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Publication: Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization

2024-11-28T08:30:37Z

JDoerfler:

{{Publication
|Title=Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization
|Topic=Selenium
|Author=Muecke, R; Micke, O; Schomburg, L; Glatzel, M; Reichl, B; Kisters, K; Schaefer, U; Huebner, J; Eich, HT; Fakhrian, K; Adamietz, IA; Buentzel, J
|Year=2014
|Journal=Integrative Cancer Therapies
|DOI=https://doi.org/10.1177/1534735414541963
|Authors Abstract=Purpose: In 2010, we reported that selenium (Se) supplementation during radiation therapy (RT) is effective for increasing blood Se levels in Se-deficient cervical and uterine cancer patients, and reduced the number of episodes and severity of RT-induced diarrhea. In the current study, we examine whether Se supplementation during adjuvant RT affects long-term survival of these patients.

Patients and Methods: Former patients were identified and questioned with respect to their health and well-being.

Results: A total of 81 patients were randomized in the initial supplementation study, 39 of whom received Se (selenium group, SeG) and 42 of whom served as controls (control group, CG). When former patients were reidentified after a median follow-up of 70 months (range = 0-136), the actuarial 10-year disease-free survival rate in the SeG was 80.1% compared to 83.2% in the CG (P = .65), and the actuarial 10-year overall survival rate of patients in the SeG was 55.3% compared to 42.7% in the CG (P = .09).

Conclusions: Our extended follow-up analysis demonstrates that Se supplementation had no influence on the effectiveness of the anticancer irradiation therapy and did not negatively affect patients’ long-term survival. In view of its positive effects on RT-induced diarrhea, we consider Se supplementation to be a meaningful and beneficial adjuvant treatment in Se-deficient cervical and uterine cancer patients while undergoing pelvic radiation therapy.
}}

Muecke et al. (2014): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization

2024-11-28T08:15:43Z

JDoerfler:

{{Reference
|Reference=Publication: Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization
}}
{{Study Note
|Study Note=This study is a follow-up analysis of [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]]. There is a study with a subgroup-analysis of the 2010 study: [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]].
}}
=Brief summary=
This study included 81 patients with uterine or cervical cancer. They were randomly divided into two arms and received either 500µg selenium in addition to radiotherapy or no additional preparations. All participants had a selenium deficiency at the beginning of the study. This is a further analysis of the [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] - the follow-up study shows that after ten years there is no difference between the arms in terms of overall survival or disease-free survival.

Diese Studie schloss 81 Patientinnen mit Gebärmutter- oder Gebärmutterhalskrebs ein. Sie wurden zufällig in zwei Gruppen eingeteilt und erhielten entweder zusätzlich zur Radiotherapie 500µg Selen oder keine zusätzlichen Präparate. Alle Probanden hatten zu Beginn der Studie ein Selendefizit. Die Follow-Up Studie zeigt, dass nach zehn Jahren kein Unterschied zwischen den Gruppen bezüglich des Gesamtüberlebens oder dem Krankheitsfreien-Überleben besteht. Es ist eine weitere Analyse der Studie [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] - die Follow-Up Studie zeigt, dass nach zehn Jahren kein Unterschied zwischen den Gruppen bezüglich des Gesamtüberlebens oder dem Krankheitsfreien-Überleben besteht.

=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=NA
|Exclusion criteria=NA
|N randomized=81
|Analysis=NI
|Specifications on analyses=No information about possible drop-out
|Countries of data collection=Germany
|LoE=1b Oxford 2009
|Outcome timeline=NA
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=NI
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=Selenium concentration lower than 84µg/L at start of the original study (Muecke et al., 2010)
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery, Radiation therapy
|Gender=Female
|Gender specifications=NA
|Age groups=Adults (18+)
|Age groups specification=Start of the original study (Muecke et al., 2010): mean (SD); range: 64.3 (10.1); 31–80 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=39
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Sodium Selenite
|Dosage and regime=500 µg selenium in the form of sodium selenite [selenase®), orally on radiotherapy days and 300 µg on days without radiotherapy
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=1
|Arm topic=Selenium
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=42
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Usual care
|Dosage and regime=NA
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NA
|Order number=2
|Arm topic=Selenium
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=10-year disease-free survival
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=10-year disease-free survival intervention arm 80.1% vs. control arm 83.2%; not significant; p = 0.65
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=high risk
|Order number=1
|Outcome topic=Selenium
}}
{{Outcome
|Outcome type=NI
|Outcome name=OS (Overall Survival)
|Outcome specification=10-year overall survival
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=10-year overall survival intervention arm 55.3% vs. control arm 42.7%; not significant; p = 0.09
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=high risk
|Order number=2
|Outcome topic=Selenium
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by a grant from the pharmaceutical company biosyn-Arzneimittel GmbH Fellbach, Germany.
|Conflicts of Interest=The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ralph Muecke has had conference and travel expenses reimbursed and has received lecture fees from the pharmaceutical company biosyn-Arzneimittel GmbH to help run the study.
}}
=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=NA
|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=NI
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Testing for selenium deficiency.
* Power analysis conducted.
* Comparability of arms established.
* Very detailed and clear presentation of results.

