH before the intervention; significant difference among the three arms 8 weeks after the intervention (pH reduced by 1.59 units in the vitamin E arm and by 1.53 units in the vitamin D arm, but increased by 0.04 units in the placebo arm)
* no significant differences in vaginal maturation index before the intervention; difference among the arms was statistically significant at the end of the eighth week of the intervention (VMI increased in the vitamin E and vitamin D arms by the end of the eighth week, and this difference was due to the increase in the mean percentage of superficial cells and the decrease in the mean percentage of parabasal cells in these two arms compared to before the intervention, while no such change was observed in the placebo arm)

Vaginal atrophy: no significant differences before the intervention, but the difference was significant at the second, fourth, and eighth weeks of the intervention (significant reduction in the mean score in the vitamin E and D arms compared with that in the placebo arm)
|Results after intervention=NI
|Bias arising from the randomization process=low risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=No
|Possibility of placebo effects=No
|Other reasons=We do not know anything about the vitamin E and D levels.
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=No
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=No
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Triple blinding (patients, researchers, pathologists and analysts)
* Comparability of groups to baseline for characteristics

CONTRA:
* Under “Eligibility” inclusion of VMI≤51, but under “Procedure” inclusion of VMI≥52
* No indication of vitamin D or vitamin E levels
* No individual comparisons carried out in ANOVA, therefore unclear which arms actually differ
* No results for individual scales of the atrophy questionnaire
* No power analysis
* No correction for multiple testing
}}

Keshavarzi et al. (2019): The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer

2024-11-05T12:25:49Z

CHoppe:

{{Reference
|Reference=Publication: The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer
}}
{{Study Note}}
=Brief summary=
In this study, the influence of vitamin D and E on vaginal atrophy in breast cancer patients undergoing hormone therapy was investigated. Vaginal atrophy includes symptoms such as itching, burning and pain during sexual intercourse, which are caused by a lack of oestrogen. The 96 participants in the study were divided equally into three groups. All subjects in each arm received either a daily vaginal suppository containing vitamin D, vitamin E or a placebo. After 8 weeks, an improvement in symptoms was achieved in both vitamin arms. No comparisons were made between the two vitamin arms in the analysis, so it is unclear whether either was more effective. Many tests were done, which statistically increases the risk of finding an effect that is not there. No measures were taken, so the result should be interpreted with caution.

In dieser Studie wurde der Einfluss von Vitamin D und E auf vaginale Atrophie bei Brustkrebspatientinnen unter Hormontherapie untersucht. Vaginale Atrophie umfasst Symptome wie Juckreiz, Brennen und Schmerzen beim Geschlechtsverkehr, welche durch Östrogenmangel hervorgerufen werden. Die 96 Teilnehmerinnen der Studie wurden zu gleichen Teilen in drei Gruppen eingeteilt. Alle Probandinnen der jeweiligen Arme erhielten entweder täglich ein Vaginalzäpfchen mit Vitamin D, mit Vitamin E oder ein Placebo. Nach 8 Wochen konnte eine Besserung der Symptome in den beiden Vitamin-Armen erzielt werden. In der Analyse werden keine Vergleiche zwischen den beiden Vitaminarme gemacht, so dass unklar ist, ob eine von beiden wirksamer war. Es wurden viele Tests gemacht, wodurch das Risiko einen Effekt zu finden, der nicht da ist statistisch erhöht ist. Es wurden keine Maßnahmen dahingegen unternommen, wodurch das Ergebnis mit Vorsicht zu interpretieren ist.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Triple
|Is randomized=Yes
|Cross-over=No
|Number of arms=3
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Being married, having stage 1 or 2 breast cancer based on the surgery stage, age below 50, receiving tamoxifen, not undergoing chemotherapy or radiotherapy during the study, a normal Pap smear during the last 3 years, no proven malignancies in other parts of the body, being sexually active during the study, meeting at least one of the criteria set in the genitourinary atrophy self-assessment, vaginal pH ≥ 5 according to Chollet et al. study at the time of the study, and a Vaginal Maturation Index (VMI) ≤52 according to Speroff’s study
|Exclusion criteria=Unwillingness to participate in the study, vaginal infection, estrogen therapy in the last 8 weeks, idiopathic vaginal bleeding, and disease recurrence based on the diagnosis recorded in the patient’s file
|N randomized=96
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Iran
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline
T1: week 2
T2: week 4
T3: week 8
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer - Ductal Carcinoma, Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I and II
|Comorbidity=NI
|Current cancer therapy=Hormone therapy
|Specifications on cancer therapies=Tamoxifen
|Previous cancer therapies=Chemotherapy, Radiation therapy
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Vitamin D arm: mean (SD): 43.7 (3.9)

vitamin E arm: mean (SD): 44.1 (4.6)

placebo arm: mean (SD): 42.0 (6.3)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=32
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=Vitamin D
|Dosage and regime=Vaginal suppositories containing 2 g of the base substance plus 1000 IU of vitamin D (0.025 mg), every day before bedtime
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=32
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=Vitamin E
|Dosage and regime=Vaginal suppositories containing 1 mg of vitamin E plus 2 g of the base substance, every day before bedtime
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=32
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Vaginal suppositories containing only 2 g of the base substance, every day before bedtime
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NI
|Order number=3
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Vaginal atrophy
|Outcome specification=Vaginal atrophy, pH, and vaginal maturation index
|Type of measurement=Genitourinary atrophy self-assessment tool, pH-value
|Results during intervention=Controlling the duration of tamoxifen use:
* significant difference of mean vaginal pH before the intervention; significant difference among the three arms 8 weeks after the intervention (pH reduced by 1.59 units in the vitamin E arm and by 1.53 units in the vitamin D arm, but increased by 0.04 units in the placebo arm)
* no significant differences in vaginal maturation index before the intervention; difference among the arms was statistically significant at the end of the eighth week of the intervention (VMI increased in the vitamin E and vitamin D arms by the end of the eighth week, and this difference was due to the increase in the mean percentage of superficial cells and the decrease in the mean percentage of parabasal cells in these two arms compared to before the intervention, while no such change was observed in the placebo arm)

Vaginal atrophy: no significant differences before the intervention, but the difference was significant at the second, fourth, and eighth weeks of the intervention (significant reduction in the mean score in the vitamin E and D arms compared with that in the placebo arm)
|Results after intervention=NI
|Bias arising from the randomization process=low risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=No
|Possibility of placebo effects=No
|Other reasons=We do not know anything about the vitamin E and D levels.
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=No
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=No
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Triple blinding (patients, researchers, pathologists and analysts)
* Comparability of groups to baseline for characteristics

CONTRA:
* Under “Eligibility” inclusion of VMI≤51, but under “Procedure” inclusion of VMI≥52
* No indication of vitamin D or vitamin E levels
* No individual comparisons carried out in ANOVA, therefore unclear which arms actually differ
* No results for individual scales of the atrophy questionnaire
* No power analysis
* No correction for multiple testing
}}

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

2024-11-05T11:42:57Z

CHoppe:

{{Reference
|Reference=Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial
}}
=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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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 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 2 Oxford 2011
|Outcome timeline=T0: Baseline
T1-T3: every worth week
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=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
|Stage cancer=Advanced Stage
|Cancer stage specification=Advanced and/or metastatic cancer in palliative phase
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=121
|Drop-out=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=84
|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
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=123
|Drop-out=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=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
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Long-acting opioid dose, measured as fentanyl ug/hour during 12 weeks
|Type of measurement=Observation
|Results during intervention=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=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Infection
|Outcome specification=Antibiotic use, measured as the number of days with antibiotics in the previous 30 days
|Type of measurement=Observation
|Results during intervention=No significant difference
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|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=No significant difference
|Results after intervention=NA
|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
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|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=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=NA
|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
|Order number=4
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=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=NA
|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
|Order number=5
}}
{{Outcome
|Outcome type=Others
|Outcome name=OS (Overall Survival)
|Outcome specification=Post-hoc survival analysis
|Type of measurement=Observation
|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
|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
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=NI
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|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
}}

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

2024-11-05T11:36:34Z

CHoppe:

{{Reference
|Reference=Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial
}}
{{Study Note}}
=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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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 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 2 Oxford 2011
|Outcome timeline=T0: Baseline
T1-T3: every worth week
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=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
|Stage cancer=Advanced Stage
|Cancer stage specification=Advanced and/or metastatic cancer in palliative phase
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=121
|Drop-out=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=84
|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
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=123
|Drop-out=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=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
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Long-acting opioid dose, measured as fentanyl ug/hour during 12 weeks
|Type of measurement=Observation
|Results during intervention=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=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Infection
|Outcome specification=Antibiotic use, measured as the number of days with antibiotics in the previous 30 days
|Type of measurement=Observation
|Results during intervention=No significant difference
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|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=No significant difference
|Results after intervention=NA
|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
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|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=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=NA
|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
|Order number=4
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=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=NA
|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
|Order number=5
}}
{{Outcome
|Outcome type=Others
|Outcome name=OS (Overall Survival)
|Outcome specification=Post-hoc survival analysis
|Type of measurement=Observation
|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
|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
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=NI
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|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
}}

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

2024-11-05T11:24:20Z

CHoppe:

{{Reference
|Reference=Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial
}}
{{Study Note}}
=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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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 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 2 Oxford 2011
|Outcome timeline=T0: Baseline
T1-T3: every worth week
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=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
|Stage cancer=Advanced Stage
|Cancer stage specification=Advanced and/or metastatic cancer in palliative phase
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=121
|Drop-out=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=84
|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
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=123
|Drop-out=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=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
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Long-acting opioid dose, measured as fentanyl ug/hour during 12 weeks
|Type of measurement=Observation
|Results during intervention=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=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Infection
|Outcome specification=Antibiotic use, measured as the number of days with antibiotics in the previous 30 days
|Type of measurement=Observation
|Results during intervention=No significant difference
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|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=No significant difference
|Results after intervention=NA
|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
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|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=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=NA
|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
|Order number=4
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=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=NA
|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
|Order number=5
}}
{{Outcome
|Outcome type=Others
|Outcome name=OS (Overall Survival)
|Outcome specification=Post-hoc survival analysis
|Type of measurement=Observation
|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
|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=?
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|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
}}

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

2024-11-05T11:21:45Z

CHoppe:

{{Reference
|Reference=Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial
}}
{{Study Note}}
=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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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 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 2 Oxford 2011
|Outcome timeline=T0: Baseline
T1-T3: every worth week
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=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
|Stage cancer=Advanced Stage
|Cancer stage specification=Advanced and/or metastatic cancer in palliative phase
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=121
|Drop-out=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=84
|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
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=123
|Drop-out=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=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
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Long-acting opioid dose, measured as fentanyl ug/hour during 12 weeks
|Type of measurement=Observation
|Results during intervention=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=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Infection
|Outcome specification=Antibiotic use, measured as the number of days with antibiotics in the previous 30 days
|Type of measurement=Observation
|Results during intervention=No significant difference
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|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=No significant difference
|Results after intervention=NA
|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
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|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=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=NA
|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
|Order number=4
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=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=NA
|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
|Order number=5
}}
{{Outcome
|Outcome type=Others
|Outcome name=OS (Overall Survival)
|Outcome specification=Post-hoc survival analysis
|Type of measurement=Observation
|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
|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=?
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|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
}}

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

2024-11-05T10:56:19Z

CHoppe:

{{Reference
|Reference=Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial
}}
{{Study Note}}
=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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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 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 2 Oxford 2011
|Outcome timeline=T0: Baseline
T1-T3: every worth week
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=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
|Stage cancer=Advanced Stage
|Cancer stage specification=Advanced and/or metastatic cancer in palliative phase
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=121
|Drop-out=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=84
|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
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=123
|Drop-out=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=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
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Long-acting opioid dose, measured as fentanyl ug/hour during 12 weeks
|Type of measurement=Observation
|Results during intervention=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=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Infection
|Outcome specification=Antibiotic use, measured as the number of days with antibiotics in the previous 30 days
|Type of measurement=Observation
|Results during intervention=No significant difference
|Results after intervention=NA
|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=?
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|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=No significant difference
|Results after intervention=NA
|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=?
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|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=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=NA
|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=?
|Order number=4
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=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=NA
|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=?
|Order number=5
}}
{{Outcome
|Outcome type=Others
|Outcome name=OS (Overall Survival)
|Outcome specification=Post-hoc survival analysis
|Type of measurement=Observation
|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
|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=?
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|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
}}

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

2024-11-05T10:35:42Z

CHoppe:

{{Reference
|Reference=Publication: Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial
}}
{{Study Note
|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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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=ITT Analysis
|Specifications on analyses=All analyses adhered to the modified intention-to-treat principle.
|Countries of data collection=United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: basline
T1: after cycle 4 of chemotherapy (8 weeks)

T2: after cycle 8 of chemotherapy (16 weeks)

Follow-Up
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=69
|Drop-out=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=-999
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=70
|Drop-out=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=-999
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Body composition
|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=No significant differences
|Results after intervention=NI
|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
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=Change in Plasma 25(OH)D
|Type of measurement=Blood Test
|Results during intervention=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=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=NI
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=''Overall:''
In the subgroup of 105 participants randomization to high-dose vitamin D3 was associated with a lower risk of disease progression or death as compared with low-dose vitamin D3 [HR: 0.67; (95% CI: 0.42, 1.07)]; the magnitude of risk reduction was similar to that observed in the full analysis set of 139 participants as previously reported;

Change in body composition over the first 8 cycles of chemotherapy did not mediate the association between randomized arm and progression-free survival
|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
|Order number=3
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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

The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Pharmavite and Genentech reviewed and approved the manuscript.
|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=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
}}
{{Additional Notes
|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
}}

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

2024-11-05T10:25:03Z

CHoppe:

{{Reference
|Reference=Publication: Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial
}}
{{Study Note
|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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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=ITT Analysis
|Specifications on analyses=All analyses adhered to the modified intention-to-treat principle.
|Countries of data collection=United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: basline
T1: after cycle 4 of chemotherapy (8 weeks)

T2: after cycle 8 of chemotherapy (16 weeks)

Follow-Up
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=69
|Drop-out=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=-999
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=70
|Drop-out=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=-999
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Body composition
|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=No significant differences
|Results after intervention=NI
|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
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=Change in Plasma 25(OH)D
|Type of measurement=Blood Test
|Results during intervention=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=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=NI
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=''Overall:''
In the subgroup of 105 participants randomization to high-dose vitamin D3 was associated with a lower risk of disease progression or death as compared with low-dose vitamin D3 [HR: 0.67; (95% CI: 0.42, 1.07)]; the magnitude of risk reduction was similar to that observed in the full analysis set of 139 participants as previously reported;

Change in body composition over the first 8 cycles of chemotherapy did not mediate the association between randomized arm and progression-free survival
|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=?
|Order number=3
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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

The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Pharmavite and Genentech reviewed and approved the manuscript.
|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=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
}}
{{Additional Notes
|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
}}

Hajimohammadebrahim-Ketabforoush et al. (2019): Effect of Vitamin D Supplementation on Postcraniotomy Pain After Brain Tumor Surgery: A Randomized Clinical Trial

2024-10-31T12:20:54Z

CHoppe:

{{Reference
|Reference=Publication: Effect of Vitamin D Supplementation on Postcraniotomy Pain After Brain Tumor Surgery: A Randomized Clinical Trial
}}

=Brief summary=
This study examined the effect of high-dose vitamin D3 before tumor surgery on the subjective perception of pain and the use of painkillers after surgery in 60 patients with brain tumors and low vitamin D levels. Three days after the operation, there were no significant differences between patients who had been injected with 300,000 IU 2-14 days before the operation and the control patients in terms of subjective pain perception and painkiller use. Numerous criticisms can be made of this study, e.g. significant differences between the intervention and control arms at the start of the study, inadequate descriptions of the interventions in the intervention and control arms, and unclear calculations.

Diese Studie untersuchte bei 60 Patienten mit Gehirntumoren und zu niedrigem Vitamin D Spiegel die Wirkung von hochdosiertem Vitamin D3 vor der Tumoroperation auf die subjektive Schmerzwahrnehmung und den Schmerzmittelgebrauch nach der Operation. Jeweils 3 Tage nach der Operation zeigten sich zwischen Patienten, die 2-14 Tage vor der Operation 300,000 IU injiziert bekamen und den Kontrollpatienten keine bedeutsamen Unterschiede hinsichtlich subjektiver Schmerzwahrnehmung und Schmerzmittelgebrauch. An dieser Studie lassen sich zahlreiche Kritikpunkte nennen, z.B. bedeutsame Unterschiede zwischen Interventions- und Kontrollarm zum Beginn der Studie, unzureichende Beschreibungen der Interventionen in Interventions- und Kontrollarm, sowie unklare Berechnungen.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=At least 18 years of age with newly diagnosed brain tumor with serum level of 25 (OH) vitamin D ≤20 ng/dL
|Exclusion criteria=Having another trial participation session, including previous participation in the pilot trial, pregnant or lactating women, hypercalcemia, hyperphosphatemia, tuberculosis, sarcoidosis, history of nephrolithiasis, history of hyperparathyroidism, medications interfering with vitamin D metabolism, renal insufficiency, patients having psychological diseases, abnormal mental function, and unconscious patients
|N randomized=71
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Iran
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: before operation

T1-T3: on day 1-3 after operation

T4: on day 5 after operation
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Brain and Central Nervous System (CNS) Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=Headache, hypertension, diabetes
|Current cancer therapy=Surgery
|Specifications on cancer therapies=The patients undergoing general anesthesia were induced with thiopental sodium 5e7 mg/kg, fentanyl 5 mg/kg, midazolam 0.02 mg/kg, lidocaine 1 mg/kg, atracurium 0.5 mg/kg, endotracheal intubation, and maintained with propofol 50e150 mg/kg/min in a 3 L/min oxygen/air mixture. Eventually, the patient’s awakening was induced with neostigmine and atropine to an extent of 0.07 mg/kg and 0.02 mg/kg, respectively.
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Intervention arm: 16 (53.3%) male
Control arm: 14 (46.7%) male
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: mean (SD): 48.2 (15.3)
Control arm: mean (SD): 4.3 (15.2)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=35
|Drop-out=5
|Drop-out reasons=Missed follow-up
|Intervention=Vitamin D
|Dosage and regime=Intramuscular injection of 300,000 IU vitamin D 2-14 days (with an average of 5 days) before surgery

+ all participants: pain medication, including intravenous injection of apotel 1 g, morphine sulfate 3 mg, and oral acet-aminophen 500 mg, depending on each patient’s need in the intensive care unit and ward
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=36
|Drop-out=6
|Drop-out reasons=Missed follow-up
|Intervention=Nothing
|Dosage and regime=All participants: pain medication, including intravenous injection of apotel 1 g, morphine sulfate 3 mg, and oral acet-aminophen 500 mg, depending on each patient’s need in the intensive care unit and ward
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Pain
|Outcome specification=Postoperative pain (doses of analgesic medication consumption)
|Type of measurement=VAS (Visual Analogue Scale), Observation
|Results during intervention=No significant differences in VAS scores;

No significant differences in doses of analgesic medication consumption
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=Increase in 25(OH) D on the fifth postoperative day in intervention arm was statistically significant compared with the control arm (p = 0.001)
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Financially supported by Shahid Beheshti University of Medical Sciences, Tehran, Iran.
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=No
|Possibility of placebo effects=Yes, one arm without any treatment.
|Other reasons=No
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=No
|Consistent reporting in numbers=No
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO
* Ethics vote;
* Pre/post level control of vitamin D (25 (OH) D level, mean (SD): Arm A: T0: 15.9 (3.8), T4: 22.5 (4.3), Arm B: T0:14.5 (3.6), T4: 13.7 (3.8); A vs. B: p<0.001)

CONTRA
* No power analysis
* Unclear blinding
* Descriptive differences regarding tumor pathology
* Unclear randomization
* Insufficient description of interventions in arm A and B
* Unclear calculations (e.g. no information on control variables in the model)
* Poor report quality
}}

Hajimohammadebrahim-Ketabforoush et al. (2019): Effect of Vitamin D Supplementation on Postcraniotomy Pain After Brain Tumor Surgery: A Randomized Clinical Trial

2024-10-31T12:20:27Z

CHoppe:

{{Reference
|Reference=Publication: Effect of Vitamin D Supplementation on Postcraniotomy Pain After Brain Tumor Surgery: A Randomized Clinical Trial
}}
{{Study Note
|Study Note=This study examined the effect of high-dose vitamin D3 before tumor surgery on the subjective perception of pain and the use of painkillers after surgery in 60 patients with brain tumors and low vitamin D levels. Three days after the operation, there were no significant differences between patients who had been injected with 300,000 IU 2-14 days before the operation and the control patients in terms of subjective pain perception and painkiller use. Numerous criticisms can be made of this study, e.g. significant differences between the intervention and control arms at the start of the study, inadequate descriptions of the interventions in the intervention and control arms, and unclear calculations.

Diese Studie untersuchte bei 60 Patienten mit Gehirntumoren und zu niedrigem Vitamin D Spiegel die Wirkung von hochdosiertem Vitamin D3 vor der Tumoroperation auf die subjektive Schmerzwahrnehmung und den Schmerzmittelgebrauch nach der Operation. Jeweils 3 Tage nach der Operation zeigten sich zwischen Patienten, die 2-14 Tage vor der Operation 300,000 IU injiziert bekamen und den Kontrollpatienten keine bedeutsamen Unterschiede hinsichtlich subjektiver Schmerzwahrnehmung und Schmerzmittelgebrauch. An dieser Studie lassen sich zahlreiche Kritikpunkte nennen, z.B. bedeutsame Unterschiede zwischen Interventions- und Kontrollarm zum Beginn der Studie, unzureichende Beschreibungen der Interventionen in Interventions- und Kontrollarm, sowie unklare Berechnungen.
}}
=Brief summary=

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=At least 18 years of age with newly diagnosed brain tumor with serum level of 25 (OH) vitamin D ≤20 ng/dL
|Exclusion criteria=Having another trial participation session, including previous participation in the pilot trial, pregnant or lactating women, hypercalcemia, hyperphosphatemia, tuberculosis, sarcoidosis, history of nephrolithiasis, history of hyperparathyroidism, medications interfering with vitamin D metabolism, renal insufficiency, patients having psychological diseases, abnormal mental function, and unconscious patients
|N randomized=71
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Iran
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: before operation

T1-T3: on day 1-3 after operation

T4: on day 5 after operation
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Brain and Central Nervous System (CNS) Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=Headache, hypertension, diabetes
|Current cancer therapy=Surgery
|Specifications on cancer therapies=The patients undergoing general anesthesia were induced with thiopental sodium 5e7 mg/kg, fentanyl 5 mg/kg, midazolam 0.02 mg/kg, lidocaine 1 mg/kg, atracurium 0.5 mg/kg, endotracheal intubation, and maintained with propofol 50e150 mg/kg/min in a 3 L/min oxygen/air mixture. Eventually, the patient’s awakening was induced with neostigmine and atropine to an extent of 0.07 mg/kg and 0.02 mg/kg, respectively.
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Intervention arm: 16 (53.3%) male
Control arm: 14 (46.7%) male
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: mean (SD): 48.2 (15.3)
Control arm: mean (SD): 4.3 (15.2)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=35
|Drop-out=5
|Drop-out reasons=Missed follow-up
|Intervention=Vitamin D
|Dosage and regime=Intramuscular injection of 300,000 IU vitamin D 2-14 days (with an average of 5 days) before surgery

+ all participants: pain medication, including intravenous injection of apotel 1 g, morphine sulfate 3 mg, and oral acet-aminophen 500 mg, depending on each patient’s need in the intensive care unit and ward
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=36
|Drop-out=6
|Drop-out reasons=Missed follow-up
|Intervention=Nothing
|Dosage and regime=All participants: pain medication, including intravenous injection of apotel 1 g, morphine sulfate 3 mg, and oral acet-aminophen 500 mg, depending on each patient’s need in the intensive care unit and ward
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Pain
|Outcome specification=Postoperative pain (doses of analgesic medication consumption)
|Type of measurement=VAS (Visual Analogue Scale), Observation
|Results during intervention=No significant differences in VAS scores;

No significant differences in doses of analgesic medication consumption
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=high 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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=Increase in 25(OH) D on the fifth postoperative day in intervention arm was statistically significant compared with the control arm (p = 0.001)
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Financially supported by Shahid Beheshti University of Medical Sciences, Tehran, Iran.
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=No
|Possibility of placebo effects=Yes, one arm without any treatment.
|Other reasons=No
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=No
|Consistent reporting in numbers=No
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO
* Ethics vote;
* Pre/post level control of vitamin D (25 (OH) D level, mean (SD): Arm A: T0: 15.9 (3.8), T4: 22.5 (4.3), Arm B: T0:14.5 (3.6), T4: 13.7 (3.8); A vs. B: p<0.001)

CONTRA
* No power analysis
* Unclear blinding
* Descriptive differences regarding tumor pathology
* Unclear randomization
* Insufficient description of interventions in arm A and B
* Unclear calculations (e.g. no information on control variables in the model)
* Poor report quality
}}

Johansson et al. (2021): Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial

2024-10-31T11:42:04Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial
}}
=Brief summary=
104 patients with surgically removed melanomas were included in the study. Divided equally and randomly into 2 arms, one half received 100,000 I.U. vitamin D3 every 50 days for 3 years and the other half received a placebo. The time to relapse was investigated. At the end of the study, no differences were found between the arms in this respect. In further analyses, benefits were only found for patients with a low tumor thickness alone and in combination with a high serum vitamin D level after 12 months of supplementation. It is unclear why most of the reported results of the study were calculated “after 12 months of supplementation”, although the intervention took place over 3 years.

In der Studie von wurden 104 Patienten mit operativ entfernten Melanomen eingeschlossen. Gleichmäßig und zufällig in 2 Arme eingeteilt, erhielt die eine Hälfte alle 50 Tage 100.000 I.E. Vitamin D3 über 3 Jahre und die andere Hälfte ein Placebo. Untersucht wurde die Zeit bis zu einem Rückfall. Am Ende der Studie konnten diesbezüglich keine Unterschiede zwischen den Armen gefunden werden. In weiteren Analysen konnten nur Vorteile gefunden werden für Patienten mit einer geringen Tumordicke allein und in Kombination mit einem hohen Serum Vitamin D Wert nach 12 Monaten Supplementierung. Unklar ist, warum die meisten berichteten Ergebnisse der Studie „nach 12 Monaten Supplementierung“ berechnet wurden, obwohl die Intervention über 3 Jahre stattfand.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Aged 75 years or younger with recent resected stage II cutaneous malignant melanoma; Hematopoietic, hepatic, and renal functionality within normal ranges
|Exclusion criteria=Current use of at least 600 IU/day of supplemental vitamin D or high-dose calcium therapy within the prior 6 month and any prior cancer or other significant diseases that could hamper the participant’s safety or preclude the benefit of vitamin D supplementation
|N randomized=114
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Italy
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
13 follow-up visits (4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 42nd, 48th, 54th, and 60th month)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=NI
|Types of cancer=Skin Cancer – Melanoma
|Stage cancer=Early Stage
|Cancer stage specification=Stage II
|Comorbidity=NI
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Gender=Mixed
|Gender specifications=57% male, 43% female
|Age groups=Adults (18+)
|Age groups specification=Median: 51
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Vitamin D
|Dosage and regime=Oral solution in ampoule containing 100,000 IU of vitamin D3 (an average of 2000 IU/day), every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events, neither of the events were linked to 25OHD serum levels
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Placebo
|Dosage and regime=Oral solution in ampoule containing placebo, every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After a median follow-up of 3 years: no difference by treatment in disease-free survival
|Results after intervention=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Vitamin D level
|Outcome specification=Time of serum 25OHD levels and percentage of patients that reached the 25OHD cut-off level of sufficiency (>30 ng/mL from August to November and >20 ng/mL from January to July) during the 1st year
|Type of measurement=Blood Test
|Results during intervention=Majority of participants: low levels of 25OHD (80%);

Serum levels of 25OHD sharply rose already after 4 months of supplementation in the intervention arm (Median: 33 ng/mL), compared to the placebo arm (Median: 19 ng/mL), the increase persisted with the duration of the treatment (42 ng/mL vs. 22 ng/mL after 3 years treatment)

Additionally: difference in 25OHD increase by Breslow thickness: patients with Breslow thickness below 3 mm had a doubling of 25OHD serum levels from baseline after 12 months, patients with greater thickness experienced a much lower increases in 25OHD by time
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Foundation Umberto Veronesi; partially supported by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=NI
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Randomization with stratification
* Adherence tested by serum concentration
* Comparability of the groups given

CONTRA:
* Further drop-out over time, without information in the flowchart
* Intervention length 3 years, but additional analyses to DFS analyses with supplementation after one year
* No precise indication of the side effects that occurred
* No report on power analysis, but in the discussion it is reported that the study is “underpowered” for the primary endpoint
* Lack of scientific data on the selected dose regimen

Johansson et al. (2021): Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial

2024-10-31T11:41:49Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial
}}
{{Study Note}}
=Brief summary=
104 patients with surgically removed melanomas were included in the study. Divided equally and randomly into 2 arms, one half received 100,000 I.U. vitamin D3 every 50 days for 3 years and the other half received a placebo. The time to relapse was investigated. At the end of the study, no differences were found between the arms in this respect. In further analyses, benefits were only found for patients with a low tumor thickness alone and in combination with a high serum vitamin D level after 12 months of supplementation. It is unclear why most of the reported results of the study were calculated “after 12 months of supplementation”, although the intervention took place over 3 years.

In der Studie von wurden 104 Patienten mit operativ entfernten Melanomen eingeschlossen. Gleichmäßig und zufällig in 2 Arme eingeteilt, erhielt die eine Hälfte alle 50 Tage 100.000 I.E. Vitamin D3 über 3 Jahre und die andere Hälfte ein Placebo. Untersucht wurde die Zeit bis zu einem Rückfall. Am Ende der Studie konnten diesbezüglich keine Unterschiede zwischen den Armen gefunden werden. In weiteren Analysen konnten nur Vorteile gefunden werden für Patienten mit einer geringen Tumordicke allein und in Kombination mit einem hohen Serum Vitamin D Wert nach 12 Monaten Supplementierung. Unklar ist, warum die meisten berichteten Ergebnisse der Studie „nach 12 Monaten Supplementierung“ berechnet wurden, obwohl die Intervention über 3 Jahre stattfand.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Aged 75 years or younger with recent resected stage II cutaneous malignant melanoma; Hematopoietic, hepatic, and renal functionality within normal ranges
|Exclusion criteria=Current use of at least 600 IU/day of supplemental vitamin D or high-dose calcium therapy within the prior 6 month and any prior cancer or other significant diseases that could hamper the participant’s safety or preclude the benefit of vitamin D supplementation
|N randomized=114
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Italy
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
13 follow-up visits (4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 42nd, 48th, 54th, and 60th month)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=NI
|Types of cancer=Skin Cancer – Melanoma
|Stage cancer=Early Stage
|Cancer stage specification=Stage II
|Comorbidity=NI
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Gender=Mixed
|Gender specifications=57% male, 43% female
|Age groups=Adults (18+)
|Age groups specification=Median: 51
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Vitamin D
|Dosage and regime=Oral solution in ampoule containing 100,000 IU of vitamin D3 (an average of 2000 IU/day), every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events, neither of the events were linked to 25OHD serum levels
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Placebo
|Dosage and regime=Oral solution in ampoule containing placebo, every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After a median follow-up of 3 years: no difference by treatment in disease-free survival
|Results after intervention=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Vitamin D level
|Outcome specification=Time of serum 25OHD levels and percentage of patients that reached the 25OHD cut-off level of sufficiency (>30 ng/mL from August to November and >20 ng/mL from January to July) during the 1st year
|Type of measurement=Blood Test
|Results during intervention=Majority of participants: low levels of 25OHD (80%);

Serum levels of 25OHD sharply rose already after 4 months of supplementation in the intervention arm (Median: 33 ng/mL), compared to the placebo arm (Median: 19 ng/mL), the increase persisted with the duration of the treatment (42 ng/mL vs. 22 ng/mL after 3 years treatment)

Additionally: difference in 25OHD increase by Breslow thickness: patients with Breslow thickness below 3 mm had a doubling of 25OHD serum levels from baseline after 12 months, patients with greater thickness experienced a much lower increases in 25OHD by time
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Foundation Umberto Veronesi; partially supported by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=NI
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Randomization with stratification
* Adherence tested by serum concentration
* Comparability of the groups given

CONTRA:
* Further drop-out over time, without information in the flowchart
* Intervention length 3 years, but additional analyses to DFS analyses with supplementation after one year
* No precise indication of the side effects that occurred
* No report on power analysis, but in the discussion it is reported that the study is “underpowered” for the primary endpoint
* Lack of scientific data on the selected dose regimen

Johansson et al. (2021): Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial

2024-10-31T11:41:27Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial
}}
{{Study Note}}
=Brief summary=
104 patients with surgically removed melanomas were included in the study. Divided equally and randomly into 2 arms, one half received 100,000 I.U. vitamin D3 every 50 days for 3 years and the other half received a placebo. The time to relapse was investigated. At the end of the study, no differences were found between the arms in this respect. In further analyses, benefits were only found for patients with a low tumor thickness alone and in combination with a high serum vitamin D level after 12 months of supplementation. It is unclear why most of the reported results of the study were calculated “after 12 months of supplementation”, although the intervention took place over 3 years.

In der Studie von wurden 104 Patienten mit operativ entfernten Melanomen eingeschlossen. Gleichmäßig und zufällig in 2 Arme eingeteilt, erhielt die eine Hälfte alle 50 Tage 100.000 I.E. Vitamin D3 über 3 Jahre und die andere Hälfte ein Placebo. Untersucht wurde die Zeit bis zu einem Rückfall. Am Ende der Studie konnten diesbezüglich keine Unterschiede zwischen den Armen gefunden werden. In weiteren Analysen konnten nur Vorteile gefunden werden für Patienten mit einer geringen Tumordicke allein und in Kombination mit einem hohen Serum Vitamin D Wert nach 12 Monaten Supplementierung. Unklar ist, warum die meisten berichteten Ergebnisse der Studie „nach 12 Monaten Supplementierung“ berechnet wurden, obwohl die Intervention über 3 Jahre stattfand.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Aged 75 years or younger with recent resected stage II cutaneous malignant melanoma; Hematopoietic, hepatic, and renal functionality within normal ranges
|Exclusion criteria=Current use of at least 600 IU/day of supplemental vitamin D or high-dose calcium therapy within the prior 6 month and any prior cancer or other significant diseases that could hamper the participant’s safety or preclude the benefit of vitamin D supplementation
|N randomized=114
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Italy
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
13 follow-up visits (4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 42nd, 48th, 54th, and 60th month)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=NI
|Types of cancer=Skin Cancer – Melanoma
|Stage cancer=Early Stage
|Cancer stage specification=Stage II
|Comorbidity=NI
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Gender=Mixed
|Gender specifications=57% male, 43% female
|Age groups=Adults (18+)
|Age groups specification=Median: 51
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Vitamin D
|Dosage and regime=Oral solution in ampoule containing 100,000 IU of vitamin D3 (an average of 2000 IU/day), every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events, neither of the events were linked to 25OHD serum levels
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Placebo
|Dosage and regime=Oral solution in ampoule containing placebo, every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After a median follow-up of 3 years: no difference by treatment in disease-free survival
|Results after intervention=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Vitamin D level
|Outcome specification=Time of serum 25OHD levels and percentage of patients that reached the 25OHD cut-off level of sufficiency (>30 ng/mL from August to November and >20 ng/mL from January to July) during the 1st year
|Type of measurement=Blood Test
|Results during intervention=Majority of participants: low levels of 25OHD (80%);

Serum levels of 25OHD sharply rose already after 4 months of supplementation in the intervention arm (Median: 33 ng/mL), compared to the placebo arm (Median: 19 ng/mL), the increase persisted with the duration of the treatment (42 ng/mL vs. 22 ng/mL after 3 years treatment)

Additionally: difference in 25OHD increase by Breslow thickness: patients with Breslow thickness below 3 mm had a doubling of 25OHD serum levels from baseline after 12 months, patients with greater thickness experienced a much lower increases in 25OHD by time
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Foundation Umberto Veronesi; partially supported by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=NI
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
PRO:
* Ethics vote
* Randomization with stratification
* Adherence tested by serum concentration
* Comparability of the groups given

CONTRA:
* Further drop-out over time, without information in the flowchart
* Intervention length 3 years, but additional analyses to DFS analyses with supplementation after one year
* No precise indication of the side effects that occurred
* No report on power analysis, but in the discussion it is reported that the study is “underpowered” for the primary endpoint
* Lack of scientific data on the selected dose regimen
}}

Johansson et al. (2021): Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial

2024-10-31T11:41:11Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial
}}
{{Study Note}}
=Brief summary=
104 patients with surgically removed melanomas were included in the study. Divided equally and randomly into 2 arms, one half received 100,000 I.U. vitamin D3 every 50 days for 3 years and the other half received a placebo. The time to relapse was investigated. At the end of the study, no differences were found between the arms in this respect. In further analyses, benefits were only found for patients with a low tumor thickness alone and in combination with a high serum vitamin D level after 12 months of supplementation. It is unclear why most of the reported results of the study were calculated “after 12 months of supplementation”, although the intervention took place over 3 years.

In der Studie von wurden 104 Patienten mit operativ entfernten Melanomen eingeschlossen. Gleichmäßig und zufällig in 2 Arme eingeteilt, erhielt die eine Hälfte alle 50 Tage 100.000 I.E. Vitamin D3 über 3 Jahre und die andere Hälfte ein Placebo. Untersucht wurde die Zeit bis zu einem Rückfall. Am Ende der Studie konnten diesbezüglich keine Unterschiede zwischen den Armen gefunden werden. In weiteren Analysen konnten nur Vorteile gefunden werden für Patienten mit einer geringen Tumordicke allein und in Kombination mit einem hohen Serum Vitamin D Wert nach 12 Monaten Supplementierung. Unklar ist, warum die meisten berichteten Ergebnisse der Studie „nach 12 Monaten Supplementierung“ berechnet wurden, obwohl die Intervention über 3 Jahre stattfand.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Aged 75 years or younger with recent resected stage II cutaneous malignant melanoma; Hematopoietic, hepatic, and renal functionality within normal ranges
|Exclusion criteria=Current use of at least 600 IU/day of supplemental vitamin D or high-dose calcium therapy within the prior 6 month and any prior cancer or other significant diseases that could hamper the participant’s safety or preclude the benefit of vitamin D supplementation
|N randomized=114
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Italy
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
13 follow-up visits (4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 42nd, 48th, 54th, and 60th month)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=NI
|Types of cancer=Skin Cancer – Melanoma
|Stage cancer=Early Stage
|Cancer stage specification=Stage II
|Comorbidity=NI
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Gender=Mixed
|Gender specifications=57% male, 43% female
|Age groups=Adults (18+)
|Age groups specification=Median: 51
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Vitamin D
|Dosage and regime=Oral solution in ampoule containing 100,000 IU of vitamin D3 (an average of 2000 IU/day), every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events, neither of the events were linked to 25OHD serum levels
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Placebo
|Dosage and regime=Oral solution in ampoule containing placebo, every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After a median follow-up of 3 years: no difference by treatment in disease-free survival
|Results after intervention=NA
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Vitamin D level
|Outcome specification=Time of serum 25OHD levels and percentage of patients that reached the 25OHD cut-off level of sufficiency (>30 ng/mL from August to November and >20 ng/mL from January to July) during the 1st year
|Type of measurement=Blood Test
|Results during intervention=Majority of participants: low levels of 25OHD (80%);

Serum levels of 25OHD sharply rose already after 4 months of supplementation in the intervention arm (Median: 33 ng/mL), compared to the placebo arm (Median: 19 ng/mL), the increase persisted with the duration of the treatment (42 ng/mL vs. 22 ng/mL after 3 years treatment)

Additionally: difference in 25OHD increase by Breslow thickness: patients with Breslow thickness below 3 mm had a doubling of 25OHD serum levels from baseline after 12 months, patients with greater thickness experienced a much lower increases in 25OHD by time
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Foundation Umberto Veronesi; partially supported by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=NI
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Randomization with stratification
* Adherence tested by serum concentration
* Comparability of the groups given

CONTRA:
* Further drop-out over time, without information in the flowchart
* Intervention length 3 years, but additional analyses to DFS analyses with supplementation after one year
* No precise indication of the side effects that occurred
* No report on power analysis, but in the discussion it is reported that the study is “underpowered” for the primary endpoint
* Lack of scientific data on the selected dose regimen
}}

Johansson et al. (2021): Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial

2024-10-31T11:40:11Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial
}}
{{Study Note}}
=Brief summary=
104 patients with surgically removed melanomas were included in the study. Divided equally and randomly into 2 arms, one half received 100,000 I.U. vitamin D3 every 50 days for 3 years and the other half received a placebo. The time to relapse was investigated. At the end of the study, no differences were found between the arms in this respect. In further analyses, benefits were only found for patients with a low tumor thickness alone and in combination with a high serum vitamin D level after 12 months of supplementation. It is unclear why most of the reported results of the study were calculated “after 12 months of supplementation”, although the intervention took place over 3 years.