CONTRA:
* No placebo control.
* No information on possible blinding.
* No information on potential dropouts.
* "Total dose of external radiotherapy (Gy)" at p=0.06 — close to significance between arms.
* No testing whether selenium significantly decreases in the control arm.
* No verification of supplementation outside the study.
* Few demographic variables provided.
}}

Uthaipaisanwong et al. (2020): Effects of ginger adjunct to the standard prophylaxis on reducing carboplatin and paclitaxel-induced nausea vomiting: a randomized controlled study

2024-11-25T09:10:49Z

JDoerfler:

{{Reference
|Reference=Publication: Effects of ginger adjunct to the standard prophylaxis on reducing carboplatin and paclitaxel-induced nausea vomiting: a randomized controlled study
}}

=Brief summary=
In this study, 48 patients with gynecological cancer were randomly divided into two groups. One group received a capsule containing 500mg of ginger powder four times a day from the first to the fifth day of chemotherapy, while the other group received a placebo. Both groups also received standard anti-nausea/anti-vomiting medication. The groups were switched for the next chemotherapy cycle. The intake of ginger led to a decrease in the severity of acute nausea after chemotherapy compared to placebo (day 1). No differences were found for day 2-5. In terms of frequency of vomiting, degree of nausea and side effects such as diarrhea, constipation and heartburn, there were no benefits of ginger intake. The study is characterized by a clear and comprehensible presentation of the results. Missing effects could have been influenced by a generally low incidence of vomiting and nausea.

In dieser Studie wurden 48 Patientinnen mit gynäkologischen Krebserkrankungen zufällig in zwei Gruppen aufgeteilt. Die eine Gruppe erhielt vom ersten bis zum fünften Tag der Chemotherapie viermal täglich eine Kapsel mit 500mg Ingwerpulver, die andere Gruppe erhielt ein Placebo. Beide Gruppen erhielten zusätzlich Standardmedikamente gegen Übelkeit/Erbrechen. Für den nächsten Chemotherapie-Zyklus wurden die Gruppen getauscht. Die Einnahme von Ingwer hat im Vergleich zu Placebo zu einer Abnahme der Schwere der akuten Übelkeit nach Chemotherapie geführt (1. Tag). Es wurden keine Unterschiede für Tag 2-5 gefunden. In Bezug auf Häufigkeit von Erbrechen, Grad der Übelkeit und Nebenwirkungen wie Durchfall, Verstopfung und Sodbrennen zeigte sich keine Vorteile durch Ingwereinnahme. Die Studie zeichnet sich durch eine übersichtliche und verständliche Darstellung der Ergebnisse aus. Fehlende Effekte könnten durch ein allgemein geringes Auftreten von Erbrechen und Übelkeit beeinflusst worden sein.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Patients with gynecological cancers (ovarian, cervical, endometrial, vulvar carcinoma; stage 1-4, recurrence), ECOG status 0-2, carboplatin-paclitaxel chemotherapy
|Exclusion criteria=Patients using other gingers or the other antiemetic medication such as NK1 receptor antagonist or long-acting 5HT3 receptor antagonists to current study treatment; patients with gut obstruction or brain or bowel metastasis, patients using anticoagulant medication, and patients with allergy to ginger
|N randomized=48
|Analysis=PP Analysis
|Specifications on analyses=All statistical analyses were performed using STATA version 15.1. P values less than 0.05 were considered significant. Demographic data of all participants were analyzed by using mean, 95%CI, and percentage.
Nausea score from day 1 to day 5 was showed in mean, and analysis of variance (ANOVA) for a 2 × 2 crossover study was analyzed comparing treatment, sequence, and period effect.
Nausea grading for each day was compared using proportion f grading between treatment after adjusted sequence and period by using random-effects ordered logistic regression.
Vomiting and side effects were analyzed by comparing percentages between groups using random-effects logistic regression.
|Countries of data collection=Thailand
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
T1: Day 1 of chemotherapy
T2: Day 2-5 of chemotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Neo-adjuvant, Adjuvant
|Types of cancer=Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Endometrial Cancer, Gynecologic Cancers - Vulvar Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Cancer stage, n (%)
Stage 1: 13 (27.7), stage 2: 2 (4.3), stage 3: 16 (34.0), stage 4: 3 (6.4), recurrent: 13 (27.7)
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Carboplatin-paclitaxel chemotherapy
Types of chemotherapy, n (%)
neoadjuvant: 4 (8.5), adjuvant: 43 (91.5)
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=Female n (%): 48 (100)
|Age groups=Adults (18+)
|Age groups specification=Age in years, mean (SD): 53.9 (13.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=24
|Drop-out=1
|Drop-out reasons=Excluded due to changing chemotherapy (n=1)
|Intervention=Ginger powder capsules (certified quality)
+ all participants received standard antiemetic medication including dexamethasone, ondansetron, and ranitidine; if necessary dimenhydrinate
|Dosage and regime=Daily dose 4x500mg before meals and one in the evening from day 1 to day 5 of chemotherapy
+ standard antiemetic medication included 20 mg of dexamethasone, 8 mg of ondansetron, and 50 mg of ranitidine which were injected 30 min before chemotherapy administration; if necessary 50mg dimenhydrinate before chemotherapy and 5 days at home
|One-time application=No
|Duration in days=5
|Side Effects / Interactions=According to data, no serious side effects in ginger-group or differences to placebo (p>0.05, not significant)
|Order number=1
|Arm topic=Ginger
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=24
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo in corn starch capsules
+ all participants received standard antiemetic medication including dexamethasone, ondansetron, and ranitidine; if necessary dimenhydrinate
|Dosage and regime=Daily dose before meals and one in the evening from day 1 to day 5 of chemotherapy
+ standard antiemetic medication included 20 mg of dexamethasone, 8 mg of ondansetron, and 50 mg of ranitidine which were injected 30 min before chemotherapy administration; if necessary 50mg dimenhydrinate before chemotherapy and 5 days at home
|One-time application=No
|Duration in days=5
|Side Effects / Interactions=According to data, no serious side effects in placebo-group or differences to ginger (p>0.05, not significant)
|Order number=2
|Arm topic=Ginger
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Nausea
|Outcome specification=Severity of nausea at T1 (acute) and T2 (delayed) (0-10, 0 = none, 10 = strongest possible nausea)
Nausea was defined a disorder characterized by a queasy sensation and/or the urge to vomit
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Significant difference between ginger vs. placebo (mean): 0.96 vs. 1.49 (p=0.03) on day 1 of chemotherapy
No significant group differences (p=0.39-0.94) on day 2-5 of chemotherapy
|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=1
|Outcome topic=Ginger
}}
{{Outcome
|Outcome type=NI
|Outcome name=Nausea
|Outcome specification=Degree of nausea
Grade 0 defined as normal appetite; Grade 1 defined as loss of appetite without alteration in eating habits; Grade 2 defined as decreased oral intake without significant weight loss, dehydration, or malnutrition; Grade 3 defined as inadequate oral caloric or fluid intake
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=No significant differences p>0.05 on day 1-5 of chemotherapy
|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 topic=Ginger
}}
{{Outcome
|Outcome type=NI
|Outcome name=Vomiting
|Outcome specification=Frequency of vomiting
Vomiting was defined a disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=No significant difference ginger vs. placebo: 10.6% vs. 8.5% (p=0.78) on day 1 of chemotherapy
No significant group differences (p>0.05) on day 2-5 of chemotherapy
|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 topic=Ginger
}}
{{Outcome
|Outcome type=NI
|Outcome name=Toxicity
|Outcome specification=Side effects included diarrhea, constipation, heartburn.
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=Diarrhea: ginger vs. placebo: 27.7% vs. 36.2% (p=0.34), no significant difference
Heartburn: ginger vs. placebo: 8.5% vs. 12.8% (p=0.38), no significant difference
Constipation: ginger vs. placebo: 14.9% vs. 4.3% (p=0.09), 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=4
|Outcome topic=Ginger
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=The authors thank the Ratchadapisek Sompotch Fund, Faculty of Medicine, Chulalongkorn University (grant number RA61/019) which provided funding support.
|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=erh
|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=?
|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}}
=Additional Notes=

Uthaipaisanwong et al. (2020): Effects of ginger adjunct to the standard prophylaxis on reducing carboplatin and paclitaxel-induced nausea vomiting: a randomized controlled study

2024-11-25T09:09:37Z

JDoerfler:

{{Reference
|Reference=Publication: Effects of ginger adjunct to the standard prophylaxis on reducing carboplatin and paclitaxel-induced nausea vomiting: a randomized controlled study
}}
{{Study Note}}
=Brief summary=
In this study, 48 patients with gynecological cancer were randomly divided into two groups. One group received a capsule containing 500mg of ginger powder four times a day from the first to the fifth day of chemotherapy, while the other group received a placebo. Both groups also received standard anti-nausea/anti-vomiting medication. The groups were switched for the next chemotherapy cycle. The intake of ginger led to a decrease in the severity of acute nausea after chemotherapy compared to placebo (day 1). No differences were found for day 2-5. In terms of frequency of vomiting, degree of nausea and side effects such as diarrhea, constipation and heartburn, there were no benefits of ginger intake. The study is characterized by a clear and comprehensible presentation of the results. Missing effects could have been influenced by a generally low incidence of vomiting and nausea.