In der Studie von wurden 104 Patienten mit operativ entfernten Melanomen eingeschlossen. Gleichmäßig und zufällig in 2 Arme eingeteilt, erhielt die eine Hälfte alle 50 Tage 100.000 I.E. Vitamin D3 über 3 Jahre und die andere Hälfte ein Placebo. Untersucht wurde die Zeit bis zu einem Rückfall. Am Ende der Studie konnten diesbezüglich keine Unterschiede zwischen den Armen gefunden werden. In weiteren Analysen konnten nur Vorteile gefunden werden für Patienten mit einer geringen Tumordicke allein und in Kombination mit einem hohen Serum Vitamin D Wert nach 12 Monaten Supplementierung. Unklar ist, warum die meisten berichteten Ergebnisse der Studie „nach 12 Monaten Supplementierung“ berechnet wurden, obwohl die Intervention über 3 Jahre stattfand.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Aged 75 years or younger with recent resected stage II cutaneous malignant melanoma; Hematopoietic, hepatic, and renal functionality within normal ranges
|Exclusion criteria=Current use of at least 600 IU/day of supplemental vitamin D or high-dose calcium therapy within the prior 6 month and any prior cancer or other significant diseases that could hamper the participant’s safety or preclude the benefit of vitamin D supplementation
|N randomized=114
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Italy
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
13 follow-up visits (4th, 8th, 12th, 16th, 20th, 24th, 28th, 32nd, 36th, 42nd, 48th, 54th, and 60th month)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=NI
|Types of cancer=Skin Cancer – Melanoma
|Stage cancer=Early Stage
|Cancer stage specification=Stage II
|Comorbidity=NI
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Gender=Mixed
|Gender specifications=57% male, 43% female
|Age groups=Adults (18+)
|Age groups specification=Median: 51
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Vitamin D
|Dosage and regime=Oral solution in ampoule containing 100,000 IU of vitamin D3 (an average of 2000 IU/day), every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events, neither of the events were linked to 25OHD serum levels
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=52
|Drop-out=Not arm specified before analysis: 10
|Drop-out reasons=Not arm specified: 1 pregnancy, 2 voluntary withdrawal,1 osteoporosis treatment
|Intervention=Placebo
|Dosage and regime=Oral solution in ampoule containing placebo, every 50 days, for 3 years
|One-time application=No
|Duration in days=1096
|Side Effects / Interactions=No severe adverse events: 7% grade 1–2 adverse events, no grade 3–4 events
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After a median follow-up of 3 years: no difference by treatment in disease-free survival
|Results after intervention=NA
|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=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Vitamin D level
|Outcome specification=Time of serum 25OHD levels and percentage of patients that reached the 25OHD cut-off level of sufficiency (>30 ng/mL from August to November and >20 ng/mL from January to July) during the 1st year
|Type of measurement=Blood Test
|Results during intervention=Majority of participants: low levels of 25OHD (80%);

Serum levels of 25OHD sharply rose already after 4 months of supplementation in the intervention arm (Median: 33 ng/mL), compared to the placebo arm (Median: 19 ng/mL), the increase persisted with the duration of the treatment (42 ng/mL vs. 22 ng/mL after 3 years treatment)

Additionally: difference in 25OHD increase by Breslow thickness: patients with Breslow thickness below 3 mm had a doubling of 25OHD serum levels from baseline after 12 months, patients with greater thickness experienced a much lower increases in 25OHD by time
|Results after intervention=NA
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Foundation Umberto Veronesi; partially supported by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=NI
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Randomization with stratification
* Adherence tested by serum concentration
* Comparability of the groups given

CONTRA:
* Further drop-out over time, without information in the flowchart
* Intervention length 3 years, but additional analyses to DFS analyses with supplementation after one year
* No precise indication of the side effects that occurred
* No report on power analysis, but in the discussion it is reported that the study is “underpowered” for the primary endpoint
* Lack of scientific data on the selected dose regimen
}}

Walsh et al. (2010): Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma

2024-10-31T09:14:12Z

CHoppe:

{{Reference
|Reference=Publication: Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma
}}
{{Study Note}}
=Brief summary=
In this study, two groups of neck and head tumor patients were compared with regard to the progression-free interval. One group received vitamin D for 3 weeks before the tumor operation and the other group received nothing. In the vitamin D group, it took significantly longer for the disease to progress. As only a very small sample was examined (16 patients per group), this study only provides initial indications of the effectiveness of vitamin D prior to surgery.

In dieser Studie wurden zwei Gruppen von Hals-Kopf Tumor Patienten hinsichtlich des progressionsfreien Intervalls miteinander verglichen. Eine Gruppe bekam 3 Wochen vor der der Tumoroperation 3 Wochen lang Vitamin D und die andere Gruppe bekam nichts. Bei der Vitamin-D-Gruppe dauerte es bedeutsam länger bis zum Fortschreiten der Krankheit. Da nur eine sehr kleine Stichprobe untersucht wurde (16 Patienten pro Gruppe), liefert diese Studie nur erste Hinweise auf die Wirksamkeit von Vitamin D vor einer Operation.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Patients with newly diagnosed head and neck squamous cell carcinoma who were being scheduled for surgery
|Exclusion criteria=Had received immunotherapy or radiation treatment in the previous 3 weeks or concurrent malignancies
|N randomized=32
|Analysis=NI
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=NI
|LoE=1b Oxford 2009
|Outcome timeline=NI
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers - Oral Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=The range of disease stages, based on pathologic evaluation, did not differ among patients enrolled in the two arms
|Comorbidity=No
|Current cancer therapy=Surgery
|Specifications on cancer therapies=Surgical excision
|Previous cancer therapies=Chemotherapy, No therapy, Radiation therapy
|Gender=Mixed
|Gender specifications=44% female, 56% male
|Age groups=Adults (18+)
|Age groups specification=Range: 45-92
Intervention arm: mean: 66
Control arm: mean: 63
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=16
|Drop-out=0
|Drop-out reasons=NA
|Intervention=1,25(OH)2 D
|Dosage and regime=4 μg of 1,25(OH)2 D for each of 3 sequential days, followed by 4 days of no treatment
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=No side effects
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=16
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Untreated
|Dosage and regime=NA
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NA
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=Time between surgical treatment and recurrence of detectable disease
|Type of measurement=Observation
|Results during intervention=Longer time to recurrence in the intervention arm than in the control arm (p = 0.048),
median time to recurrence for the control arm was 181 days, whereas the median time to recurrence for the intervention arm was 620 days
|Results after intervention=NI
|Bias arising from the randomization process=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs and by grants R01CA85266 and R01CA128837 from the National Institutes of Health to MRIY
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=Probably no
|Possibility of placebo effects=Yes
|Other reasons=There was no placebo, the control arm was not treated; possible group differences in vitamin D levels
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=NI
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* No dropout

CONTRA:
* No blinding, control group receives nothing
* No information on vitamin D level, possible group differences
* Very small sample size
* Poor report quality, e.g. hardly any information on baseline characteristics

Walsh et al. (2010): Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma

2024-10-31T08:49:55Z

CHoppe:

{{Reference
|Reference=Publication: Use of alpha,25-dihydroxyvitamin D3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma
}}
{{Study Note}}
=Brief summary=
In this study, two groups of neck and head tumor patients were compared with regard to the progression-free interval. One group received vitamin D for 3 weeks before the tumor operation and the other group received nothing. In the vitamin D group, it took significantly longer for the disease to progress. As only a very small sample was examined (16 patients per group), this study only provides initial indications of the effectiveness of vitamin D prior to surgery.

In dieser Studie wurden zwei Gruppen von Hals-Kopf Tumor Patienten hinsichtlich des progressionsfreien Intervalls miteinander verglichen. Eine Gruppe bekam 3 Wochen vor der der Tumoroperation 3 Wochen lang Vitamin D und die andere Gruppe bekam nichts. Bei der Vitamin-D-Gruppe dauerte es bedeutsam länger bis zum Fortschreiten der Krankheit. Da nur eine sehr kleine Stichprobe untersucht wurde (16 Patienten pro Gruppe), liefert diese Studie nur erste Hinweise auf die Wirksamkeit von Vitamin D vor einer Operation.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Patients with newly diagnosed head and neck squamous cell carcinoma who were being scheduled for surgery
|Exclusion criteria=Had received immunotherapy or radiation treatment in the previous 3 weeks or concurrent malignancies
|N randomized=32
|Analysis=NI
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=NI
|LoE=1b Oxford 2009
|Outcome timeline=NI
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers - Oral Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=The range of disease stages, based on pathologic evaluation, did not differ among patients enrolled in the two arms
|Comorbidity=No
|Current cancer therapy=Surgery
|Specifications on cancer therapies=Surgical excision
|Previous cancer therapies=Chemotherapy, No therapy, Radiation therapy
|Gender=Mixed
|Gender specifications=44% female, 56% male
|Age groups=Adults (18+)
|Age groups specification=Range: 45-92
Intervention arm: mean: 66
Control arm: mean: 63
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=16
|Drop-out=0
|Drop-out reasons=NA
|Intervention=1,25(OH)2 D
|Dosage and regime=4 μg of 1,25(OH)2 D for each of 3 sequential days, followed by 4 days of no treatment
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=No side effects
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=16
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Untreated
|Dosage and regime=NA
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NA
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=Time between surgical treatment and recurrence of detectable disease
|Type of measurement=Observation
|Results during intervention=Longer time to recurrence in the intervention arm than in the control arm (p = 0.048),
median time to recurrence for the control arm was 181 days, whereas the median time to recurrence for the intervention arm was 620 days
|Results after intervention=NI
|Bias arising from the randomization process=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported by the Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs and by grants R01CA85266 and R01CA128837 from the National Institutes of Health to MRIY
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=Probably no
|Possibility of placebo effects=Yes
|Other reasons=There was no placebo, the control arm was not treated
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=NI
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* No dropout

CONTRA:
* No blinding, control group receives nothing
* No information on vitamin D level, possible group differences
* Very small sample size
* Poor report quality, e.g. hardly any information on baseline characteristics

Shapiro et al. (2016): Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)

2024-10-31T08:22:41Z

CHoppe:

{{Reference
|Reference=Publication: Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of high-dose vitamin D3 with regard to muscular symptoms associated with aromatase inhibitors. No significant differences were found between the arms that received high-dose vitamin D and the control arm that only received standard vitamin D therapy. A positive aspect of this study is the consideration of the vitamin D level and the high rate of patients who took the medication as prescribed.

In dieser Studie wurde die Wirksamkeit von hochdosiertem Vitamin D3 hinsichtlich mit Aromatasehemmer assoziierter muskulärer Symptome untersucht. Es fanden sich keine bedeutsamen Unterschiede zwischen den Armen, die hochdosiertes Vitamin D bekam und der Kontrollarm, die nur eine Vitamin-D-Standardtherapie erhielt. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Medikation wie vorgegeben eingenommen haben.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Post-menopausal women >18 years of age, with stage I-IIIA breast cancer, being treated with anastrozole, letrozole or exemestane for at least 30 days and experiencing aromatase inhibitor (AI)–associated musculoskeletal symptoms (AIMSS) at enrollment (prior to the run-in period)
|Exclusion criteria=Received previous aromatase inhibitor treatment, had a history of rheumatoid arthritis, hypercalcemia or were taking excluded medications, unwilling to discontinue other oral supplements containing D3 and/or calcium;
patients with osteoporosis in some cases
|N randomized=116
|Analysis=ITT Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Basline
T1: after 1.5 months

T2: after 3 months

T3: after 6 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=n=53 (46.9%) stage I, n=45 (39.8%) stage II, n=15 (13.3%) stage IIIA
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Hormone therapy, Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 60.9 (8.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=57
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Cholecalciferol (D3)
|Dosage and regime=All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize

Usual care dose of 600 IU D3 capsules daily

+ all participants: 1,000 mg calcium carbonate
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences
|Order number=1
}}
{{Arm
|Arm type=Active control
|Number of participants (arm)=59
|Drop-out=3
|Drop-out reasons=Dropped out during run-in period
|Intervention=Usual Care
|Dosage and regime=All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize

High-dose of 4,000 IU D3 capsules daily

+ all participants: 1,000 mg calcium carbonate
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=Serum 25(OH)D
|Type of measurement=Chemiluminescent immunoassay
|Results during intervention=After the run-in period, the mean baseline serum total 25(OH)D level for all participants was 36.6 (13.0) ng/mL (mean (SD)), and free serum 25(OH)D was 8.0 (3.2) pg/mL,
5 participants in the intervention arm and 4 participants in the control arm had insufficient 25(OH)D levels of ≤ 20ng/mL and no participants were vitamin D deficient;

At 6 months, all participants were vitamin D sufficient,
statistically significant difference in the change in serum 25(OH)D between arms (a decrease of 2.6 (7.6) ng/mL in control arm vs an increase of 9.3 (10.4) in the intervention arm, p < 0.0001).
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Aromatase inhibitor-associated musculoskeletal symptoms
|Type of measurement=AUSCAN (Australian/Canadian Osteoarthritis Hand Index), BCPT (Breast Cancer Prevention Symptom Scales), HGST Maximum (Handgrip Strength Test), PROMIS (Patient-Reported Outcomes Measurement Information System), Western Ontario and McMaster Osteoarthritis Index
|Results during intervention=No statistically significant differences in the change in BCPT-MS scores between arms;
The subscales for pain, stiffness, and physical function on the AUSCAN, WOMAC, PROMIS and the HGST did not show any differences between arms for the change from baseline to 6 months;

Exploratory analyses within each arm did not show clinically significant correlations between free or total serum 25(OH)D and BCPT-MS scores, hand-grip strength or estradiol concentrations
|Results after intervention=NI
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Interaction with cancer treatment
|Outcome specification=Interactions between D3 and anastrozole and letrozole
|Type of measurement=Blood Test
|Results during intervention=High-dose vitamin D3 did not affect steady-state concentrations of anastrozole and letrozole, neither serum total nor free 25(OH)D was significantly associated with the steady-state concentrations
|Results after intervention=NI
|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
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hormone level
|Outcome specification=Reproductive hormone concentrations for estrone, estradiol, testosterone (free and total) and sex-hormone binding globulin
|Type of measurement=Blood Test
|Results during intervention=No significant differences in the change from baseline to 6 months
|Results after intervention=NI
|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
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Research relating to this analysis was funded by grants from the: National Cancer Institute (R21 CA149934), National Institutes of Health Office of Dietary Supplements and the Park Nicollet Institute and Park Nicollet Foundation. This work was supported in part by NIHP30CA77598, using the following University of Minnesota Masonic Cancer Center resource: Clinical Pharmacology and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH UL1TR000114)
|Conflicts of Interest=No conflicts of interest reported by any of the authors
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=NI
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
}}
{{Additional Notes}}
PRO:
* Ethics vote
* High compliance (<95%)
* Intention-to-treat analysis, only low dropout (A: 5%, B: 3%)
* Change in vitamin D levels examined; A significant more change than B (total vitamin D: p < 0.0001; free vit. D: p < 0.0001)

CONTRA:
* Sample too small according to power analysis (< 58 per group)

Shapiro et al. (2016): Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)

2024-10-31T08:22:10Z

CHoppe:

{{Reference
|Reference=Publication: Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of high-dose vitamin D3 with regard to muscular symptoms associated with aromatase inhibitors. No significant differences were found between the arms that received high-dose vitamin D and the control arm that only received standard vitamin D therapy. A positive aspect of this study is the consideration of the vitamin D level and the high rate of patients who took the medication as prescribed.

In dieser Studie wurde die Wirksamkeit von hochdosiertem Vitamin D3 hinsichtlich mit Aromatasehemmer assoziierter muskulärer Symptome untersucht. Es fanden sich keine bedeutsamen Unterschiede zwischen den Armen, die hochdosiertes Vitamin D bekam und der Kontrollarm, die nur eine Vitamin-D-Standardtherapie erhielt. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Medikation wie vorgegeben eingenommen haben.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Post-menopausal women >18 years of age, with stage I-IIIA breast cancer, being treated with anastrozole, letrozole or exemestane for at least 30 days and experiencing aromatase inhibitor (AI)–associated musculoskeletal symptoms (AIMSS) at enrollment (prior to the run-in period)
|Exclusion criteria=Received previous aromatase inhibitor treatment, had a history of rheumatoid arthritis, hypercalcemia or were taking excluded medications, unwilling to discontinue other oral supplements containing D3 and/or calcium;
patients with osteoporosis in some cases
|N randomized=116
|Analysis=ITT Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Basline
T1: after 1.5 months
T2: after 3 months
T3: after 6 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=n=53 (46.9%) stage I, n=45 (39.8%) stage II, n=15 (13.3%) stage IIIA
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Hormone therapy, Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 60.9 (8.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=57
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Cholecalciferol (D3)
|Dosage and regime=All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize

Usual care dose of 600 IU D3 capsules daily

+ all participants: 1,000 mg calcium carbonate
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences
|Order number=1
}}
{{Arm
|Arm type=Active control
|Number of participants (arm)=59
|Drop-out=3
|Drop-out reasons=Dropped out during run-in period
|Intervention=Usual Care
|Dosage and regime=All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize

High-dose of 4,000 IU D3 capsules daily

+ all participants: 1,000 mg calcium carbonate
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=Serum 25(OH)D
|Type of measurement=Chemiluminescent immunoassay
|Results during intervention=After the run-in period, the mean baseline serum total 25(OH)D level for all participants was 36.6 (13.0) ng/mL (mean (SD)), and free serum 25(OH)D was 8.0 (3.2) pg/mL,
5 participants in the intervention arm and 4 participants in the control arm had insufficient 25(OH)D levels of ≤ 20ng/mL and no participants were vitamin D deficient;

At 6 months, all participants were vitamin D sufficient,
statistically significant difference in the change in serum 25(OH)D between arms (a decrease of 2.6 (7.6) ng/mL in control arm vs an increase of 9.3 (10.4) in the intervention arm, p < 0.0001).
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Aromatase inhibitor-associated musculoskeletal symptoms
|Type of measurement=AUSCAN (Australian/Canadian Osteoarthritis Hand Index), BCPT (Breast Cancer Prevention Symptom Scales), HGST Maximum (Handgrip Strength Test), PROMIS (Patient-Reported Outcomes Measurement Information System), Western Ontario and McMaster Osteoarthritis Index
|Results during intervention=No statistically significant differences in the change in BCPT-MS scores between arms;
The subscales for pain, stiffness, and physical function on the AUSCAN, WOMAC, PROMIS and the HGST did not show any differences between arms for the change from baseline to 6 months;

Exploratory analyses within each arm did not show clinically significant correlations between free or total serum 25(OH)D and BCPT-MS scores, hand-grip strength or estradiol concentrations
|Results after intervention=NI
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Interaction with cancer treatment
|Outcome specification=Interactions between D3 and anastrozole and letrozole
|Type of measurement=Blood Test
|Results during intervention=High-dose vitamin D3 did not affect steady-state concentrations of anastrozole and letrozole, neither serum total nor free 25(OH)D was significantly associated with the steady-state concentrations
|Results after intervention=NI
|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
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hormone level
|Outcome specification=Reproductive hormone concentrations for estrone, estradiol, testosterone (free and total) and sex-hormone binding globulin
|Type of measurement=Blood Test
|Results during intervention=No significant differences in the change from baseline to 6 months
|Results after intervention=NI
|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
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Research relating to this analysis was funded by grants from the: National Cancer Institute (R21 CA149934), National Institutes of Health Office of Dietary Supplements and the Park Nicollet Institute and Park Nicollet Foundation. This work was supported in part by NIHP30CA77598, using the following University of Minnesota Masonic Cancer Center resource: Clinical Pharmacology and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH UL1TR000114)
|Conflicts of Interest=No conflicts of interest reported by any of the authors
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=NI
|Samples sufficiently large=Yes
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
}}
{{Additional Notes}}
PRO:
* Ethics vote
* High compliance (<95%)
* Intention-to-treat analysis, only low dropout (A: 5%, B: 3%)
* Change in vitamin D levels examined; A significant more change than B (total vitamin D: p < 0.0001; free vit. D: p < 0.0001)

CONTRA:
* Sample too small according to power analysis (< 58 per group)

Shapiro et al. (2016): Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)

2024-10-31T08:20:31Z

CHoppe:

{{Reference
|Reference=Publication: Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of high-dose vitamin D3 with regard to muscular symptoms associated with aromatase inhibitors. No significant differences were found between the arms that received high-dose vitamin D and the control arm that only received standard vitamin D therapy. A positive aspect of this study is the consideration of the vitamin D level and the high rate of patients who took the medication as prescribed.