In dieser Studie wurden 48 Patientinnen mit gynäkologischen Krebserkrankungen zufällig in zwei Gruppen aufgeteilt. Die eine Gruppe erhielt vom ersten bis zum fünften Tag der Chemotherapie viermal täglich eine Kapsel mit 500mg Ingwerpulver, die andere Gruppe erhielt ein Placebo. Beide Gruppen erhielten zusätzlich Standardmedikamente gegen Übelkeit/Erbrechen. Für den nächsten Chemotherapie-Zyklus wurden die Gruppen getauscht. Die Einnahme von Ingwer hat im Vergleich zu Placebo zu einer Abnahme der Schwere der akuten Übelkeit nach Chemotherapie geführt (1. Tag). Es wurden keine Unterschiede für Tag 2-5 gefunden. In Bezug auf Häufigkeit von Erbrechen, Grad der Übelkeit und Nebenwirkungen wie Durchfall, Verstopfung und Sodbrennen zeigte sich keine Vorteile durch Ingwereinnahme. Die Studie zeichnet sich durch eine übersichtliche und verständliche Darstellung der Ergebnisse aus. Fehlende Effekte könnten durch ein allgemein geringes Auftreten von Erbrechen und Übelkeit beeinflusst worden sein.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Monocentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Patients with gynecological cancers (ovarian, cervical, endometrial, vulvar carcinoma; stage 1-4, recurrence), ECOG status 0-2, carboplatin-paclitaxel chemotherapy
|Exclusion criteria=Patients using other gingers or the other antiemetic medication such as NK1 receptor antagonist or long-acting 5HT3 receptor antagonists to current study treatment; patients with gut obstruction or brain or bowel metastasis, patients using anticoagulant medication, and patients with allergy to ginger
|N randomized=48
|Analysis=PP Analysis
|Specifications on analyses=All statistical analyses were performed using STATA version 15.1. P values less than 0.05 were considered significant. Demographic data of all participants were analyzed by using mean, 95%CI, and percentage.
Nausea score from day 1 to day 5 was showed in mean, and analysis of variance (ANOVA) for a 2 × 2 crossover study was analyzed comparing treatment, sequence, and period effect.
Nausea grading for each day was compared using proportion f grading between treatment after adjusted sequence and period by using random-effects ordered logistic regression.
Vomiting and side effects were analyzed by comparing percentages between groups using random-effects logistic regression.
|Countries of data collection=Thailand
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: Baseline
T1: Day 1 of chemotherapy
T2: Day 2-5 of chemotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Neo-adjuvant, Adjuvant
|Types of cancer=Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Endometrial Cancer, Gynecologic Cancers - Vulvar Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Cancer stage, n (%)
Stage 1: 13 (27.7), stage 2: 2 (4.3), stage 3: 16 (34.0), stage 4: 3 (6.4), recurrent: 13 (27.7)
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Carboplatin-paclitaxel chemotherapy
Types of chemotherapy, n (%)
neoadjuvant: 4 (8.5), adjuvant: 43 (91.5)
|Previous cancer therapies=NI
|Gender=Female
|Gender specifications=Female n (%): 48 (100)
|Age groups=Adults (18+)
|Age groups specification=Age in years, mean (SD): 53.9 (13.8)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=24
|Drop-out=1
|Drop-out reasons=Excluded due to changing chemotherapy (n=1)
|Intervention=Ginger powder capsules (certified quality)
+ all participants received standard antiemetic medication including dexamethasone, ondansetron, and ranitidine; if necessary dimenhydrinate
|Dosage and regime=Daily dose 4x500mg before meals and one in the evening from day 1 to day 5 of chemotherapy
+ standard antiemetic medication included 20 mg of dexamethasone, 8 mg of ondansetron, and 50 mg of ranitidine which were injected 30 min before chemotherapy administration; if necessary 50mg dimenhydrinate before chemotherapy and 5 days at home
|One-time application=No
|Duration in days=5
|Side Effects / Interactions=According to data, no serious side effects in ginger-group or differences to placebo (p>0.05, not significant)
|Order number=1
|Arm topic=Ginger
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=24
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo in corn starch capsules
+ all participants received standard antiemetic medication including dexamethasone, ondansetron, and ranitidine; if necessary dimenhydrinate
|Dosage and regime=Daily dose before meals and one in the evening from day 1 to day 5 of chemotherapy
+ standard antiemetic medication included 20 mg of dexamethasone, 8 mg of ondansetron, and 50 mg of ranitidine which were injected 30 min before chemotherapy administration; if necessary 50mg dimenhydrinate before chemotherapy and 5 days at home
|One-time application=No
|Duration in days=5
|Side Effects / Interactions=According to data, no serious side effects in placebo-group or differences to ginger (p>0.05, not significant)
|Order number=2
|Arm topic=Ginger
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Nausea
|Outcome specification=Severity of nausea at T1 (acute) and T2 (delayed) (0-10, 0 = none, 10 = strongest possible nausea)
Nausea was defined a disorder characterized by a queasy sensation and/or the urge to vomit
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Significant difference between ginger vs. placebo (mean): 0.96 vs. 1.49 (p=0.03) on day 1 of chemotherapy
No significant group differences (p=0.39-0.94) on day 2-5 of chemotherapy
|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=1
|Outcome topic=Ginger
}}
{{Outcome
|Outcome type=NI
|Outcome name=Nausea
|Outcome specification=Degree of nausea
Grade 0 defined as normal appetite; Grade 1 defined as loss of appetite without alteration in eating habits; Grade 2 defined as decreased oral intake without significant weight loss, dehydration, or malnutrition; Grade 3 defined as inadequate oral caloric or fluid intake
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=No significant differences p>0.05 on day 1-5 of chemotherapy
|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 topic=Ginger
}}
{{Outcome
|Outcome type=NI
|Outcome name=Vomiting
|Outcome specification=Frequency of vomiting
Vomiting was defined a disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=No significant difference ginger vs. placebo: 10.6% vs. 8.5% (p=0.78) on day 1 of chemotherapy
No significant group differences (p>0.05) on day 2-5 of chemotherapy
|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 topic=Ginger
}}
{{Outcome
|Outcome type=NI
|Outcome name=Toxicity
|Outcome specification=Side effects included diarrhea, constipation, heartburn.
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=Diarrhea: ginger vs. placebo: 27.7% vs. 36.2% (p=0.34), no significant difference
Heartburn: ginger vs. placebo: 8.5% vs. 12.8% (p=0.38), no significant difference
Constipation: ginger vs. placebo: 14.9% vs. 4.3% (p=0.09), 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=4
|Outcome topic=Ginger
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=The authors thank the Ratchadapisek Sompotch Fund, Faculty of Medicine, Chulalongkorn University (grant number RA61/019) which provided funding support.
|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=erh
|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=?
|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}}
=Additional Notes=

Strasser et al. (2006): Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled (…)

2024-11-22T13:52:24Z

JDoerfler:

{{Reference
|Reference=Publication: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled (…)
}}

=Brief summary=
The study included 243 patients with various types of advanced cancer. Randomly divided into three arms, one received a cannabis extract (THC and cannabidiol) for six weeks, one only THC and one a placebo. The main focus was on the influence on appetite and quality of life. After six weeks, no differences were found for appetite, quality of life, weight, mood or nausea. Also no differences were found with regard to the side effects associated with the use of cannabis extract/ THC. This elaborate study is characterised by a good study design and detailed statistics. Unfortunately, few tables are given with exact statistical values of the symptoms symptoms recorded.

In der Studie wurden 243 Patienten mit verschiedenen Krebsarten im fortgeschrittenen Stadium eingeschlossen. Zufällig in drei Gruppen eingeteilt bekam eine über sechs Wochen ein Cannabis-Extrakt (THC und Cannabidiol), eine nur THC und eine ein Placebo. Gemessen wurde vor allem der Einfluss auf Appetit und Lebensqualität. Nach sechs Wochen konnten keine Unterschiede gefunden werden für Appetit, Lebensqualität, Gewicht, Stimmung oder Übelkeit. Auch konnten keine Unterschiede bezüglich den Nebenwirkungen im Zusammenhang mit der Einnahme von Cannabisextrakt/ THC gefunden werden. Diese aufwändige Studie zeichnet sich durch ein gutes Studiendesign und detaillierte Statistik aus. Leider werden wenig Tabellen gegeben mit genauen statistischen Werten der erhobenen Symptome.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Advanced, incurable cancer; cancer-related anorexia-cachexia syndrome; weight loss (≥ 5% over 6 months), not explained by other diseases or recent surgery; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2: estimated life expectancy of 3 months; Creatinine, bilirubin, and transaminase values no higher than 3x the maximum normal value; Unchanged antineoplastic therapy for 4 weeks and unchanged supportive treatment (analgesics, sedatives, tranquilizers, and anticholinergics) for 1 week before baseline assessments
|Exclusion criteria=Enteral or parenteral nutrition; had taken; taken anabolic agents, gestagens, cannabinoids, or corticosteroids within the past month; significant cause of secondary anorexia or psychiatric disorder (substance abuse or schizophrenia)
|N randomized=243
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=n for ITT: 243, only for tests between THC/Cannabis extract vs. Placebo

n for PP: 80, tests between THC vs. Cannabis extract

ITT and PP only for primary endpoint, sucessive testing labeled explorative
|Countries of data collection=Germany, Netherlands, Switzerland
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: after 2 weeks