In dieser Studie wurde die Wirksamkeit von hochdosiertem Vitamin D3 hinsichtlich mit Aromatasehemmer assoziierter muskulärer Symptome untersucht. Es fanden sich keine bedeutsamen Unterschiede zwischen den Armen, die hochdosiertes Vitamin D bekam und der Kontrollarm, die nur eine Vitamin-D-Standardtherapie erhielt. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Medikation wie vorgegeben eingenommen haben.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Post-menopausal women >18 years of age, with stage I-IIIA breast cancer, being treated with anastrozole, letrozole or exemestane for at least 30 days and experiencing aromatase inhibitor (AI)–associated musculoskeletal symptoms (AIMSS) at enrollment (prior to the run-in period)
|Exclusion criteria=Received previous aromatase inhibitor treatment, had a history of rheumatoid arthritis, hypercalcemia or were taking excluded medications, unwilling to discontinue other oral supplements containing D3 and/or calcium;
patients with osteoporosis in some cases
|N randomized=116
|Analysis=ITT Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Basline
T1: after 1.5 months
T2: after 3 months
T3: after 6 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=n=53 (46.9%) stage I, n=45 (39.8%) stage II, n=15 (13.3%) stage IIIA
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Hormone therapy, Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 60.9 (8.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=57
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Cholecalciferol (D3)
|Dosage and regime=All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize

Usual care dose of 600 IU D3 capsules daily

+ all participants: 1,000 mg calcium carbonate
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences
|Order number=1
}}
{{Arm
|Arm type=Active control
|Number of participants (arm)=59
|Drop-out=3
|Drop-out reasons=Dropped out during run-in period
|Intervention=Usual Care
|Dosage and regime=All participants: 4-week run-in period with 600 IU D3 to allow serum levels to begin to normalize

High-dose of 4,000 IU D3 capsules daily

+ all participants: 1,000 mg calcium carbonate
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Not separated between arms: musculoskeletal (18%) and gastrointestinal (17%), no significant differences
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=Serum 25(OH)D
|Type of measurement=Chemiluminescent immunoassay
|Results during intervention=After the run-in period, the mean baseline serum total 25(OH)D level for all participants was 36.6 (13.0) ng/mL (mean (SD)), and free serum 25(OH)D was 8.0 (3.2) pg/mL,
5 participants in the intervention arm and 4 participants in the control arm had insufficient 25(OH)D levels of ≤ 20ng/mL and no participants were vitamin D deficient;

At 6 months, all participants were vitamin D sufficient,
statistically significant difference in the change in serum 25(OH)D between arms (a decrease of 2.6 (7.6) ng/mL in control arm vs an increase of 9.3 (10.4) in the intervention arm, p < 0.0001).
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Aromatase inhibitor-associated musculoskeletal symptoms
|Type of measurement=AUSCAN (Australian/Canadian Osteoarthritis Hand Index), BCPT (Breast Cancer Prevention Symptom Scales), HGST Maximum (Handgrip Strength Test), PROMIS (Patient-Reported Outcomes Measurement Information System), Western Ontario and McMaster Osteoarthritis Index
|Results during intervention=No statistically significant differences in the change in BCPT-MS scores between arms;
The subscales for pain, stiffness, and physical function on the AUSCAN, WOMAC, PROMIS and the HGST did not show any differences between arms for the change from baseline to 6 months;

Exploratory analyses within each arm did not show clinically significant correlations between free or total serum 25(OH)D and BCPT-MS scores, hand-grip strength or estradiol concentrations
|Results after intervention=NI
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Interaction with cancer treatment
|Outcome specification=Interactions between D3 and anastrozole and letrozole
|Type of measurement=Blood Test
|Results during intervention=High-dose vitamin D3 did not affect steady-state concentrations of anastrozole and letrozole, neither serum total nor free 25(OH)D was significantly associated with the steady-state concentrations
|Results after intervention=NI
|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
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hormone level
|Outcome specification=Reproductive hormone concentrations for estrone, estradiol, testosterone (free and total) and sex-hormone binding globulin
|Type of measurement=Blood Test
|Results during intervention=No significant differences in the change from baseline to 6 months
|Results after intervention=NI
|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
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Research relating to this analysis was funded by grants from the: National Cancer Institute (R21 CA149934), National Institutes of Health Office of Dietary Supplements and the Park Nicollet Institute and Park Nicollet Foundation. This work was supported in part by NIHP30CA77598, using the following University of Minnesota Masonic Cancer Center resource: Clinical Pharmacology and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH UL1TR000114)
|Conflicts of Interest=No conflicts of interest reported by any of the authors
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
}}
{{Additional Notes}}
PRO:
* Ethics vote
* High compliance (<95%)
* Intention-to-treat analysis, only low dropout (A: 5%, B: 3%)
* Change in vitamin D levels examined; A significant more change than B (total vitamin D: p < 0.0001; free vit. D: p < 0.0001)

CONTRA:
* Sample too small according to power analysis (< 58 per group)

Nasser et al. (2017): Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients

2024-10-29T11:55:52Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients
}}
{{Study Note}}
=Brief summary=
In this study, the effectiveness of a vitamin D ointment was investigated with regard to typical adverse skin reactions associated with radiotherapy treatment. Breast cancer patients were given a vitamin D ointment on one side of the treated breast and a normal control ointment on the other half. There were no significant differences between the vitamin D ointment and the control ointment in terms of undesirable skin irritation. A positive aspect of this study is that the patients received both vitamin D and the control ointment at the same time, thus ruling out arm differences at the start of the study. A negative aspect, however, is that only a very small sample was examined and therefore arm differences could not be calculated correctly.

In dieser Studie wurde die Wirksamkeit einer Vitamin D Salbe hinsichtlich typischer unerwünschter Hautreaktionen, die mit der Radiotherapie- Behandlung assoziiert sind, untersucht. Dafür bekamen Brustkrebspatientinnen auf eine Seite der behandelten Brust eine Vitamin D Salbe und auf die andere Hälfte eine normale Kontroll-Salbe. Es zeigten sich keine bedeutsamen Unterschiede zwischen der Vitamin D Salbe und der Kontrollsalbe hinsichtlich der unerwünschten Hautreizungen. Positiv an dieser Studie ist, dass die Patientinnen gleichzeitig sowohl Vitamin D, als auch die Kontrollsalbe bekamen und damit Gruppenunterschiede zum Beginn der Studie ausgeschlossen sind. Negativ ist jedoch, dass nur eine sehr kleine Stichprobe untersucht wurde und deswegen Gruppenunterschiede nicht richtig berechnet werden konnten.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Women aged 18 to 75 years with a confirmed histological diagnosis of localized breast cancer, after breast lumpectomy, and scheduled to receive adjuvant radiotherapy
|Exclusion criteria=Scleroderma, large breast with an inter-field of more than 25cm, or prior radiotherapy to the same breast, indication to lymph node irradiation
|N randomized=23
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Israel
|LoE=1b Oxford 2009
|Outcome timeline=Each week of treatment (T1-T5)
Follow-Up: 2 weeks after treatment end
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=Radiation therapy to the involved breast was delivered by two tangential fields, delivered as a single fraction per day, 5 days a week;
radiation dose was either 42.72 Gy in 16 fractions or 50 Gy in 25 fractions, when indicated, a boost was provided to the tumor bed, to a total dose of 10 Gy administered in 5 fractions of 2 Gy each
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 63 (8), range: 37-74
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=14
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcipotriol and Aqua cream
|Dosage and regime=Calcipotriol to the lateral side of the breast,
Duration: while radiotherapy treatment
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=9
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcipotriol and Aqua cream
|Dosage and regime=Calcipotriol to the medial side of the breast,
Duration: while radiotherapy treatment
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Dermatitis
|Outcome specification=Skin toxicity
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=In 20 out of 23 patients (87%) there was no difference in the skin reaction between the calcipotriol and the Aqua cream treated skin parts of the breast,
in two patients the skin reaction in the calcipotriol treated part of the breast was more intense compared to the Aqua cream treated part, while one patient had lesser skin toxicity in the calcipotriol treated breast part, compared to the breast part treated with Aqua cream,
there was no correlation between breast size, eye color, ethnic background or age, and radiation dermatitis
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=The authors declare no competing interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=NA
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO
* Ethical vote
* All patients receive vitamin D ointment and control ointment on various breast areas

CONTRA
* Very small sample size
* No statistical comparisons made between the groups
* Poor report quality

Nasser et al. (2017): Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients

2024-10-29T11:47:56Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients
}}
{{Study Note}}
=Brief summary=
In this study, the effectiveness of a vitamin D ointment was investigated with regard to typical adverse skin reactions associated with radiotherapy treatment. Breast cancer patients were given a vitamin D ointment on one side of the treated breast and a normal control ointment on the other half. There were no significant differences between the vitamin D ointment and the control ointment in terms of undesirable skin irritation. A positive aspect of this study is that the patients received both vitamin D and the control ointment at the same time, thus ruling out arm differences at the start of the study. A negative aspect, however, is that only a very small sample was examined and therefore arm differences could not be calculated correctly.

In dieser Studie wurde die Wirksamkeit einer Vitamin D Salbe hinsichtlich typischer unerwünschter Hautreaktionen, die mit der Radiotherapie- Behandlung assoziiert sind, untersucht. Dafür bekamen Brustkrebspatientinnen auf eine Seite der behandelten Brust eine Vitamin D Salbe und auf die andere Hälfte eine normale Kontroll-Salbe. Es zeigten sich keine bedeutsamen Unterschiede zwischen der Vitamin D Salbe und der Kontrollsalbe hinsichtlich der unerwünschten Hautreizungen. Positiv an dieser Studie ist, dass die Patientinnen gleichzeitig sowohl Vitamin D, als auch die Kontrollsalbe bekamen und damit Gruppenunterschiede zum Beginn der Studie ausgeschlossen sind. Negativ ist jedoch, dass nur eine sehr kleine Stichprobe untersucht wurde und deswegen Gruppenunterschiede nicht richtig berechnet werden konnten.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Women aged 18 to 75 years with a confirmed histological diagnosis of localized breast cancer, after breast lumpectomy, and scheduled to receive adjuvant radiotherapy
|Exclusion criteria=Scleroderma, large breast with an inter-field of more than 25cm, or prior radiotherapy to the same breast, indication to lymph node irradiation
|N randomized=23
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Israel
|LoE=1b Oxford 2009
|Outcome timeline=Each week of treatment (T1-T5)
Follow-Up: 2 weeks after treatment end
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=Radiation therapy to the involved breast was delivered by two tangential fields, delivered as a single fraction per day, 5 days a week;
radiation dose was either 42.72 Gy in 16 fractions or 50 Gy in 25 fractions, when indicated, a boost was provided to the tumor bed, to a total dose of 10 Gy administered in 5 fractions of 2 Gy each
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 63 (8), range: 37-74
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=14
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcipotriol and Aqua cream
|Dosage and regime=Calcipotriol to the lateral side of the breast,
Duration: while radiotherapy treatment
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=9
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcipotriol and Aqua cream
|Dosage and regime=Calcipotriol to the medial side of the breast,
Duration: while radiotherapy treatment
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Dermatitis
|Outcome specification=Skin toxicity
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=In 20 out of 23 patients (87%) there was no difference in the skin reaction between the calcipotriol and the Aqua cream treated skin parts of the breast,
in two patients the skin reaction in the calcipotriol treated part of the breast was more intense compared to the Aqua cream treated part, while one patient had lesser skin toxicity in the calcipotriol treated breast part, compared to the breast part treated with Aqua cream,
there was no correlation between breast size, eye color, ethnic background or age, and radiation dermatitis
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=The authors declare no competing interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=NA
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO
* Ethical vote
* All patients receive vitamin D ointment and control ointment on various breast areas

CONTRA
* Very small sample size
* No statistical comparisons made between the groups
* Poor report quality

Nasser et al. (2017): Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients

2024-10-29T11:47:30Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients
}}
{{Study Note}}
=Brief summary=
In this study, the effectiveness of a vitamin D ointment was investigated with regard to typical adverse skin reactions associated with radiotherapy treatment. Breast cancer patients were given a vitamin D ointment on one side of the treated breast and a normal control ointment on the other half. There were no significant differences between the vitamin D ointment and the control ointment in terms of undesirable skin irritation. A positive aspect of this study is that the patients received both vitamin D and the control ointment at the same time, thus ruling out arm differences at the start of the study. A negative aspect, however, is that only a very small sample was examined and therefore arm differences could not be calculated correctly.

In dieser Studie wurde die Wirksamkeit einer Vitamin D Salbe hinsichtlich typischer unerwünschter Hautreaktionen, die mit der Radiotherapie- Behandlung assoziiert sind, untersucht. Dafür bekamen Brustkrebspatientinnen auf eine Seite der behandelten Brust eine Vitamin D Salbe und auf die andere Hälfte eine normale Kontroll-Salbe. Es zeigten sich keine bedeutsamen Unterschiede zwischen der Vitamin D Salbe und der Kontrollsalbe hinsichtlich der unerwünschten Hautreizungen. Positiv an dieser Studie ist, dass die Patientinnen gleichzeitig sowohl Vitamin D, als auch die Kontrollsalbe bekamen und damit Gruppenunterschiede zum Beginn der Studie ausgeschlossen sind. Negativ ist jedoch, dass nur eine sehr kleine Stichprobe untersucht wurde und deswegen Gruppenunterschiede nicht richtig berechnet werden konnten.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=No
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Women aged 18 to 75 years with a confirmed histological diagnosis of localized breast cancer, after breast lumpectomy, and scheduled to receive adjuvant radiotherapy
|Exclusion criteria=Scleroderma, large breast with an inter-field of more than 25cm, or prior radiotherapy to the same breast, indication to lymph node irradiation
|N randomized=23
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Israel
|LoE=1b Oxford 2009
|Outcome timeline=Each week of treatment (T1-T5)
Follow-Up: 2 weeks after treatment end
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=Radiation therapy to the involved breast was delivered by two tangential fields, delivered as a single fraction per day, 5 days a week;
radiation dose was either 42.72 Gy in 16 fractions or 50 Gy in 25 fractions, when indicated, a boost was provided to the tumor bed, to a total dose of 10 Gy administered in 5 fractions of 2 Gy each
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 63 (8), range: 37-74
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=14
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcipotriol and Aqua cream
|Dosage and regime=Calcipotriol to the lateral side of the breast,
Duration: while radiotherapy treatment
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=9
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcipotriol and Aqua cream
|Dosage and regime=Calcipotriol to the medial side of the breast,
Duration: while radiotherapy treatment
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Vitamin D was well tolerated by patients with no localized or systemic allergic reactions.
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Dermatitis
|Outcome specification=Skin toxicity
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=In 20 out of 23 patients (87%) there was no difference in the skin reaction between the calcipotriol and the Aqua cream treated skin parts of the breast,
in two patients the skin reaction in the calcipotriol treated part of the breast was more intense compared to the Aqua cream treated part, while one patient had lesser skin toxicity in the calcipotriol treated breast part, compared to the breast part treated with Aqua cream,
there was no correlation between breast size, eye color, ethnic background or age, and radiation dermatitis
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=The authors declare no competing interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=No
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=NA
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO
* Ethical vote
* All patients receive vitamin D ointment and control ointment on various breast areas. breast areas

CONTRA
* Very small sample size
* No statistical comparisons made between the groups
* Poor report quality

Rastelli et al. (2011): Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial

2024-10-29T10:50:32Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial
}}
{{Study Note}}
=Brief summary=
In this study, breast cancer patients who had already received aromatase inhibitor therapy for at least 8 weeks before the start of the study were examined with regard to typical side effects (musculoskeletal disorders, AIMSS) of this treatment. One arm received vitamin D2 in addition to the standard vitamin D/calcium treatment, initially weekly and then monthly, and the other arm received a placebo. The duration of the weekly dose differed depending on the vitamin D level at the start of treatment. After two months, there were significant differences between the two arms in terms of pain experienced in favor of the vitamin D2 arm, but not in terms of AIMSS symptoms. After four and six months, no differences were seen between the arms. In a further analysis, the group differences were considered separately for patients with higher vitamin D levels at the start of the study and those with lower levels. There were no differences between the vitamin D2 and placebo arms for patients with higher levels over the entire duration of the study, but significantly less pain was reported in the vitamin D2 arm for those with lower levels. A positive aspect of this study is the inclusion of vitamin D levels and the high rate of patients who took the medication as prescribed. However, due to the very small sample size and a high drop-out rate, especially in the vitamin D2 arm, this study has a significantly reduced validity.

In dieser Studie wurden Brustkrebspatientinnen, die vor Studienbeginn schon mind. 8 Wochen eine Aromatasehemmer-Therapie erhalten hatten hinsichtlich typischer Nebenwirkungen (Muskel-Skelett Erkrankungen, AIMSS) dieser Behandlung untersucht. Ein Arm bekam zusätzlich zur Vitamin-D/Kalzium Standardbehandlung anfangs wöchentlich und danach monatlich Vitamin D2 und der andere Arm bekam ein Placebo. Je nach Vitamin-D-Spiegel zu Beginn der Behandlung unterschied sich die Dauer der wöchentlichen Dosis. Nach zwei Monaten fanden sich bedeutsame Unterschiede zwischen den beiden Armen bezüglich des erlebten Schmerzes zugunsten des Vitamin-D2-Arms, aber nicht bezüglich der AIMSS-Symptome. Nach vier und sechs Monaten waren keine Unterschiede zwischen den Armen mehr zu sehen. In einer weiteren Analyse wurden die Gruppenunterschiede getrennt für Patienten mit höherem Vitamin D Spiegel zu Beginn der Studie und denen mit niedrigerem Spiegel betrachtet. Dabei zeigte sich bei Patientinnen mit höherem Spiegel über die gesamte Studiendauer keine Unterschiede zwischen Vitamin-D2- und Placebo-Arm, aber bei denen mit niedrigerem Spiegel wurde im Vitamin-D2-Arm bedeutsam weniger Schmerz berichtet. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Mediakation wie vorgegeben eingenommen haben. Diese Studie hat jedoch durch die sehr kleine Stichprobe und eine hohe Ausfallrate vor allem im Vitamin-D2-Arm eine deutlich geminderte Aussagekraft.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB), had completed at least 8 weeks of anastrozole as adjuvant therapy prior to study entry, and were experiencing new or worsening musculoskeletal pain unrelated to any history of trauma;
serum 25OHD level between 10 and 29 ng/ml, serum calcium B10.3 mg/dl, and 24 h urine calcium excretion B250 mg/g creatinine
|Exclusion criteria=Had known metastatic disease to the bone, kidney stones, primary hyperparathyroidism, Paget’s disease of the bone, severe arthritis, rheumatoid arthritis, severe neuropathy or 25OHD C 30 ng/ml;
treatment on the trial was stopped if the patient developed hypercalciuria (C250 mg/g creatinine) or hypercalcemia (C10.3 mg/dl)
|N randomized=60
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline
T1: At 2 months
T2: At 4 months
T3: At 6 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB)
|Comorbidity=NI
|Current cancer therapy=Hormone therapy
|Specifications on cancer therapies=Anastrozole
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: mean (SD): 60 (8.8)
Placebo arm: mean (SD): 63 (7.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=30
|Drop-out=2
|Drop-out reasons=Never started treatment
|Intervention=Vitamin D
|Dosage and regime=Daily supplementation with 1,000 mg of calcium carbonate and 400 IU of Vitamin D3:
Baseline 25OHD levels between 20 and 29 ng/ml were randomized to receive vitamin D2, one 50,000 IU capsule, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study;
Baseline 25OHD levels between 10 and 19 ng/ml received Vitamin D2 50,000 IU capsule or a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No toxicities or significant adverse events.
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=30
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Baseline 25OHD levels between 20 and 29 ng/ml got a placebo, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study;
Baseline 25OHD levels between 10 and 19 ng/ml received a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No.
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Syndrome may resemble arthritis, but may also mimic fibromyalg
|Type of measurement=BPI-SF (Brief Pain Inventory - Short Form), FIQ (Fibromyalgia Impact Questionnaire), HAQ-DI (Health Assessment Questionnaire-Disability Index)
|Results during intervention=Pain decreased significantly at 2 months in the intervention arm compared to placebo,
significant differences were found on several measures of pain intensity including FIQ pain (3.3 vs. 4.6, p = 0.0045), BPI worst pain (3.6 vs. 5.1, p = 0.04), BPI average pain (2.7 vs. 3.7, p = 0.0067), and BPI pain severity (2.7 vs. 3.5, p = 0.04), as well as on a measure of interference on subjects’ life activities (BPI interference, 1.8 vs. 2.5, p = 0.034);
the effect on pain was not observed at 4 and 6 months when the majority of subjects were switched from weekly to monthly vitamin D supplementation;

The improvement in pain severity and interference with daily activities was significant when averaging across all time points (2, 4, 6 months) for the patients with baseline vitamin D deficiency (10–19 ng/ml), but not in the patients with baseline insufficiency (20–29 ng/ml);

No significant effect was found on the HAQ-DI questionnaire in the overall or strata analysis
|Results after intervention=NI
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=BMD (Bone Mineral Density)
|Outcome specification=Bone Mineral Density of the lumbar spine, total femur, and femoral neck
|Type of measurement=DXA (Dual energy X-ray Absorptiometry)
|Results during intervention=No significant differences between the arms
|Results after intervention=NI
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=mean serum 25OHD
|Type of measurement=Blood Test
|Results during intervention=At the end of the study, mean serum 25OHD was higher in the intervention arm (p = 0.03) and a greater proportion of subjects normalized serum 25OHD (43% vs. 11.5%, p = 0.02);
no linear relationship (r = 0.15, p = 0.5) was found between changes in vitamin D levels and changes in pain scores from baseline to 6 months
|Results after intervention=NI
|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
|Order number=3
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=Some patients never started treatment
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NI
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Double blinding
* High compliance rate (96%)
* Intention-to-treat
* Information on the development of vitamin D levels

CONTRA:
* Small sample (according to power analysis > 30 per group)
* High dropout rate after 6 months: A: 30%, B: 13%
* Multiple testing (all time points compared individually)
* Poor report quality

Rastelli et al. (2011): Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial

2024-10-29T10:48:44Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial
}}
{{Study Note}}
=Brief summary=
In this study, breast cancer patients who had already received aromatase inhibitor therapy for at least 8 weeks before the start of the study were examined with regard to typical side effects (musculoskeletal disorders, AIMSS) of this treatment. One arm received vitamin D2 in addition to the standard vitamin D/calcium treatment, initially weekly and then monthly, and the other arm received a placebo. The duration of the weekly dose differed depending on the vitamin D level at the start of treatment. After two months, there were significant differences between the two arms in terms of pain experienced in favor of the vitamin D2 arm, but not in terms of AIMSS symptoms. After four and six months, no differences were seen between the arms. In a further analysis, the group differences were considered separately for patients with higher vitamin D levels at the start of the study and those with lower levels. There were no differences between the vitamin D2 and placebo arms for patients with higher levels over the entire duration of the study, but significantly less pain was reported in the vitamin D2 arm for those with lower levels. A positive aspect of this study is the inclusion of vitamin D levels and the high rate of patients who took the medication as prescribed. However, due to the very small sample size and a high drop-out rate, especially in the vitamin D2 arm, this study has a significantly reduced validity.