T2: after 4 weeks

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

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=Gastrointestinal Cancers, Head and Neck Cancers, Hematologic Cancers, Lung Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=Advanced, incurable cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, NI
|Specifications on cancer therapies=Chemotherapy patients (received chemotherapy in the 4 weeks before baseline and who intended to continue chemotherapy during the study), per arm:

THC = 52%

Cannabis extract = 47%

Placebo = 52%
|Previous cancer therapies=Chemotherapy, NI
|Gender=Mixed
|Gender specifications=Male per arm:

THC = 54%

Cannabis extract = 56%

Placebo = 52%
|Age groups=Adults (18+)
|Age groups specification=Mean age = 61 years

Mean (SD) age per arm:

THC = 60 (12) years

Cannabis extract = 61 (12) years

Placebo = 62 (10) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=100
|Drop-out=35
|Drop-out reasons=Reason (n):

Withdrawn consent (20)

Serious adverse event (3)

Other exclusion criterion (1)

Death (8)

Loss to follow-up (3)
|Intervention=THC
|Dosage and regime=2.5mg THC orally, 2x a day, preferably taken before lunch and dinner/at bedtime
|One-time application=No
|Duration in days=42
|Side Effects / Interactions=Total adverse events:
* n=197, of which possibly intervention-associated n=45 and likely intervention-associated n=7
* Temporary or permanent dose reduction was necessary for 30 patients
* Adverse events that occurred more than 10 times were: Nausea/vomiting (n=21), fatigue (n=14), pain (n=17), anemia (n=14), dizziness (n=11), dyspnea (n=7), diarrhea (n=7), obstipation (n=7), vertigo (n not reported); no differences in frequencies between arm
* Of all side effects n=101 were mild, n=71 moderate, n=24 severe (mainly dizziness, nausea/vomiting, dyspnea)
* 33 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 6 of which were life-threatening, 27 required hospitalization
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=95
|Drop-out=29
|Drop-out reasons=Reason (n):

Withdrawn consent (17)

Serious adverse event (4)

Other exclusion criterion (1)

Death (4)

Loss to follow-up (1)

Other protocol violation (2)
|Intervention=Cannabis extract
|Dosage and regime=2,5mg THC + 1mg cannabidiol, 2x a day, preferably taken before lunch and dinner/at bedtime
|One-time application=No
|Duration in days=42
|Side Effects / Interactions=Total adverse events:
* n=238, of which possibly intervention-associated n=28 and likely intervention-associated n=9
* Temporary or permanent dose reduction was necessary for 34 patients
* Adverse events that occurred more than 10 times were: Nausea/vomiting (n=23), fatigue (n=16), pain (n=11), anemia (n=9), dizziness (n=9), dyspnea (n=9), diarrhea (n=6), obstipation (n=6), vertigo (n not reported); no differences in frequencies between arms
* Of all side effects n=104 were mild, n=113 moderate, n=21 severe (mainly dizziness, nausea/vomiting, dyspnea)
* 32 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 6 of which were life-threatening, 25 required hospitalization
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=48
|Drop-out=15
|Drop-out reasons=Reason (n):

Withdrawn consent (8)

Serious adverse event (4)

Other exclusion criterion (2)

Death (1)
|Intervention=Placebo
|Dosage and regime=2x a day, preferably taken before lunch and dinner/at bedtime
|One-time application=No
|Duration in days=42
|Side Effects / Interactions=Total adverse events:
* n=91, of which possibly intervention-associated n=17 and likely intervention-associated n=4
* Temporary or permanent dose reduction was necessary for 14 patients
* Adverse events that occurred more than 10 times were: Nausea/vomiting (n=11), fatigue (n=4), pain (n=5), anemia (n=6), dizziness (n=7), dyspnea (n=2), diarrhea (n=2), obstipation (n=2), vertigo (n not reported); no differences in frequencies between arms
* Of all side effects n=36 were mild, n=43 moderate, n=12 severe (mainly dizziness, nausea/vomiting, dyspnea)
* 17 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 1 of which were life-threatening, 16 required hospitalization
|Order number=3
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Appetite
|Outcome specification=Change from baseline to week 6
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=After 6 weeks:

No significant differences between the intervention arms and placebo arm for mean improvement (ITT Cannabis extract vs. Placebo p=0.46, THC vs. Placebo p=0.95) or increased appetite (p=0.068)
|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=high risk
|Bias in measurement of the outcome=high risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Change from baseline to week 6, measured with a composite score (mean) of questions 29 (Global Health Status) and 30 (QOL) of the EORTC QLQ-C30, twice a week
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=After 6 weeks:

No significant differences between Cannabis extract arm and Placebo arm (ITT p=0.80) or THC arm and Placebo arm (ITT p=0.43), as well as THC arm and Cannabis extract arm (PP analysis p=0.90)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Mood/Affect
|Outcome specification=Mood, measured daily
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention='''Overall'''