In dieser Studie wurden Brustkrebspatientinnen, die vor Studienbeginn schon mind. 8 Wochen eine Aromatasehemmer-Therapie erhalten hatten hinsichtlich typischer Nebenwirkungen (Muskel-Skelett Erkrankungen, AIMSS) dieser Behandlung untersucht. Ein Arm bekam zusätzlich zur Vitamin-D/Kalzium Standardbehandlung anfangs wöchentlich und danach monatlich Vitamin D2 und der andere Arm bekam ein Placebo. Je nach Vitamin-D-Spiegel zu Beginn der Behandlung unterschied sich die Dauer der wöchentlichen Dosis. Nach zwei Monaten fanden sich bedeutsame Unterschiede zwischen den beiden Armen bezüglich des erlebten Schmerzes zugunsten des Vitamin-D2-Arms, aber nicht bezüglich der AIMSS-Symptome. Nach vier und sechs Monaten waren keine Unterschiede zwischen den Armen mehr zu sehen. In einer weiteren Analyse wurden die Gruppenunterschiede getrennt für Patienten mit höherem Vitamin D Spiegel zu Beginn der Studie und denen mit niedrigerem Spiegel betrachtet. Dabei zeigte sich bei Patientinnen mit höherem Spiegel über die gesamte Studiendauer keine Unterschiede zwischen Vitamin-D2- und Placebo-Arm, aber bei denen mit niedrigerem Spiegel wurde im Vitamin-D2-Arm bedeutsam weniger Schmerz berichtet. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Mediakation wie vorgegeben eingenommen haben. Diese Studie hat jedoch durch die sehr kleine Stichprobe und eine hohe Ausfallrate vor allem im Vitamin-D2-Arm eine deutlich geminderte Aussagekraft.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB), had completed at least 8 weeks of anastrozole as adjuvant therapy prior to study entry, and were experiencing new or worsening musculoskeletal pain unrelated to any history of trauma;
serum 25OHD level between 10 and 29 ng/ml, serum calcium B10.3 mg/dl, and 24 h urine calcium excretion B250 mg/g creatinine
|Exclusion criteria=Had known metastatic disease to the bone, kidney stones, primary hyperparathyroidism, Paget’s disease of the bone, severe arthritis, rheumatoid arthritis, severe neuropathy or 25OHD C 30 ng/ml;
treatment on the trial was stopped if the patient developed hypercalciuria (C250 mg/g creatinine) or hypercalcemia (C10.3 mg/dl)
|N randomized=60
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline
T1: At 2 months
T2: At 4 months
T3: At 6 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB)
|Comorbidity=NI
|Current cancer therapy=Hormone therapy
|Specifications on cancer therapies=Anastrozole
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: mean (SD): 60 (8.8)
Placebo arm: mean (SD): 63 (7.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=30
|Drop-out=2
|Drop-out reasons=Never started treatment
|Intervention=Vitamin D
|Dosage and regime=Daily supplementation with 1,000 mg of calcium carbonate and 400 IU of Vitamin D3:
Baseline 25OHD levels between 20 and 29 ng/ml were randomized to receive vitamin D2, one 50,000 IU capsule, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study;
Baseline 25OHD levels between 10 and 19 ng/ml received Vitamin D2 50,000 IU capsule or a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No toxicities or significant adverse events.
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=30
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Baseline 25OHD levels between 20 and 29 ng/ml got a placebo, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study;
Baseline 25OHD levels between 10 and 19 ng/ml received a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No.
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Syndrome may resemble arthritis, but may also mimic fibromyalg
|Type of measurement=BPI-SF (Brief Pain Inventory - Short Form), FIQ (Fibromyalgia Impact Questionnaire), HAQ-DI (Health Assessment Questionnaire-Disability Index)
|Results during intervention=Pain decreased significantly at 2 months in the intervention arm compared to placebo,
significant differences were found on several measures of pain intensity including FIQ pain (3.3 vs. 4.6, p = 0.0045), BPI worst pain (3.6 vs. 5.1, p = 0.04), BPI average pain (2.7 vs. 3.7, p = 0.0067), and BPI pain severity (2.7 vs. 3.5, p = 0.04), as well as on a measure of interference on subjects’ life activities (BPI interference, 1.8 vs. 2.5, p = 0.034);
the effect on pain was not observed at 4 and 6 months when the majority of subjects were switched from weekly to monthly vitamin D supplementation;

The improvement in pain severity and interference with daily activities was significant when averaging across all time points (2, 4, 6 months) for the patients with baseline vitamin D deficiency (10–19 ng/ml), but not in the patients with baseline insufficiency (20–29 ng/ml);

No significant effect was found on the HAQ-DI questionnaire in the overall or strata analysis
|Results after intervention=NI
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=BMD (Bone Mineral Density)
|Outcome specification=Bone Mineral Density of the lumbar spine, total femur, and femoral neck
|Type of measurement=DXA (Dual energy X-ray Absorptiometry)
|Results during intervention=No significant differences between the arms
|Results after intervention=NI
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=mean serum 25OHD
|Type of measurement=Blood Test
|Results during intervention=At the end of the study, mean serum 25OHD was higher in the intervention arm (p = 0.03) and a greater proportion of subjects normalized serum 25OHD (43% vs. 11.5%, p = 0.02);
no linear relationship (r = 0.15, p = 0.5) was found between changes in vitamin D levels and changes in pain scores from baseline to 6 months
|Results after intervention=NI
|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
|Order number=3
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=Some patients never started treatment
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Double blinding
* High compliance rate (96%)
* Intention-to-treat
* Information on the development of vitamin D levels

CONTRA:
* Small sample (according to power analysis > 30 per group)
* High dropout rate after 6 months: A: 30%, B: 13%
* Multiple testing (all time points compared individually)
* Poor report quality

Rastelli et al. (2011): Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial

2024-10-29T10:48:00Z

CHoppe:

{{Reference
|Reference=Publication: Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial
}}
{{Study Note}}
=Brief summary=
In this study, breast cancer patients who had already received aromatase inhibitor therapy for at least 8 weeks before the start of the study were examined with regard to typical side effects (musculoskeletal disorders, AIMSS) of this treatment. One arm received vitamin D2 in addition to the standard vitamin D/calcium treatment, initially weekly and then monthly, and the other arm received a placebo. The duration of the weekly dose differed depending on the vitamin D level at the start of treatment. After two months, there were significant differences between the two arms in terms of pain experienced in favor of the vitamin D2 arm, but not in terms of AIMSS symptoms. After four and six months, no differences were seen between the arms. In a further analysis, the group differences were considered separately for patients with higher vitamin D levels at the start of the study and those with lower levels. There were no differences between the vitamin D2 and placebo arms for patients with higher levels over the entire duration of the study, but significantly less pain was reported in the vitamin D2 arm for those with lower levels. A positive aspect of this study is the inclusion of vitamin D levels and the high rate of patients who took the medication as prescribed. However, due to the very small sample size and a high drop-out rate, especially in the vitamin D2 arm, this study has a significantly reduced validity.

In dieser Studie wurden Brustkrebspatientinnen, die vor Studienbeginn schon mind. 8 Wochen eine Aromatasehemmer-Therapie erhalten hatten hinsichtlich typischer Nebenwirkungen (Muskel-Skelett Erkrankungen, AIMSS) dieser Behandlung untersucht. Ein Arm bekam zusätzlich zur Vitamin-D/Kalzium Standardbehandlung anfangs wöchentlich und danach monatlich Vitamin D2 und der andere Arm bekam ein Placebo. Je nach Vitamin-D-Spiegel zu Beginn der Behandlung unterschied sich die Dauer der wöchentlichen Dosis. Nach zwei Monaten fanden sich bedeutsame Unterschiede zwischen den beiden Armen bezüglich des erlebten Schmerzes zugunsten des Vitamin-D2-Arms, aber nicht bezüglich der AIMSS-Symptome. Nach vier und sechs Monaten waren keine Unterschiede zwischen den Armen mehr zu sehen. In einer weiteren Analyse wurden die Gruppenunterschiede getrennt für Patienten mit höherem Vitamin D Spiegel zu Beginn der Studie und denen mit niedrigerem Spiegel betrachtet. Dabei zeigte sich bei Patientinnen mit höherem Spiegel über die gesamte Studiendauer keine Unterschiede zwischen Vitamin-D2- und Placebo-Arm, aber bei denen mit niedrigerem Spiegel wurde im Vitamin-D2-Arm bedeutsam weniger Schmerz berichtet. Positiv an dieser Studie ist die Berücksichtigung des Vitamin-D-Spiegels und die hohe Rate an Patientinnen, die die Mediakation wie vorgegeben eingenommen haben. Diese Studie hat jedoch durch die sehr kleine Stichprobe und eine hohe Ausfallrate vor allem im Vitamin-D2-Arm eine deutlich geminderte Aussagekraft.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB), had completed at least 8 weeks of anastrozole as adjuvant therapy prior to study entry, and were experiencing new or worsening musculoskeletal pain unrelated to any history of trauma;
serum 25OHD level between 10 and 29 ng/ml, serum calcium B10.3 mg/dl, and 24 h urine calcium excretion B250 mg/g creatinine
|Exclusion criteria=Had known metastatic disease to the bone, kidney stones, primary hyperparathyroidism, Paget’s disease of the bone, severe arthritis, rheumatoid arthritis, severe neuropathy or 25OHD C 30 ng/ml;
treatment on the trial was stopped if the patient developed hypercalciuria (C250 mg/g creatinine) or hypercalcemia (C10.3 mg/dl)
|N randomized=60
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline
T1: At 2 months
T2: At 4 months
T3: At 6 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Hormone receptor positive invasive nonmetastatic breast cancer (Stage I-IIIB)
|Comorbidity=NI
|Current cancer therapy=Hormone therapy
|Specifications on cancer therapies=Anastrozole
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: mean (SD): 60 (8.8)
Placebo arm: mean (SD): 63 (7.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=30
|Drop-out=2
|Drop-out reasons=Never started treatment
|Intervention=Vitamin D
|Dosage and regime=Daily supplementation with 1,000 mg of calcium carbonate and 400 IU of Vitamin D3:
Baseline 25OHD levels between 20 and 29 ng/ml were randomized to receive vitamin D2, one 50,000 IU capsule, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study;
Baseline 25OHD levels between 10 and 19 ng/ml received Vitamin D2 50,000 IU capsule or a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No toxicities or significant adverse events.
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=30
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Baseline 25OHD levels between 20 and 29 ng/ml got a placebo, orally once a week for a total of eight consecutive weeks, and then once a month for the rest of the study;
Baseline 25OHD levels between 10 and 19 ng/ml received a matching placebo orally for 16 consecutive weeks and then once a month for the rest of the study
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No.
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Syndrome may resemble arthritis, but may also mimic fibromyalg
|Type of measurement=BPI-SF (Brief Pain Inventory - Short Form), FIQ (Fibromyalgia Impact Questionnaire), HAQ-DI (Health Assessment Questionnaire-Disability Index)
|Results during intervention=Pain decreased significantly at 2 months in the intervention arm compared to placebo,
significant differences were found on several measures of pain intensity including FIQ pain (3.3 vs. 4.6, p = 0.0045), BPI worst pain (3.6 vs. 5.1, p = 0.04), BPI average pain (2.7 vs. 3.7, p = 0.0067), and BPI pain severity (2.7 vs. 3.5, p = 0.04), as well as on a measure of interference on subjects’ life activities (BPI interference, 1.8 vs. 2.5, p = 0.034);
the effect on pain was not observed at 4 and 6 months when the majority of subjects were switched from weekly to monthly vitamin D supplementation;

The improvement in pain severity and interference with daily activities was significant when averaging across all time points (2, 4, 6 months) for the patients with baseline vitamin D deficiency (10–19 ng/ml), but not in the patients with baseline insufficiency (20–29 ng/ml);

No significant effect was found on the HAQ-DI questionnaire in the overall or strata analysis
|Results after intervention=NI
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=BMD (Bone Mineral Density)
|Outcome specification=Bone Mineral Density of the lumbar spine, total femur, and femoral neck
|Type of measurement=DXA (Dual energy X-ray Absorptiometry)
|Results during intervention=No significant differences between the arms
|Results after intervention=NI
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=mean serum 25OHD
|Type of measurement=Blood Test
|Results during intervention=At the end of the study, mean serum 25OHD was higher in the intervention arm (p = 0.03) and a greater proportion of subjects normalized serum 25OHD (43% vs. 11.5%, p = 0.02);
no linear relationship (r = 0.15, p = 0.5) was found between changes in vitamin D levels and changes in pain scores from baseline to 6 months
|Results after intervention=NI
|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
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=NI
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=No
|Reasons given for samples being too small according to power analysis=Some patients never started treatment
|Samples sufficiently large=No
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=No
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Double blinding
* High compliance rate (96%)
* Intention-to-treat
* Information on the development of vitamin D levels

CONTRA:
* Small sample (according to power analysis > 30 per group)
* High dropout rate after 6 months: A: 30%, B: 13%
* Multiple testing (all time points compared individually)
* Poor report quality

Scher et al. (2011): Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer

2024-10-29T09:48:43Z

CHoppe:

{{Reference
|Reference=Publication: Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer
}}
{{Study Note}}
=Brief summary=
In this study, prostate cancer patients were examined, with one half receiving docetaxel and a vitamin D analog (arm A) and the other half docetaxel and prednisone (arm B). Patients in arm A lived significantly shorter than those in arm B. There were no significant differences with regard to events such as pulmonary embolism or thrombosis. A positive aspect of this study is the large sample from different countries. A negative aspect, however, is that the two arms differed with regard to docetaxel treatment and therefore it cannot be conclusively clarified whether the shorter survival time was caused by vitamin D or by the other differences in treatment.

In dieser Studie wurden Prostatakarzinompatienten untersucht, wobei die eine Hälfte Docetaxel und ein Vitamin D-Analog (Arm A) und die andere Docetaxel und Prednison (Arm B) bekam. In Arm A lebten die Patienten bedeutsam kürzer als in Arm B. Hinsichtlich Ereignisse wie Lungenembolie oder Thrombose zeigten sich keine bedeutsamen Unterschiede. Positiv an dieser Studie ist die große Stichprobe aus verschiedenen Ländern. Negativ ist jedoch, dass sich die beiden Arme hinsichtlich der Docetaxel-Behandlung unterschieden und deswegen nicht abschließend geklärt werden kann, ob die verkürzte Überlebenszeit durch Vitamin D oder durch die anderen Unterschiede in der Behandlung hervorgerufen wurde.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Pathologically or cytologically proven adenocarcinoma of the prostate, metastatic disease (documented by computed tomograpghy, magnetic resonance imaging, or bone scan), disease progression after medical or surgical castration (documented by PSA, radiologic imaging of soft-tissue lesions, and/or bone scan;
life expectancy longer than 3 months, normal liver and kidney function, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and testosterone lower than 50 ng/dL
|Exclusion criteria=Prior cytotoxic chemotherapy (except estramustine monotherapy), bone-seeking radioisotope therapy, prior untreated CNS involvement, or malignancy other than prostate cancer (except adequately treated basal or squamous cell skin cancer or any other cancer from which the individual had been disease free for > 5 years), history of hypercalcemia or vitamin D toxicity, active uncontrolled infection, symptomatic peripheral neuropathy of grade > 2, or hypersensitivity to any treatment component;
use of calcium supplements higher than 500 mg and pharmacologic doses of vitamin D or its derivatives (> 400 U or 10 μg)
|N randomized=953
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Canada, Czech Republic, Germany, Hungary, Romania, Serbia, Slovakia, United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: within 14 days of random assignment
72 hours preceding each day 2

Follow-Up: after 48 weeks (only for survival)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Intervention arm: 36 mg/m2 docetaxel for 30-minute infusion on days 2, 9, and 16; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel; nine doses of dexamethasone per 28-day, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression
Control arm: 1-hour infusion of docetaxel at 75 mg/m2 body-surface area on day 2; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel infusion; three doses per 21-day cycle, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups specification=Intervention arm: mean: 70.4
Control arm: mean: 70.9
}}
=Arms=

{{Arm
|Arm type=Active control
|Number of participants (arm)=476
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Prednisone
|Dosage and regime=21-day dosing cycles with 5-mg oral prednisone twice daily
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Overall adverse events 93.3%, severe adverse events: 33%;
highest incidence of adverse events occurred in the gastrointestinal system: 72%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent,
most common severe adverse events: febrile neutropenia 4.6%, pneumonia 2.9%, dehydration 2.7%, disease progression 1.3%, dyspnea 1.1%, deep vein thrombosis 2.5%, 0.6% hypercalcemia, 0.2% hypercalcemia grade ≥ 3
|Order number=2
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=477
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Vitamin D
|Dosage and regime=28-day dosing cycles of 45-μg oral DN-101 on days 1, 8, and 15, continue DN-101 for up to 48 weeks or until unacceptable DN-101 toxicity or experimental agents were initiated
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Overall adverse events 93.5%, severe adverse events: 35%;
highest incidence of adverse events occurred in the gastrointestinal system: 79%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent,
most common severe adverse events: febrile neutropenia 1.0%, pneumonia 3.1%, dehydration 2.5%, disease progression 2.5%, dyspnea 2.1%, deep vein thrombosis 0.6%, 5.9% hypercalcemia, 0.8% hypercalcemia grade ≥ 3
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=Time between random assignment and death, regardless of cause
|Type of measurement=Observation
|Results during intervention=At study termination, 129 deaths (13.5%) had occurred; 48 deaths (10.1%) in the control arm and 81 (17.0%) in intervention arm
|Results after intervention=Six months after study termination, a total of 312 deaths (32.7%) had occurred: 138 (29.0%) in the control arm and 174 (36.5%) in intervention arm;
primary cause of death was prostate cancer in 108 participants (78.3%) in control arm and 142 (81.6%) in intervention arm,
median overall survival was 20.2 months (95% CI, 18.8 to 23.0) in control arm and 17.8 months (95% CI, 16.0 to 19.5) in intervention arm,
survival rate was significantly lower in the intervention arm (p = .002)
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Thromboembolic event rates
|Outcome specification=Defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis, and arterial thrombosis
|Type of measurement=NI
|Results during intervention=Similar rates of thromboembolic events
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Fees/research allowance from pharmaceutical companies or some authors advice them
|Conflicts of Interest=According to given information there are some financial conflicts or conflicts of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=There is no data concerning vitamin D levels and the arms are receiving different kinds of chemotherapy
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Double blinding
* Active control group
* Large sample size
* Intention-to-treat

CONTRA:
* Vitamin D levels not assessed
* Group differences not excluded
* Different treatment regimens for chemotherapy, per arm, no comparability of arm A and B
* High dropout at follow-up A: 44%, B: 43%

Scher et al. (2011): Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer

2024-10-29T09:48:12Z

CHoppe:

{{Reference
|Reference=Publication: Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer
}}
{{Study Note}}
=Brief summary=
In this study, prostate cancer patients were examined, with one half receiving docetaxel and a vitamin D analog (arm A) and the other half docetaxel and prednisone (arm B). Patients in arm A lived significantly shorter than those in arm B. There were no significant differences with regard to events such as pulmonary embolism or thrombosis. A positive aspect of this study is the large sample from different countries. A negative aspect, however, is that the two arms differed with regard to docetaxel treatment and therefore it cannot be conclusively clarified whether the shorter survival time was caused by vitamin D or by the other differences in treatment.

In dieser Studie wurden Prostatakarzinompatienten untersucht, wobei die eine Hälfte Docetaxel und ein Vitamin D-Analog (Arm A) und die andere Docetaxel und Prednison (Arm B) bekam. In Arm A lebten die Patienten bedeutsam kürzer als in Arm B. Hinsichtlich Ereignisse wie Lungenembolie oder Thrombose zeigten sich keine bedeutsamen Unterschiede. Positiv an dieser Studie ist die große Stichprobe aus verschiedenen Ländern. Negativ ist jedoch, dass sich die beiden Arme hinsichtlich der Docetaxel-Behandlung unterschieden und deswegen nicht abschließend geklärt werden kann, ob die verkürzte Überlebenszeit durch Vitamin D oder durch die anderen Unterschiede in der Behandlung hervorgerufen wurde.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Pathologically or cytologically proven adenocarcinoma of the prostate, metastatic disease (documented by computed tomograpghy, magnetic resonance imaging, or bone scan), disease progression after medical or surgical castration (documented by PSA, radiologic imaging of soft-tissue lesions, and/or bone scan;
life expectancy longer than 3 months, normal liver and kidney function, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and testosterone lower than 50 ng/dL
|Exclusion criteria=Prior cytotoxic chemotherapy (except estramustine monotherapy), bone-seeking radioisotope therapy, prior untreated CNS involvement, or malignancy other than prostate cancer (except adequately treated basal or squamous cell skin cancer or any other cancer from which the individual had been disease free for > 5 years), history of hypercalcemia or vitamin D toxicity, active uncontrolled infection, symptomatic peripheral neuropathy of grade > 2, or hypersensitivity to any treatment component;
use of calcium supplements higher than 500 mg and pharmacologic doses of vitamin D or its derivatives (> 400 U or 10 μg)
|N randomized=953
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Canada, Czech Republic, Germany, Hungary, Romania, Serbia, Slovakia, United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: within 14 days of random assignment
72 hours preceding each day 2

Follow-Up: after 48 weeks (only for survival)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Intervention arm: 36 mg/m2 docetaxel for 30-minute infusion on days 2, 9, and 16; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel; nine doses of dexamethasone per 28-day, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression
Control arm: 1-hour infusion of docetaxel at 75 mg/m2 body-surface area on day 2; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel infusion; three doses per 21-day cycle, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups specification=Intervention arm: mean: 70.4
Control arm: mean: 70.9
}}
=Arms=

{{Arm
|Arm type=Active control
|Number of participants (arm)=476
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Prednisone
|Dosage and regime=21-day dosing cycles with 5-mg oral prednisone twice daily
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Overall adverse events 93.3%, severe adverse events: 33%;
highest incidence of adverse events occurred in the gastrointestinal system: 72%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent,
most common severe adverse events: febrile neutropenia 4.6%, pneumonia 2.9%, dehydration 2.7%, disease progression 1.3%, dyspnea 1.1%, deep vein thrombosis 2.5%, 0.6% hypercalcemia, 0.2% hypercalcemia grade ≥ 3
|Order number=2
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=477
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Vitamin D
|Dosage and regime=28-day dosing cycles of 45-μg oral DN-101 on days 1, 8, and 15, continue DN-101 for up to 48 weeks or until unacceptable DN-101 toxicity or experimental agents were initiated
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Overall adverse events 93.5%, severe adverse events: 35%;
highest incidence of adverse events occurred in the gastrointestinal system: 79%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent,
most common severe adverse events: febrile neutropenia 1.0%, pneumonia 3.1%, dehydration 2.5%, disease progression 2.5%, dyspnea 2.1%, deep vein thrombosis 0.6%, 5.9% hypercalcemia, 0.8% hypercalcemia grade ≥ 3
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=Time between random assignment and death, regardless of cause
|Type of measurement=Observation
|Results during intervention=At study termination, 129 deaths (13.5%) had occurred; 48 deaths (10.1%) in the control arm and 81 (17.0%) in intervention arm
|Results after intervention=Six months after study termination, a total of 312 deaths (32.7%) had occurred: 138 (29.0%) in the control arm and 174 (36.5%) in intervention arm;
primary cause of death was prostate cancer in 108 participants (78.3%) in control arm and 142 (81.6%) in intervention arm,
median overall survival was 20.2 months (95% CI, 18.8 to 23.0) in control arm and 17.8 months (95% CI, 16.0 to 19.5) in intervention arm,
survival rate was significantly lower in the intervention arm (p = .002)
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Thromboembolic event rates
|Outcome specification=Defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis, and arterial thrombosis
|Type of measurement=NI
|Results during intervention=Similar rates of thromboembolic events
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Fees/research allowance from pharmaceutical companies or some authors advice them
|Conflicts of Interest=According to given information there are some financial conflicts or conflicts of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=There is no data concerning vitamin D levels and the arms are receiving different kinds of chemotherapy
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Double blinding
* Active control group
* Large sample size
* Intention-to-treat

CONTRA:
* Vitamin D levels not assessed,
* Group differences not excluded
* Different treatment regimens for chemotherapy, per arm, no comparability of arm A and B
* High dropout at follow-up A: 44%, B: 43%

Scher et al. (2011): Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer

2024-10-29T09:30:11Z

CHoppe:

{{Reference
|Reference=Publication: Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer
}}
{{Study Note}}
=Brief summary=
In this study, prostate cancer patients were examined, with one half receiving docetaxel and a vitamin D analog (arm A) and the other half docetaxel and prednisone (arm B). Patients in arm A lived significantly shorter than those in arm B. There were no significant differences with regard to events such as pulmonary embolism or thrombosis. A positive aspect of this study is the large sample from different countries. A negative aspect, however, is that the two arms differed with regard to docetaxel treatment and therefore it cannot be conclusively clarified whether the shorter survival time was caused by vitamin D or by the other differences in treatment.

In dieser Studie wurden Prostatakarzinompatienten untersucht, wobei die eine Hälfte Docetaxel und ein Vitamin D-Analog (Arm A) und die andere Docetaxel und Prednison (Arm B) bekam. In Arm A lebten die Patienten bedeutsam kürzer als in Arm B. Hinsichtlich Ereignisse wie Lungenembolie oder Thrombose zeigten sich keine bedeutsamen Unterschiede. Positiv an dieser Studie ist die große Stichprobe aus verschiedenen Ländern. Negativ ist jedoch, dass sich die beiden Arme hinsichtlich der Docetaxel-Behandlung unterschieden und deswegen nicht abschließend geklärt werden kann, ob die verkürzte Überlebenszeit durch Vitamin D oder durch die anderen Unterschiede in der Behandlung hervorgerufen wurde.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Pathologically or cytologically proven adenocarcinoma of the prostate, metastatic disease (documented by computed tomograpghy, magnetic resonance imaging, or bone scan), disease progression after medical or surgical castration (documented by PSA, radiologic imaging of soft-tissue lesions, and/or bone scan;
life expectancy longer than 3 months, normal liver and kidney function, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and testosterone lower than 50 ng/dL
|Exclusion criteria=Prior cytotoxic chemotherapy (except estramustine monotherapy), bone-seeking radioisotope therapy, prior untreated CNS involvement, or malignancy other than prostate cancer (except adequately treated basal or squamous cell skin cancer or any other cancer from which the individual had been disease free for > 5 years), history of hypercalcemia or vitamin D toxicity, active uncontrolled infection, symptomatic peripheral neuropathy of grade > 2, or hypersensitivity to any treatment component;
use of calcium supplements higher than 500 mg and pharmacologic doses of vitamin D or its derivatives (> 400 U or 10 μg)
|N randomized=953
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=Canada, Czech Republic, Germany, Hungary, Romania, Serbia, Slovakia, United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: within 14 days of random assignment
72 hours preceding each day 2

Follow-Up: after 48 weeks (only for survival)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Intervention arm: 36 mg/m2 docetaxel for 30-minute infusion on days 2, 9, and 16; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel; nine doses of dexamethasone per 28-day, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression
Control arm: 1-hour infusion of docetaxel at 75 mg/m2 body-surface area on day 2; and 8-mg oral dexamethasone about 12 hours, 3 hours, and 1 hour before docetaxel infusion; three doses per 21-day cycle, continued for up to 30 weeks or until unacceptable docetaxel toxicity or clinical disease progression
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups specification=Intervention arm: mean: 70.4
Control arm: mean: 70.9
}}
=Arms=

{{Arm
|Arm type=Active control
|Number of participants (arm)=476
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Prednisone
|Dosage and regime=21-day dosing cycles with 5-mg oral prednisone twice daily
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Overall adverse events 93.3%, severe adverse events: 33%;
highest incidence of adverse events occurred in the gastrointestinal system: 72%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent,
most common severe adverse events: febrile neutropenia 4.6%, pneumonia 2.9%, dehydration 2.7%, disease progression 1.3%, dyspnea 1.1%, deep vein thrombosis 2.5%, 0.6% hypercalcemia, 0.2% hypercalcemia grade ≥ 3
|Order number=2
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=477
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Vitamin D
|Dosage and regime=28-day dosing cycles of 45-μg oral DN-101 on days 1, 8, and 15, continue DN-101 for up to 48 weeks or until unacceptable DN-101 toxicity or experimental agents were initiated
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Overall adverse events 93.5%, severe adverse events: 35%;
highest incidence of adverse events occurred in the gastrointestinal system: 79%, of which nausea, diarrhea, constipation, vomiting, and stomatitis were most frequent,
most common severe adverse events: febrile neutropenia 1.0%, pneumonia 3.1%, dehydration 2.5%, disease progression 2.5%, dyspnea 2.1%, deep vein thrombosis 0.6%, 5.9% hypercalcemia, 0.8% hypercalcemia grade ≥ 3
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=Time between random assignment and death, regardless of cause
|Type of measurement=Observation
|Results during intervention=At study termination, 129 deaths (13.5%) had occurred; 48 deaths (10.1%) in the control arm and 81 (17.0%) in intervention arm
|Results after intervention=Six months after study termination, a total of 312 deaths (32.7%) had occurred: 138 (29.0%) in the control arm and 174 (36.5%) in intervention arm;
primary cause of death was prostate cancer in 108 participants (78.3%) in control arm and 142 (81.6%) in intervention arm,
median overall survival was 20.2 months (95% CI, 18.8 to 23.0) in control arm and 17.8 months (95% CI, 16.0 to 19.5) in intervention arm,
survival rate was significantly lower in the intervention arm (p = .002)
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Thromboembolic event rates
|Outcome specification=Defined as myocardial infarction, cerebrovascular accident, pulmonary embolism, deep vein thrombosis, and arterial thrombosis
|Type of measurement=NI
|Results during intervention=Similar rates of thromboembolic events
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Fees/research allowance from pharmaceutical companies or some authors advice them
|Conflicts of Interest=According to given information there are some financial conflicts or conflicts of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=There is no data concerning vitamin D levels and the arms are receiving different kinds of chemotherapy
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=NA
|Measurement of compliance=No
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Double blinding
* Active control group
* Large sample size
* Intention-to-treat

CONTRA:
* Vitamin D levels not assessed,
* Group differences not excluded
* Different treatment regimens for chemotherapy, per arm, no comparability of arm A and B
* High dropout at follow-up A: 44%, B: 43%

Khan et al. (2017): Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial

2024-10-25T10:15:18Z

CHoppe:

{{Reference
|Reference=Publication: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of vitamin D3 in breast cancer patients with regard to typical aromatase inhibitor-associated side effects (musculoskeletal disorders, abbreviation AIMSS) compared to a placebo. There were virtually no significant differences between the vitamin D3 and placebo arms in the number of patients with worsening AIMSS symptoms and fatigue symptoms. The vitamin D3 arm also did not report a higher quality of life. A positive aspect of this study was that the authors examined and reported the development of vitamin D levels. However, on the negative side, the sample size was too small to detect potential differences in the calculations well.

In dieser Studie wurde die Wirksamkeit von Vitamin D3 bei Brustkrebspatientinnen hinsichtlich typischer Aromatasehemmer assoziierter Nebenwirkungen (Muskel-Skelett-Erkrankungen, Abkürzung AIMSS) im Vergleich zu einem Placebo untersucht. Es gab so gut wie keine bedeutsamen Unterschiede zwischen dem Vitamin D3- und Placebo-Arm bezüglich der Anzahl an Patienten mit einer Verschlechterung der AIMSS-Symptome und Erschöpfungssymptomen. Der Vitamin D3 Arm berichtete auch keine höhere Lebensqualität. Positiv an dieser Studie war, dass die Autoren die Entwicklung des Vitamin D Spiegels untersucht und berichtet haben. Negativ war jedoch, dass die Stichprobe zu klein war, um potentielle Unterschiede in den Berechnungen gut aufdecken.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Postmenopausal women with stage I–III hormone receptor positive breast cancer scheduled to start treatment with an adjuvant aromatase inhibitors and with a 25(OH)D level B40 ng/ml
|Exclusion criteria=History of renal stones, hypercalcemia, or hyper- parathyroidism
|N randomized=160
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
T1: at week 12
T2: at week 24
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I–III hormone receptor positive breast cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median and interquartile ranges of age at diagnosis: 60.5 (55-71)
Placebo arm: median and interquartile ranges of age at diagnosis: 62 (54-69)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=80
|Drop-out=10
|Drop-out reasons=n=2 protocol violations, n=7 withdrew for reasons other than study agent related adverse events
|Intervention=Vitamin D3
|Dosage and regime=Three capsules of 10,000 IU Vitamin D3 weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=No adverse events attributed to vitamin D3
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=80
|Drop-out=3
|Drop-out reasons=Withdrew for reasons other than study agent related adverse events
|Intervention=Placebo
|Dosage and regime=Three capsules of placebo weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Mild hypercalcemia at 12 week assessment
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Evidenced by any of the following three events: an increase in the HAQ-II score of 0.25 or more; an increase in CPIS score; or discontinuation of letrozole specifically due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|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=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=Placebo arm: median increase in 25(OH)D was 7.1 ng/ml between week 0 and 12, and then no further increase from 12 to 24 weeks; 9 subjects achieved a level >40 ng/ml;
Intervention arm: increased 25(OH)D levels by a median of 32 ng/ml between week 0 and 12, with a slight further increase between weeks 12 and 24 (median 3.0 ng/ml); 91% achieved a level >40 ng/ml by 24 weeks; maximum value measured was 87 ng/ml
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hand grip strength
|Outcome specification=NI
|Type of measurement=Dynamometer
|Results during intervention=No significant differences
|Results after intervention=NI
|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=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=high risk
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|Outcome specification=NI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=No significant differences
|Results after intervention=NI
|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=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=high risk
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), MENQOL (Menopause-Specific Quality of Life)
|Results during intervention=No significant differences
|Results after intervention=NI
|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=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=high risk
|Order number=5
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for support of research and clinical trials from the following companies: AstraZeneca; Bristol-Myers Squibb; Celgene, Inc.; Novartis Pharmaceutical Company, Inc.; Genentech-Roche, GlaxoSmithKline, and Pfizer. Study agent but no funding has been provided by DSM and Pfizer for trials conducted by Dr. Fabian.
|Conflicts of Interest=Within the past three years, Dr. Khan has served as a consultant to Novartis Pharmaceutical Company, Inc. and Pfizer. Drs. Khan and Sharma have received during the past three years, via their institution
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Study protocol
* Information on the development of vitamin D levels

CONTRA:
* Fewer patients evaluated than according to power analysis (arm B < 72)
* Possible baseline differences e.g. descriptive Arm B higher baseline vitamin D level (25.1 (95% CI: 18.0, 30.5) A:22.5 (95% CI: 15.9, 29.7))
* Baseline differences with regard to QoL
* High dropout, but week 12 (A: 8/80, B: 10/80) and 24 (A: 15/80, B: 7/80) no significant difference in the amount of dropout between arms (p = 0.80 and p = 0.11)
* Poor report quality (e.g. no information on QoL figures)

Khan et al. (2017): Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial

2024-10-25T10:11:43Z

CHoppe:

{{Reference
|Reference=Publication: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of vitamin D3 in breast cancer patients with regard to typical aromatase inhibitor-associated side effects (musculoskeletal disorders, abbreviation AIMSS) compared to a placebo. There were virtually no significant differences between the vitamin D3 and placebo arms in the number of patients with worsening AIMSS symptoms and fatigue symptoms. The vitamin D3 arm also did not report a higher quality of life. A positive aspect of this study was that the authors examined and reported the development of vitamin D levels. However, on the negative side, the sample size was too small to detect potential differences in the calculations well.

In dieser Studie wurde die Wirksamkeit von Vitamin D3 bei Brustkrebspatientinnen hinsichtlich typischer Aromatasehemmer assoziierter Nebenwirkungen (Muskel-Skelett-Erkrankungen, Abkürzung AIMSS) im Vergleich zu einem Placebo untersucht. Es gab so gut wie keine bedeutsamen Unterschiede zwischen dem Vitamin D3- und Placebo-Arm bezüglich der Anzahl an Patienten mit einer Verschlechterung der AIMSS-Symptome und Erschöpfungssymptomen. Der Vitamin D3 Arm berichtete auch keine höhere Lebensqualität. Positiv an dieser Studie war, dass die Autoren die Entwicklung des Vitamin D Spiegels untersucht und berichtet haben. Negativ war jedoch, dass die Stichprobe zu klein war, um potentielle Unterschiede in den Berechnungen gut aufdecken.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Postmenopausal women with stage I–III hormone receptor positive breast cancer scheduled to start treatment with an adjuvant aromatase inhibitors and with a 25(OH)D level B40 ng/ml
|Exclusion criteria=History of renal stones, hypercalcemia, or hyper- parathyroidism
|N randomized=160
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
T1: at week 12
T2: at week 24
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I–III hormone receptor positive breast cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median and interquartile ranges of age at diagnosis: 60.5 (55-71)
Placebo arm: median and interquartile ranges of age at diagnosis: 62 (54-69)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=80
|Drop-out=10
|Drop-out reasons=n=2 protocol violations, n=7 withdrew for reasons other than study agent related adverse events
|Intervention=Vitamin D3
|Dosage and regime=Three capsules of 10,000 IU Vitamin D3 weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=No adverse events attributed to vitamin D3
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=80
|Drop-out=3
|Drop-out reasons=Withdrew for reasons other than study agent related adverse events
|Intervention=Placebo
|Dosage and regime=Three capsules of placebo weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Mild hypercalcemia at 12 week assessment
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Evidenced by any of the following three events: an increase in the HAQ-II score of 0.25 or more; an increase in CPIS score; or discontinuation of letrozole specifically due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|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=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=Placebo arm: median increase in 25(OH)D was 7.1 ng/ml between week 0 and 12, and then no further increase from 12 to 24 weeks; 9 subjects achieved a level >40 ng/ml;
Intervention arm: increased 25(OH)D levels by a median of 32 ng/ml between week 0 and 12, with a slight further increase between weeks 12 and 24 (median 3.0 ng/ml); 91% achieved a level >40 ng/ml by 24 weeks; maximum value measured was 87 ng/ml
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hand grip strength
|Outcome specification=NI
|Type of measurement=Dynamometer
|Results during intervention=No significant differences
|Results after intervention=NI
|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=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=high risk
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|Outcome specification=NI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=No significant differences
|Results after intervention=NI
|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=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=high risk
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), MENQOL (Menopause-Specific Quality of Life)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=5
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for support of research and clinical trials from the following companies: AstraZeneca; Bristol-Myers Squibb; Celgene, Inc.; Novartis Pharmaceutical Company, Inc.; Genentech-Roche, GlaxoSmithKline, and Pfizer. Study agent but no funding has been provided by DSM and Pfizer for trials conducted by Dr. Fabian.
|Conflicts of Interest=Within the past three years, Dr. Khan has served as a consultant to Novartis Pharmaceutical Company, Inc. and Pfizer. Drs. Khan and Sharma have received during the past three years, via their institution
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Study protocol
* Information on the development of vitamin D levels

CONTRA:
* Fewer patients evaluated than according to power analysis (arm B < 72)
* Possible baseline differences e.g. descriptive Arm B higher baseline vitamin D level (25.1 (95% CI: 18.0, 30.5) A:22.5 (95% CI: 15.9, 29.7))
* Baseline differences with regard to QoL
* High dropout, but week 12 (A: 8/80, B: 10/80) and 24 (A: 15/80, B: 7/80) no significant difference in the amount of dropout between arms (p = 0.80 and p = 0.11)
* Poor report quality (e.g. no information on QoL figures)

Khan et al. (2017): Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial

2024-10-25T10:02:29Z

CHoppe:

{{Reference
|Reference=Publication: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of vitamin D3 in breast cancer patients with regard to typical aromatase inhibitor-associated side effects (musculoskeletal disorders, abbreviation AIMSS) compared to a placebo. There were virtually no significant differences between the vitamin D3 and placebo arms in the number of patients with worsening AIMSS symptoms and fatigue symptoms. The vitamin D3 arm also did not report a higher quality of life. A positive aspect of this study was that the authors examined and reported the development of vitamin D levels. However, on the negative side, the sample size was too small to detect potential differences in the calculations well.