Improvement but without significant differences between arms (p=0.461)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Nausea
|Outcome specification=Measured daily
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention='''Overall'''

Improvement but without significant differences between arm (p=0.367)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Anorexia/Cachexia
|Outcome specification=Measured with the anorexia-cachexia module of the EORTC QLQ-C30
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=After 2 weeks: improvement of all arms by 5% (no statistical values/comparisons)

After 6 weeks: further 5% improvement for Placebo arm, after 2 weeks unchanged for THC arm and decline by 2.5% for Cannabis extract arm (no statistical values/comparisons)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Toxicity
|Outcome specification=Cannabinoid-related toxicity with CannTox module (based on the Drug Reaction Scale of adjectives describing mood, physical feelings, and perceptions of mental or cognitive functions of healthy volunteers under the influence of cannabis);
measured twice a week
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events), Self-developed measurement instrument
|Results during intervention=No significant differences in frequencies between arms for common adverse events, e.g. nausea/vomiting, fatigue, pain, anemia, dizziness, dyspnea, diarrhea, obstipation, vertigo (all p's ≥ .42)

No differences for CannTox scales dizziness, feeling good, feeling high, hallucinations, palpitations, panic attacks, feeling active or unsteady walking

See Arms/Side effects for detailed description
|Results after intervention=NA
|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=high 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=high risk
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=NI
|Outcome name=Functionality
|Outcome specification=Measured with functional scales and individual items of the EORTC QLQ-C30 (physical, role, emotional, cognitive, and social functioning; and dyspnea, diarrhea, and financial problems)
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention='''Overall'''

Steady-state or slight deterioration in all treatment arms (no statistical values/comparisons)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=7
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=NI
|Outcome name=Weight
|Outcome specification=NI
|Type of measurement=Scale
|Results during intervention=No differences for weight or weight loss after 6 weeks (no statistical values)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=8
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Sponsored by the Institute for Clinical Research, Berlin
|Conflicts of Interest=Financial interest: Martin Schnelle and Marcus Reif (Institute for Clinical Research, Berlin)
}}
=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=First unblinded interim analysis showed insufficient differences in the primary end point between placebo and intervention arms (final n=243 out of 445)
|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=NI
|Correction for multiple testing=Yes
|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=NA
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=Independent data review board recommended termination of recruitment because of insufficient differences between study arms in the primary endpoint,
n (power analysis)= 445
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Indication of the reliability of the measurement instruments
* Power analysis
* Intent-to-treat analysis (but see CONTRA)
* Very detailed description of the statistics
* Control for compliance and high compliance (44-60%), compliance with treatment was similar between arms (Cannabis extract 49%, THC 44%, and Placebo 60%; p > .15)

CONTRA:
* ITT only for tests between both intervention arm vs. placebo, tests between the 2 intervention arms with PP analysis
* Sample too small according to power analysis, recruitment was stopped after interim analysis due to lack of effects
* 84 patients had severe deviations from the protocol and/or took less than 90% of the intervention, had missing data on the primary endpoint, or had THC in serum at baseline
* Patients in PP analysis mostly male, older with better baseline scores for mood, nausea, daily food intake and QoL
}}

Strasser et al. (2006): Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled (…)

2024-11-22T13:52:17Z

JDoerfler:

{{Reference
|Reference=Publication: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled (…)
}}
{{Study Note}}
=Brief summary=
The study included 243 patients with various types of advanced cancer. Randomly divided into three arms, one received a cannabis extract (THC and cannabidiol) for six weeks, one only THC and one a placebo. The main focus was on the influence on appetite and quality of life. After six weeks, no differences were found for appetite, quality of life, weight, mood or nausea. Also no differences were found with regard to the side effects associated with the use of cannabis extract/ THC. This elaborate study is characterised by a good study design and detailed statistics. Unfortunately, few tables are given with exact statistical values of the symptoms symptoms recorded.

In der Studie wurden 243 Patienten mit verschiedenen Krebsarten im fortgeschrittenen Stadium eingeschlossen. Zufällig in drei Gruppen eingeteilt bekam eine über sechs Wochen ein Cannabis-Extrakt (THC und Cannabidiol), eine nur THC und eine ein Placebo. Gemessen wurde vor allem der Einfluss auf Appetit und Lebensqualität. Nach sechs Wochen konnten keine Unterschiede gefunden werden für Appetit, Lebensqualität, Gewicht, Stimmung oder Übelkeit. Auch konnten keine Unterschiede bezüglich den Nebenwirkungen im Zusammenhang mit der Einnahme von Cannabisextrakt/ THC gefunden werden. Diese aufwändige Studie zeichnet sich durch ein gutes Studiendesign und detaillierte Statistik aus. Leider werden wenig Tabellen gegeben mit genauen statistischen Werten der erhobenen Symptome.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Advanced, incurable cancer; cancer-related anorexia-cachexia syndrome; weight loss (≥ 5% over 6 months), not explained by other diseases or recent surgery; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2: estimated life expectancy of 3 months; Creatinine, bilirubin, and transaminase values no higher than 3x the maximum normal value; Unchanged antineoplastic therapy for 4 weeks and unchanged supportive treatment (analgesics, sedatives, tranquilizers, and anticholinergics) for 1 week before baseline assessments
|Exclusion criteria=Enteral or parenteral nutrition; had taken; taken anabolic agents, gestagens, cannabinoids, or corticosteroids within the past month; significant cause of secondary anorexia or psychiatric disorder (substance abuse or schizophrenia)
|N randomized=243
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=n for ITT: 243, only for tests between THC/Cannabis extract vs. Placebo