In dieser Studie wurde die Wirksamkeit von Vitamin D3 bei Brustkrebspatientinnen hinsichtlich typischer Aromatasehemmer assoziierter Nebenwirkungen (Muskel-Skelett-Erkrankungen, Abkürzung AIMSS) im Vergleich zu einem Placebo untersucht. Es gab so gut wie keine bedeutsamen Unterschiede zwischen dem Vitamin D3- und Placebo-Arm bezüglich der Anzahl an Patienten mit einer Verschlechterung der AIMSS-Symptome und Erschöpfungssymptomen. Der Vitamin D3 Arm berichtete auch keine höhere Lebensqualität. Positiv an dieser Studie war, dass die Autoren die Entwicklung des Vitamin D Spiegels untersucht und berichtet haben. Negativ war jedoch, dass die Stichprobe zu klein war, um potentielle Unterschiede in den Berechnungen gut aufdecken.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Postmenopausal women with stage I–III hormone receptor positive breast cancer scheduled to start treatment with an adjuvant aromatase inhibitors and with a 25(OH)D level B40 ng/ml
|Exclusion criteria=History of renal stones, hypercalcemia, or hyper- parathyroidism
|N randomized=160
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
T1: at week 12
T2: at week 24
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I–III hormone receptor positive breast cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median and interquartile ranges of age at diagnosis: 60.5 (55-71)
Placebo arm: median and interquartile ranges of age at diagnosis: 62 (54-69)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=80
|Drop-out=10
|Drop-out reasons=n=2 protocol violations, n=7 withdrew for reasons other than study agent related adverse events
|Intervention=Vitamin D3
|Dosage and regime=Three capsules of 10,000 IU Vitamin D3 weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=No adverse events attributed to vitamin D3
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=80
|Drop-out=3
|Drop-out reasons=Withdrew for reasons other than study agent related adverse events
|Intervention=Placebo
|Dosage and regime=Three capsules of placebo weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Mild hypercalcemia at 12 week assessment
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Evidenced by any of the following three events: an increase in the HAQ-II score of 0.25 or more; an increase in CPIS score; or discontinuation of letrozole specifically due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|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=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=Placebo arm: median increase in 25(OH)D was 7.1 ng/ml between week 0 and 12, and then no further increase from 12 to 24 weeks; 9 subjects achieved a level >40 ng/ml;
Intervention arm: increased 25(OH)D levels by a median of 32 ng/ml between week 0 and 12, with a slight further increase between weeks 12 and 24 (median 3.0 ng/ml); 91% achieved a level >40 ng/ml by 24 weeks; maximum value measured was 87 ng/ml
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hand grip strength
|Outcome specification=NI
|Type of measurement=Dynamometer
|Results during intervention=No significant differences
|Results after intervention=NI
|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=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=high risk
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|Outcome specification=NI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), MENQOL (Menopause-Specific Quality of Life)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=5
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for support of research and clinical trials from the following companies: AstraZeneca; Bristol-Myers Squibb; Celgene, Inc.; Novartis Pharmaceutical Company, Inc.; Genentech-Roche, GlaxoSmithKline, and Pfizer. Study agent but no funding has been provided by DSM and Pfizer for trials conducted by Dr. Fabian.
|Conflicts of Interest=Within the past three years, Dr. Khan has served as a consultant to Novartis Pharmaceutical Company, Inc. and Pfizer. Drs. Khan and Sharma have received during the past three years, via their institution
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Study protocol
* Information on the development of vitamin D levels

CONTRA:
* Fewer patients evaluated than according to power analysis (arm B < 72)
* Possible baseline differences e.g. descriptive Arm B higher baseline vitamin D level (25.1 (95% CI: 18.0, 30.5) A:22.5 (95% CI: 15.9, 29.7))
* Baseline differences with regard to QoL
* High dropout, but week 12 (A: 8/80, B: 10/80) and 24 (A: 15/80, B: 7/80) no significant difference in the amount of dropout between arms (p = 0.80 and p = 0.11)
* Poor report quality (e.g. no information on QoL figures)

Khan et al. (2017): Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial

2024-10-25T09:54:20Z

CHoppe:

{{Reference
|Reference=Publication: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of vitamin D3 in breast cancer patients with regard to typical aromatase inhibitor-associated side effects (musculoskeletal disorders, abbreviation AIMSS) compared to a placebo. There were virtually no significant differences between the vitamin D3 and placebo arms in the number of patients with worsening AIMSS symptoms and fatigue symptoms. The vitamin D3 arm also did not report a higher quality of life. A positive aspect of this study was that the authors examined and reported the development of vitamin D levels. However, on the negative side, the sample size was too small to detect potential differences in the calculations well.

In dieser Studie wurde die Wirksamkeit von Vitamin D3 bei Brustkrebspatientinnen hinsichtlich typischer Aromatasehemmer assoziierter Nebenwirkungen (Muskel-Skelett-Erkrankungen, Abkürzung AIMSS) im Vergleich zu einem Placebo untersucht. Es gab so gut wie keine bedeutsamen Unterschiede zwischen dem Vitamin D3- und Placebo-Arm bezüglich der Anzahl an Patienten mit einer Verschlechterung der AIMSS-Symptome und Erschöpfungssymptomen. Der Vitamin D3 Arm berichtete auch keine höhere Lebensqualität. Positiv an dieser Studie war, dass die Autoren die Entwicklung des Vitamin D Spiegels untersucht und berichtet haben. Negativ war jedoch, dass die Stichprobe zu klein war, um potentielle Unterschiede in den Berechnungen gut aufdecken.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Postmenopausal women with stage I–III hormone receptor positive breast cancer scheduled to start treatment with an adjuvant aromatase inhibitors and with a 25(OH)D level B40 ng/ml
|Exclusion criteria=History of renal stones, hypercalcemia, or hyper- parathyroidism
|N randomized=160
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
T1: at week 12
T2: at week 24
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I–III hormone receptor positive breast cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median and interquartile ranges of age at diagnosis: 60.5 (55-71)
Placebo arm: median and interquartile ranges of age at diagnosis: 62 (54-69)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=80
|Drop-out=10
|Drop-out reasons=n=2 protocol violations, n=7 withdrew for reasons other than study agent related adverse events
|Intervention=Vitamin D3
|Dosage and regime=Three capsules of 10,000 IU Vitamin D3 weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=No adverse events attributed to vitamin D3
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=80
|Drop-out=3
|Drop-out reasons=Withdrew for reasons other than study agent related adverse events
|Intervention=Placebo
|Dosage and regime=Three capsules of placebo weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Mild hypercalcemia at 12 week assessment
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Evidenced by any of the following three events: an increase in the HAQ-II score of 0.25 or more; an increase in CPIS score; or discontinuation of letrozole specifically due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|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=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=Placebo arm: median increase in 25(OH)D was 7.1 ng/ml between week 0 and 12, and then no further increase from 12 to 24 weeks; 9 subjects achieved a level >40 ng/ml;
Intervention arm: increased 25(OH)D levels by a median of 32 ng/ml between week 0 and 12, with a slight further increase between weeks 12 and 24 (median 3.0 ng/ml); 91% achieved a level >40 ng/ml by 24 weeks; maximum value measured was 87 ng/ml
|Results after intervention=NI
|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
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hand grip strength
|Outcome specification=NI
|Type of measurement=Dynamometer
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|Outcome specification=NI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), MENQOL (Menopause-Specific Quality of Life)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=5
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for support of research and clinical trials from the following companies: AstraZeneca; Bristol-Myers Squibb; Celgene, Inc.; Novartis Pharmaceutical Company, Inc.; Genentech-Roche, GlaxoSmithKline, and Pfizer. Study agent but no funding has been provided by DSM and Pfizer for trials conducted by Dr. Fabian.
|Conflicts of Interest=Within the past three years, Dr. Khan has served as a consultant to Novartis Pharmaceutical Company, Inc. and Pfizer. Drs. Khan and Sharma have received during the past three years, via their institution
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Study protocol
* Information on the development of vitamin D levels

CONTRA:
* Fewer patients evaluated than according to power analysis (arm B < 72)
* Possible baseline differences e.g. descriptive Arm B higher baseline vitamin D level (25.1 (95% CI: 18.0, 30.5) A:22.5 (95% CI: 15.9, 29.7))
* Baseline differences with regard to QoL
* High dropout, but week 12 (A: 8/80, B: 10/80) and 24 (A: 15/80, B: 7/80) no significant difference in the amount of dropout between arms (p = 0.80 and p = 0.11)
* Poor report quality (e.g. no information on QoL figures)

Jacot et al. (2016): Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study

2024-10-25T09:40:52Z

CHoppe:

{{Reference
|Reference=Publication: Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study
}}
{{Study Note}}
=Brief summary=
n this study, two arms of breast cancer patients with vitamin D deficiency were examined who either received high doses of vitamin D (arm A) or standard vitamin D therapy (arm B) 7 to 12 months after the start of their chemotherapy. After 6 months, a higher rate of patients with normalized levels was found in arm A (30%) than in arm B (12.6%). This was also found taking into account the vitamin D level at the beginning of the study. In a further subgroup analysis, patients were divided according to the season in which they were included. In this case, the arm differences were only found in the patients from fall and winter. In arm A, patients reported a deterioration in quality of life in many areas, while in arm B, quality of life remained largely stable over 6 months. Positive aspects of this study were the large sample size and the low drop-out rate. On the negative side, however, many patients did not take the medication as prescribed and the arm difference in quality of life was not statistically analyzed.

In dieser Studie wurden zwei Arme von Brustkrebspatientinnen mit Vitamin D Mangel untersucht, die 7 bis 12 Monate nach dem Beginn ihrer Chemotherapie entweder jeweils hohe Dosen Vitamin D erhielten (Arm A) oder eine Vitamin D-Standardtherapie bekamen (Arm B). Nach 6 Monaten wurde in Arm A eine höhere Rate an Patienten mit normalisierten Spiegeln gefunden (30%) als in Arm B (12.6%). Das fand sich auch unter Berücksichtigung des Vitamin D Spiegels zum Beginn der Studie. In einer weiteren Subgruppenanalyse wurden die Patienten nach der Jahreszeit aufgeteilt, in der sie eingeschlossen wurden. In diesem Fall fanden sich die Gruppenunterschiede nur bei den Patienten vom Herbst und Winter. In Arm A berichteten die Patientinnen in vielen Bereichen eine Verschlechterung der Lebensqualität, während in Arm B die Lebensqualität über 6 Monaten größtenteils stabil blieb. Positiv an dieser Studie waren die große Stichprobe und die geringe Ausfallrate. Negativ ist jedoch, dass viele Patientinnen die Medikation nicht so eingenommen haben, wie es vorgegeben war und dass bei der Untersuchung der Lebensqualität der Gruppenunterschied statistisch nicht untersucht wurde.

=Study Design=
Crossover to the intervention arm was allowed after 6 months of conventional treatment if the serum vitamin D level had not normalized.

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=No
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Female patients with histologically confirmed primary early-stage breast cancer, treated in the last 12 months with adjuvant or neoadjuvant chemotherapy, and with an ECOG performance status of <2,
vitamin D deficiency
|Exclusion criteria=Known hypersensitivity reaction to vitamin D or calcium com-pounds, known comorbidities affecting the vitamin D/calcium balance or bone health, concomitant vitamin D supplementation
|N randomized=195
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=All randomized patients were analyzed for efficacy, and 182 patients (93%) were evaluable for toxicity.
|Countries of data collection=France
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
At 6, 12, 18 and 24 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Neo-adjuvant, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) i.v. on day 1 every 21 days for three cycles, followed by docetaxel 100 mg/m2 i.v. on day 1 every 21 days for three cycles;
Docetaxel - 2 cyclophosphamide, methotrexate, 5-fluorouracile;
Trastuzumab
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% Kemal
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median (range): 51 (27-74)
Control arm: median (range): 49 (25-71)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=100
|Drop-out=4
|Drop-out reasons=Did not receive allocated intervention (Withdrew from study, adverse event)
|Intervention=Vitamin D3
|Dosage and regime=Baseline vitamin D deficiency level: <10 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43, 58 and at 3 months,
Baseline vitamin D deficiency level: 10-20 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43 and at 3 months,
Baseline vitamin D deficiency level: 20-30 ng/ml 100 000 IU vitamin D3 on day 1, 15 and at 3 months
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=n=1 hypercalciuria
|Order number=1
}}
{{Arm
|Arm type=Active control
|Number of participants (arm)=95
|Drop-out=9
|Drop-out reasons=Did not received allocated intervention (Withdrew from study, adverse event, other)
|Intervention=Vitamin D3
|Dosage and regime=Daily 400 IU vitamin D3
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=n=1 hypercalciuria
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Vitamin D level
|Outcome specification=Increase of normalization of serum 25OHD, defined as a 25OHD blood-level minimum target of 30 ng/ml
|Type of measurement=Blood Test
|Results during intervention=After 6 months, significantly more patients in the intervention arm had a normalized serum vitamin D level compared with the control arm patients (30% versus 12.6%; p = 0.003),
the median 6 month-vitamin D level was 24.2 ng/ml (8.1–39.2) and 28.1 ng/ml (7.3–51.8) respectively in the control and intervention arms (p < 0.001);

Percentage of correction was significantly higher in the intervention arm for patients included during fall (28% vs. 3%; p = 0.006), there was a trend in favor of intervention arm for patients included during winter (52% vs. 28%; p = 0.083), while there was no significant difference for patients included in spring and summer;
|Results after intervention=52 patients without vitamin D normalization from the control arm switched to the intervention arm after 6 months: at 12 months, 44% of these patients (n = 23) showed vitamin D normalization, median 6- and 12–month vitamin D levels were 23.9 ng/ml (8.1–29.6) and 28.6 ng/ml (16.3–53.0) respectively (p < 0.001)
|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
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria)
|Results during intervention=Difference in baseline Quality of Life for the physical function (p = 0.028), higher in the intervention arm and diarrhea, more severe in the control arm (p = 0.093);
no statistically significant difference was observed between intervention and control arms at 6 months,
there was no significant difference in overall Quality of Life between the normalized and deficient populations at 6 months
|Results after intervention=NI
|Bias arising from the randomization process=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=There was no specific funding for this study.
|Conflicts of Interest=The authors have declared no conflicts of interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=Sample size was sufficient to detect differences between intervention and placebo arm. At the same time there were not enough patients for having the right prevalence of vitamin D deficiency in the target population.
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=There were baseline differences in in QoL and diarrhea
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=Yes
|sufficient washout period=Yes
|Tested for carry-over effects=No
|Were sequence effects tested=No
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
}}
{{Additional Notes}}
PRO
* Ethics vote
* Large sample, number sufficient according to power analysis
* Low dropout: Arm A: 4%, Arm B: 9%, intention-to-treat analysis (except for side effect analysis)

CONTRA
* Compliance rate: A: 67%, B: 68.4%
* Baseline differences in QoL (physical performance (A > B) and diarrhea (A < B))
* No real group comparison in QoL between arm A and B
* Possibly selective reporting of endpoints (more endpoints described in the methods section than reported in the results section, e.g. vitamin D levels after 12, 18 and 24 months)
* Multiple testing

Khan et al. (2017): Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial

2024-10-24T08:46:38Z

CHoppe:

{{Reference
|Reference=Publication: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of vitamin D3 in breast cancer patients with regard to typical aromatase inhibitor-associated side effects (musculoskeletal disorders, abbreviation AIMSS) compared to a placebo. There were virtually no significant differences between the vitamin D3 and placebo arms in the number of patients with worsening AIMSS symptoms and fatigue symptoms. The vitamin D3 arm also did not report a higher quality of life. A positive aspect of this study was that the authors examined and reported the development of vitamin D levels. However, on the negative side, the sample size was too small to detect potential differences in the calculations well.

In dieser Studie wurde die Wirksamkeit von Vitamin D3 bei Brustkrebspatientinnen hinsichtlich typischer Aromatasehemmer assoziierter Nebenwirkungen (Muskel-Skelett-Erkrankungen, Abkürzung AIMSS) im Vergleich zu einem Placebo untersucht. Es gab so gut wie keine bedeutsamen Unterschiede zwischen dem Vitamin D3- und Placebo-Arm bezüglich der Anzahl an Patienten mit einer Verschlechterung der AIMSS-Symptome und Erschöpfungssymptomen. Der Vitamin D3 Arm berichtete auch keine höhere Lebensqualität. Positiv an dieser Studie war, dass die Autoren die Entwicklung des Vitamin D Spiegels untersucht und berichtet haben. Negativ war jedoch, dass die Stichprobe zu klein war, um potentielle Unterschiede in den Berechnungen gut aufdecken.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Postmenopausal women with stage I–III hormone receptor positive breast cancer scheduled to start treatment with an adjuvant aromatase inhibitors and with a 25(OH)D level B40 ng/ml
|Exclusion criteria=History of renal stones, hypercalcemia, or hyper- parathyroidism
|N randomized=160
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
T1: at week 12
T2: at week 24
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I–III hormone receptor positive breast cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median and interquartile ranges of age at diagnosis: 60.5 (55-71)
Placebo arm: median and interquartile ranges of age at diagnosis: 62 (54-69)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=80
|Drop-out=10
|Drop-out reasons=n=2 protocol violations, n=7 withdrew for reasons other than study agent related adverse events
|Intervention=Vitamin D3
|Dosage and regime=Three capsules of 10,000 IU Vitamin D3 weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=No adverse events attributed to vitamin D3
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=80
|Drop-out=3
|Drop-out reasons=Withdrew for reasons other than study agent related adverse events
|Intervention=Placebo
|Dosage and regime=Three capsules of placebo weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Mild hypercalcemia at 12 week assessment
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Evidenced by any of the following three events: an increase in the HAQ-II score of 0.25 or more; an increase in CPIS score; or discontinuation of letrozole specifically due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|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=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=Placebo arm: median increase in 25(OH)D was 7.1 ng/ml between week 0 and 12, and then no further increase from 12 to 24 weeks; 9 subjects achieved a level >40 ng/ml;
Intervention arm: increased 25(OH)D levels by a median of 32 ng/ml between week 0 and 12, with a slight further increase between weeks 12 and 24 (median 3.0 ng/ml); 91% achieved a level >40 ng/ml by 24 weeks; maximum value measured was 87 ng/ml
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hand grip strength
|Outcome specification=NI
|Type of measurement=Dynamometer
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|Outcome specification=NI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), MENQOL (Menopause-Specific Quality of Life)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=5
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for support of research and clinical trials from the following companies: AstraZeneca; Bristol-Myers Squibb; Celgene, Inc.; Novartis Pharmaceutical Company, Inc.; Genentech-Roche, GlaxoSmithKline, and Pfizer. Study agent but no funding has been provided by DSM and Pfizer for trials conducted by Dr. Fabian.
|Conflicts of Interest=Within the past three years, Dr. Khan has served as a consultant to Novartis Pharmaceutical Company, Inc. and Pfizer. Drs. Khan and Sharma have received during the past three years, via their institution
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Study protocol
* Information on the development of vitamin D levels

CONTRA:
* Fewer patients evaluated than according to power analysis (arm B < 72)
* Possible baseline differences e.g. descriptive Arm B higher baseline vitamin D level (25.1 (95% CI: 18.0, 30.5) A:22.5 (95% CI: 15.9, 29.7))
* Baseline differences with regard to QoL
* High dropout, but week 12 (A: 8/80, B: 10/80) and 24 (A: 15/80, B: 7/80) no significant difference in the amount of dropout between arms (p = 0.80 and p = 0.11)
* Poor report quality (e.g. no information on QoL figures)

Khan et al. (2017): Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial

2024-10-24T08:44:18Z

CHoppe:

{{Reference
|Reference=Publication: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of vitamin D3 in breast cancer patients with regard to typical aromatase inhibitor-associated side effects (musculoskeletal disorders, abbreviation AIMSS) compared to a placebo. There were virtually no significant differences between the vitamin D3 and placebo arms in the number of patients with worsening AIMSS symptoms and fatigue symptoms. The vitamin D3 arm also did not report a higher quality of life. A positive aspect of this study was that the authors examined and reported the development of vitamin D levels. However, on the negative side, the sample size was too small to detect potential differences in the calculations well.

In dieser Studie wurde die Wirksamkeit von Vitamin D3 bei Brustkrebspatientinnen hinsichtlich typischer Aromatasehemmer assoziierter Nebenwirkungen (Muskel-Skelett-Erkrankungen, Abkürzung AIMSS) im Vergleich zu einem Placebo untersucht. Es gab so gut wie keine bedeutsamen Unterschiede zwischen dem Vitamin D3- und Placebo-Arm bezüglich der Anzahl an Patienten mit einer Verschlechterung der AIMSS-Symptome und Erschöpfungssymptomen. Der Vitamin D3 Arm berichtete auch keine höhere Lebensqualität. Positiv an dieser Studie war, dass die Autoren die Entwicklung des Vitamin D Spiegels untersucht und berichtet haben. Negativ war jedoch, dass die Stichprobe zu klein war, um potentielle Unterschiede in den Berechnungen gut aufdecken.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Single
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Postmenopausal women with stage I–III hormone receptor positive breast cancer scheduled to start treatment with an adjuvant aromatase inhibitors and with a 25(OH)D level B40 ng/ml
|Exclusion criteria=History of renal stones, hypercalcemia, or hyper- parathyroidism
|N randomized=160
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
T1: at week 12
T2: at week 24
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I–III hormone receptor positive breast cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=100% female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median and interquartile ranges of age at diagnosis: 60.5 (55-71)
Placebo arm: median and interquartile ranges of age at diagnosis: 62 (54-69)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=80
|Drop-out=10
|Drop-out reasons=n=2 protocol violations, n=7 withdrew for reasons other than study agent related adverse events
|Intervention=Vitamin D3
|Dosage and regime=Three capsules of 10,000 IU Vitamin D3 weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=No adverse events attributed to vitamin D3
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=80
|Drop-out=3
|Drop-out reasons=Withdrew for reasons other than study agent related adverse events
|Intervention=Placebo
|Dosage and regime=Three capsules of placebo weekly

+ all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=Mild hypercalcemia at 12 week assessment
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Musculoskeletal symptoms
|Outcome specification=Evidenced by any of the following three events: an increase in the HAQ-II score of 0.25 or more; an increase in CPIS score; or discontinuation of letrozole specifically due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Others
|Outcome name=Vitamin D level
|Outcome specification=NI
|Type of measurement=Blood Test
|Results during intervention=Placebo arm: median increase in 25(OH)D was 7.1 ng/ml between week 0 and 12, and then no further increase from 12 to 24 weeks; 9 subjects achieved a level >40 ng/ml;
Intervention arm: increased 25(OH)D levels by a median of 32 ng/ml between week 0 and 12, with a slight further increase between weeks 12 and 24 (median 3.0 ng/ml); 91% achieved a level >40 ng/ml by 24 weeks; maximum value measured was 87 ng/ml
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Hand grip strength
|Outcome specification=NI
|Type of measurement=Dynamometer
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|Outcome specification=NI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), MENQOL (Menopause-Specific Quality of Life)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Order number=5
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for support of research and clinical trials from the following companies: AstraZeneca; Bristol-Myers Squibb; Celgene, Inc.; Novartis Pharmaceutical Company, Inc.; Genentech-Roche, GlaxoSmithKline, and Pfizer. Study agent but no funding has been provided by DSM and Pfizer for trials conducted by Dr. Fabian.
|Conflicts of Interest=Within the past three years, Dr. Khan has served as a consultant to Novartis Pharmaceutical Company, Inc. and Pfizer. Drs. Khan and Sharma have received during the past three years, via their institution
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=No
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Study protocol
* Information on the development of vitamin D levels

CONTRA:
* Fewer patients evaluated than according to power analysis (arm B < 72)
* Possible baseline differences e.g. descriptive Arm B higher baseline vitamin D level (25.1 (95% CI: 18.0, 30.5) A:22.5 (95% CI: 15.9, 29.7))
* Baseline differences with regard to QoL
* High dropout, but week 12 (A: 8/80, B: 10/80) and 24 (A: 15/80, B: 7/80) no significant difference in the amount of dropout between arms (p = 0.80 and p = 0.11)
* Poor report quality (e.g. no information on QoL figures)

Inglis et al. (2020): Effects of High-Dose Vitamin D Supplementation on Phase Angle and Physical Function in Patients with Prostate Cancer on ADT

2024-10-22T09:08:44Z

CHoppe:

{{Reference
|Reference=Publication: Effects of High-Dose Vitamin D Supplementation on Phase Angle and Physical Function in Patients with Prostate Cancer on ADT
}}
{{Study Note}}
=Brief summary=
The 59 patients suffering from prostate cancer and treated with androgen deprivation therapy were randomly divided into two arms. 29 patients received daily high-dose vitamin D and 30 patients received a placebo, and both arms received a multivitamin (low dose of vitamin D and calcium). After 24 weeks, there were small indications that the patients who received high-dose vitamin D might have healthier muscle cells. Over time, androgen deprivation therapy may result in a reduction in lean body mass, which is the lean body mass associated with muscle mass. However, for most tests (e.g. grip strength, leg extension and walking) there were no benefits for the vitamin D arm. The study has a small sample size and gives little information about the patients, which may mean that factors such as cancer stage are not taken into account in the analysis. Also, vitamin D levels are not measured at the end of the study, so it is unclear whether patients remained in deficit.

Die 59, an Prostatakrebs leidenden und mit Androgendeprivationstherapie behandelten Patienten, wurden zufällig in zwei Arme eingeteilt. 29 Patienten erhielten täglich hochdosiertes Vitamin D und 30 Patienten ein Placebo, sowie beide Arme ein Multivitamin (geringe Dosis Vitamin D und Kalzium). Nach 24 Wochen zeigen sich kleine Hinweise darauf, dass die Patienten, die hochdosiertes Vitamin D erhielten, gesündere Muskelzellen haben könnten. Unter der Androgendeprivationstherapie kann im Laufe der Zeit eine Reduktion der Lean body mass auftreten, also der der fettfreien Körpermasse, welche mit der Muskelmasse in Verbindung steht. Jedoch zeigten sich für die meisten Tests (zB. Griffstärke, Beinstreckung und Gehen) keine Vorteile für der Vitamin D Arm. Die Studie hat eine kleine Stichprobe und gibt wenig Informationen über die Patienten, wodurch möglicherweise Faktoren wie Krebsstadium in der Analyse nicht berücksichtigt werden. Auch werden am Ende der Studie keine Vitamin D Spiegel gemessen, so dass unklar ist, ob die Patienten im Defizit verblieben sind.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=A confirmed diagnosis of prostate cancer (stage I-IV) with no bone metastases; being within six months of starting androgen deprivation therapy (ADT) with an additional six more months planned; suboptimal vitamin D levels (<32 ng/ml); total serum calcium ≤10.5 mg/dl; no contraindications for fitness testing and 5) ≥60 years old
|Exclusion criteria=Adequate vitamin D levels; hypercalcemia, osteoporosis, stage IV kidney disease or myocardial infarction within the past year
|N randomized=59
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
|Countries of data collection=United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: basline
T1: week 12
T2: week 24
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Stage I-IV
|Comorbidity=NI
|Current cancer therapy=Hormone therapy
|Specifications on cancer therapies=Androgen deprivation therapy
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=67.6 (5.4)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=29
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=High-dose vitamin D3
|Dosage and regime=50,000 IU/ week, over 24 weeks

+ all participants: daily multivitamin containing the RDA for vitamin D: 600 IU/day + 210 mg/day calcium and calcium supplements (800 mg/day)
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=30
|Drop-out=NA
|Drop-out reasons=NA
|Intervention=Placebo (Low-dose vitamin D3)
|Dosage and regime=Placebo vitamin D weekly, over 24 weeks

+ all participants: daily multivitamin containing the RDA for vitamin D: 600 IU/day + 210 mg/day calcium and calcium supplements (800 mg/day)
|One-time application=No
|Duration in days=168
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Body composition
|Outcome specification=Phase angle and lean mass
|Type of measurement=BIA (Bioelectrical impedance analysis)
|Results during intervention=Phase angle: significantly wider phase angle values in intervention arm at week 12 (p=0.014;95% CI -0.824, -0.098) and at week 24 (p=0.018; 95% CI -0.922, -0.090)

Lean mass: significantly higher in intervention arm at week 12 (p=0.036; 95% C.I. 0.229, 6.556) but no significant differences between arms at any other time point
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=?
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=Physical functioning
|Outcome specification=Hand grip, lower body strength, physical performance
|Type of measurement=Dynamometer, SPPB (Short Physical Performance Battery), Physical examination
|Results during intervention=No significant differences between arms at any time point
|Results after intervention=NI
|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=?
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funded by grants NIH NCI CA175793, NIH NCI T32CA102618 and NIH NCI UG1CA189961
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Comparability of the groups to the baseline
* Adherence controlled with tablets count at T1 and T2

CONTRA:
* Small sample size
* Lack of data for factors such as cancer stage that may have further influenced the effect of the intervention
* No indication of a power analysis
* No data on vitamin D levels at the end of the study
* Very low dose of vitamin D
* Simultaneous automatic calcium administration
}}

Jacot et al. (2016): Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study

2024-10-22T08:47:49Z

CHoppe:

{{Reference
|Reference=Publication: Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study
}}
{{Study Note}}
=Brief summary=
n this study, two arms of breast cancer patients with vitamin D deficiency were examined who either received high doses of vitamin D (arm A) or standard vitamin D therapy (arm B) 7 to 12 months after the start of their chemotherapy. After 6 months, a higher rate of patients with normalized levels was found in arm A (30%) than in arm B (12.6%). This was also found taking into account the vitamin D level at the beginning of the study. In a further subgroup analysis, patients were divided according to the season in which they were included. In this case, the arm differences were only found in the patients from fall and winter. In arm A, patients reported a deterioration in quality of life in many areas, while in arm B, quality of life remained largely stable over 6 months. Positive aspects of this study were the large sample size and the low drop-out rate. On the negative side, however, many patients did not take the medication as prescribed and the arm difference in quality of life was not statistically analyzed.

In dieser Studie wurden zwei Arme von Brustkrebspatientinnen mit Vitamin D Mangel untersucht, die 7 bis 12 Monate nach dem Beginn ihrer Chemotherapie entweder jeweils hohe Dosen Vitamin D erhielten (Arm A) oder eine Vitamin D-Standardtherapie bekamen (Arm B). Nach 6 Monaten wurde in Arm A eine höhere Rate an Patienten mit normalisierten Spiegeln gefunden (30%) als in Arm B (12.6%). Das fand sich auch unter Berücksichtigung des Vitamin D Spiegels zum Beginn der Studie. In einer weiteren Subgruppenanalyse wurden die Patienten nach der Jahreszeit aufgeteilt, in der sie eingeschlossen wurden. In diesem Fall fanden sich die Gruppenunterschiede nur bei den Patienten vom Herbst und Winter. In Arm A berichteten die Patientinnen in vielen Bereichen eine Verschlechterung der Lebensqualität, während in Arm B die Lebensqualität über 6 Monaten größtenteils stabil blieb. Positiv an dieser Studie waren die große Stichprobe und die geringe Ausfallrate. Negativ ist jedoch, dass viele Patientinnen die Medikation nicht so eingenommen haben, wie es vorgegeben war und dass bei der Untersuchung der Lebensqualität der Gruppenunterschied statistisch nicht untersucht wurde.

=Study Design=
Crossover to the intervention arm was allowed after 6 months of conventional treatment if the serum vitamin D level had not normalized.

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=No
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Female patients with histologically confirmed primary early-stage breast cancer, treated in the last 12 months with adjuvant or neoadjuvant chemotherapy, and with an ECOG performance status of <2,
vitamin D deficiency
|Exclusion criteria=Known hypersensitivity reaction to vitamin D or calcium com-pounds, known comorbidities affecting the vitamin D/calcium balance or bone health, concomitant vitamin D supplementation
|N randomized=195
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=All randomized patients were analyzed for efficacy, and 182 patients (93%) were evaluable for toxicity.
|Countries of data collection=France
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
At 6, 12, 18 and 24 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Neo-adjuvant, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) i.v. on day 1 every 21 days for three cycles, followed by docetaxel 100 mg/m2 i.v. on day 1 every 21 days for three cycles;
Docetaxel - 2 cyclophosphamide, methotrexate, 5-fluorouracile;
Trastuzumab
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% Kemal
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median (range): 51 (27-74)
Control arm: median (range): 49 (25-71)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=100
|Drop-out=4
|Drop-out reasons=Did not receive allocated intervention (Withdrew from study, adverse event)
|Intervention=Vitamin D3
|Dosage and regime=Baseline vitamin D deficiency level: <10 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43, 58 and at 3 months,
Baseline vitamin D deficiency level: 10-20 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43 and at 3 months,
Baseline vitamin D deficiency level: 20-30 ng/ml 100 000 IU vitamin D3 on day 1, 15 and at 3 months
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=n=1 hypercalciuria
|Order number=1
}}
{{Arm
|Arm type=Active control
|Number of participants (arm)=95
|Drop-out=9
|Drop-out reasons=Did not received allocated intervention (Withdrew from study, adverse event, other)
|Intervention=Vitamin D3
|Dosage and regime=Daily 400 IU vitamin D3
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=n=1 hypercalciuria
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Vitamin D level
|Outcome specification=Increase of normalization of serum 25OHD, defined as a 25OHD blood-level minimum target of 30 ng/ml
|Type of measurement=Blood Test
|Results during intervention=After 6 months, significantly more patients in the intervention arm had a normalized serum vitamin D level compared with the control arm patients (30% versus 12.6%; p = 0.003),
the median 6 month-vitamin D level was 24.2 ng/ml (8.1–39.2) and 28.1 ng/ml (7.3–51.8) respectively in the control and intervention arms (p < 0.001);

Percentage of correction was significantly higher in the intervention arm for patients included during fall (28% vs. 3%; p = 0.006), there was a trend in favor of intervention arm for patients included during winter (52% vs. 28%; p = 0.083), while there was no significant difference for patients included in spring and summer;
|Results after intervention=52 patients without vitamin D normalization from the control arm switched to the intervention arm after 6 months: at 12 months, 44% of these patients (n = 23) showed vitamin D normalization, median 6- and 12–month vitamin D levels were 23.9 ng/ml (8.1–29.6) and 28.6 ng/ml (16.3–53.0) respectively (p < 0.001)
|Bias arising from the randomization process=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria)
|Results during intervention=Difference in baseline Quality of Life for the physical function (p = 0.028), higher in the intervention arm and diarrhea, more severe in the control arm (p = 0.093);
no statistically significant difference was observed between intervention and control arms at 6 months,
there was no significant difference in overall Quality of Life between the normalized and deficient populations at 6 months
|Results after intervention=NI
|Bias arising from the randomization process=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=There was no specific funding for this study.
|Conflicts of Interest=The authors have declared no conflicts of interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=Sample size was sufficient to detect differences between intervention and placebo arm. At the same time there were not enough patients for having the right prevalence of vitamin D deficiency in the target population.
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=There were baseline differences in in QoL and diarrhea
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=No
|Measurement of compliance=Yes
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=No
|Cross-over=Yes
|sufficient washout period=Yes
|Tested for carry-over effects=No
|Were sequence effects tested=No
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=Yes
}}
{{Additional Notes}}
PRO
* Ethics vote
* Large sample, number sufficient according to power analysis
* Low dropout: Arm A: 4%, Arm B: 9%, intention-to-treat analysis (except for side effect analysis)

CONTRA
* Compliance rate: A: 67%, B: 68.4%
* Baseline differences in QoL (physical performance (A > B) and diarrhea (A < B))
* No real group comparison in QoL between arm A and B
* Possibly selective reporting of endpoints (more endpoints described in the methods section than reported in the results section, e.g. vitamin D levels after 12, 18 and 24 months)
* Multiple testing

Jacot et al. (2016): Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study

2024-10-22T08:40:03Z

CHoppe:

{{Reference
|Reference=Publication: Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study
}}
{{Study Note}}
=Brief summary=
n this study, two arms of breast cancer patients with vitamin D deficiency were examined who either received high doses of vitamin D (arm A) or standard vitamin D therapy (arm B) 7 to 12 months after the start of their chemotherapy. After 6 months, a higher rate of patients with normalized levels was found in arm A (30%) than in arm B (12.6%). This was also found taking into account the vitamin D level at the beginning of the study. In a further subgroup analysis, patients were divided according to the season in which they were included. In this case, the arm differences were only found in the patients from fall and winter. In arm A, patients reported a deterioration in quality of life in many areas, while in arm B, quality of life remained largely stable over 6 months. Positive aspects of this study were the large sample size and the low drop-out rate. On the negative side, however, many patients did not take the medication as prescribed and the arm difference in quality of life was not statistically analyzed.

In dieser Studie wurden zwei Arme von Brustkrebspatientinnen mit Vitamin D Mangel untersucht, die 7 bis 12 Monate nach dem Beginn ihrer Chemotherapie entweder jeweils hohe Dosen Vitamin D erhielten (Arm A) oder eine Vitamin D-Standardtherapie bekamen (Arm B). Nach 6 Monaten wurde in Arm A eine höhere Rate an Patienten mit normalisierten Spiegeln gefunden (30%) als in Arm B (12.6%). Das fand sich auch unter Berücksichtigung des Vitamin D Spiegels zum Beginn der Studie. In einer weiteren Subgruppenanalyse wurden die Patienten nach der Jahreszeit aufgeteilt, in der sie eingeschlossen wurden. In diesem Fall fanden sich die Gruppenunterschiede nur bei den Patienten vom Herbst und Winter. In Arm A berichteten die Patientinnen in vielen Bereichen eine Verschlechterung der Lebensqualität, während in Arm B die Lebensqualität über 6 Monaten größtenteils stabil blieb. Positiv an dieser Studie waren die große Stichprobe und die geringe Ausfallrate. Negativ ist jedoch, dass viele Patientinnen die Medikation nicht so eingenommen haben, wie es vorgegeben war und dass bei der Untersuchung der Lebensqualität der Gruppenunterschied statistisch nicht untersucht wurde.

=Study Design=
Crossover to the intervention arm was allowed after 6 months of conventional treatment if the serum vitamin D level had not normalized.

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=No
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Female patients with histologically confirmed primary early-stage breast cancer, treated in the last 12 months with adjuvant or neoadjuvant chemotherapy, and with an ECOG performance status of <2,
vitamin D deficiency
|Exclusion criteria=Known hypersensitivity reaction to vitamin D or calcium com-pounds, known comorbidities affecting the vitamin D/calcium balance or bone health, concomitant vitamin D supplementation
|N randomized=195
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=All randomized patients were analyzed for efficacy, and 182 patients (93%) were evaluable for toxicity.
|Countries of data collection=France
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
At 6, 12, 18 and 24 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Neo-adjuvant, Adjuvant
|Types of cancer=Breast Cancer
|Stage cancer=Early Stage
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) i.v. on day 1 every 21 days for three cycles, followed by docetaxel 100 mg/m2 i.v. on day 1 every 21 days for three cycles;
Docetaxel - 2 cyclophosphamide, methotrexate, 5-fluorouracile;
Trastuzumab
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=100% Kemal
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median (range): 51 (27-74)
Control arm: median (range): 49 (25-71)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=100
|Drop-out=4
|Drop-out reasons=Did not receive allocated intervention (Withdrew from study, adverse event)
|Intervention=Vitamin D3
|Dosage and regime=Baseline vitamin D deficiency level: <10 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43, 58 and at 3 months,
Baseline vitamin D deficiency level: 10-20 ng/ml 100 000 IU vitamin D3 on day 1, 15, 28, 43 and at 3 months,
Baseline vitamin D deficiency level: 20-30 ng/ml 100 000 IU vitamin D3 on day 1, 15 and at 3 months
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=n=1 hypercalciuria
|Order number=1
}}
{{Arm
|Arm type=Active control
|Number of participants (arm)=95
|Drop-out=9
|Drop-out reasons=Did not received allocated intervention (Withdrew from study, adverse event, other)
|Intervention=Vitamin D3
|Dosage and regime=Daily 400 IU vitamin D3
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=n=1 hypercalciuria
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Vitamin D level
|Outcome specification=Increase of normalization of serum 25OHD, defined as a 25OHD blood-level minimum target of 30 ng/ml
|Type of measurement=Blood Test
|Results during intervention=After 6 months, significantly more patients in the intervention arm had a normalized serum vitamin D level compared with the control arm patients (30% versus 12.6%; p = 0.003),
the median 6 month-vitamin D level was 24.2 ng/ml (8.1–39.2) and 28.1 ng/ml (7.3–51.8) respectively in the control and intervention arms (p < 0.001);

Percentage of correction was significantly higher in the intervention arm for patients included during fall (28% vs. 3%; p = 0.006), there was a trend in favor of intervention arm for patients included during winter (52% vs. 28%; p = 0.083), while there was no significant difference for patients included in spring and summer;
|Results after intervention=52 patients without vitamin D normalization from the control arm switched to the intervention arm after 6 months: at 12 months, 44% of these patients (n = 23) showed vitamin D normalization, median 6- and 12–month vitamin D levels were 23.9 ng/ml (8.1–29.6) and 28.6 ng/ml (16.3–53.0) respectively (p < 0.001)
|Bias arising from the randomization process=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria)
|Results during intervention=Difference in baseline Quality of Life for the physical function (p = 0.028), higher in the intervention arm and diarrhea, more severe in the control arm (p = 0.093);
no statistically significant difference was observed between intervention and control arms at 6 months,
there was no significant difference in overall Quality of Life between the normalized and deficient populations at 6 months
|Results after intervention=NI
|Bias arising from the randomization process=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=some concerns
|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=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=There was no specific funding for this study.
|Conflicts of Interest=The authors have declared no conflicts of interest.
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=Yes
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=Sample size was sufficient to detect differences between intervention and placebo arm. At the same time there were not enough patients for having the right prevalence of vitamin D deficiency in the target population.
|Samples sufficiently large=NA
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=No
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=NA
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=Yes
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
}}
{{Additional Notes}}
PRO
* Ethics vote
* Large sample, number sufficient according to power analysis
* Low dropout: Arm A: 4%, Arm B: 9%, intention-to-treat analysis (except for side effect analysis)

CONTRA
* Compliance rate: A: 67%, B: 68.4%
* Baseline differences in QoL (physical performance (A > B) and diarrhea (A < B))
* No real group comparison in QoL between arm A and B
* Possibly selective reporting of endpoints (more endpoints described in the methods section than reported in the results section, e.g. vitamin D levels after 12, 18 and 24 months)
* Multiple testing