n for PP: 80, tests between THC vs. Cannabis extract

ITT and PP only for primary endpoint, sucessive testing labeled explorative
|Countries of data collection=Germany, Netherlands, Switzerland
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: after 2 weeks

T2: after 4 weeks

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

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=Gastrointestinal Cancers, Head and Neck Cancers, Hematologic Cancers, Lung Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=Advanced, incurable cancer
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, NI
|Specifications on cancer therapies=Chemotherapy patients (received chemotherapy in the 4 weeks before baseline and who intended to continue chemotherapy during the study), per arm:

THC = 52%

Cannabis extract = 47%

Placebo = 52%
|Previous cancer therapies=Chemotherapy, NI
|Gender=Mixed
|Gender specifications=Male per arm:

THC = 54%

Cannabis extract = 56%

Placebo = 52%
|Age groups=Adults (18+)
|Age groups specification=Mean age = 61 years

Mean (SD) age per arm:

THC = 60 (12) years

Cannabis extract = 61 (12) years

Placebo = 62 (10) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=100
|Drop-out=35
|Drop-out reasons=Reason (n):

Withdrawn consent (20)

Serious adverse event (3)

Other exclusion criterion (1)

Death (8)

Loss to follow-up (3)
|Intervention=THC
|Dosage and regime=2.5mg THC orally, 2x a day, preferably taken before lunch and dinner/at bedtime
|One-time application=No
|Duration in days=42
|Side Effects / Interactions=Total adverse events:
* n=197, of which possibly intervention-associated n=45 and likely intervention-associated n=7
* Temporary or permanent dose reduction was necessary for 30 patients
* Adverse events that occurred more than 10 times were: Nausea/vomiting (n=21), fatigue (n=14), pain (n=17), anemia (n=14), dizziness (n=11), dyspnea (n=7), diarrhea (n=7), obstipation (n=7), vertigo (n not reported); no differences in frequencies between arm
* Of all side effects n=101 were mild, n=71 moderate, n=24 severe (mainly dizziness, nausea/vomiting, dyspnea)
* 33 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 6 of which were life-threatening, 27 required hospitalization
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=95
|Drop-out=29
|Drop-out reasons=Reason (n):

Withdrawn consent (17)

Serious adverse event (4)

Other exclusion criterion (1)

Death (4)

Loss to follow-up (1)

Other protocol violation (2)
|Intervention=Cannabis extract
|Dosage and regime=2,5mg THC + 1mg cannabidiol, 2x a day, preferably taken before lunch and dinner/at bedtime
|One-time application=No
|Duration in days=42
|Side Effects / Interactions=Total adverse events:
* n=238, of which possibly intervention-associated n=28 and likely intervention-associated n=9
* Temporary or permanent dose reduction was necessary for 34 patients
* Adverse events that occurred more than 10 times were: Nausea/vomiting (n=23), fatigue (n=16), pain (n=11), anemia (n=9), dizziness (n=9), dyspnea (n=9), diarrhea (n=6), obstipation (n=6), vertigo (n not reported); no differences in frequencies between arms
* Of all side effects n=104 were mild, n=113 moderate, n=21 severe (mainly dizziness, nausea/vomiting, dyspnea)
* 32 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 6 of which were life-threatening, 25 required hospitalization
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=48
|Drop-out=15
|Drop-out reasons=Reason (n):

Withdrawn consent (8)

Serious adverse event (4)

Other exclusion criterion (2)

Death (1)
|Intervention=Placebo
|Dosage and regime=2x a day, preferably taken before lunch and dinner/at bedtime
|One-time application=No
|Duration in days=42
|Side Effects / Interactions=Total adverse events:
* n=91, of which possibly intervention-associated n=17 and likely intervention-associated n=4
* Temporary or permanent dose reduction was necessary for 14 patients
* Adverse events that occurred more than 10 times were: Nausea/vomiting (n=11), fatigue (n=4), pain (n=5), anemia (n=6), dizziness (n=7), dyspnea (n=2), diarrhea (n=2), obstipation (n=2), vertigo (n not reported); no differences in frequencies between arms
* Of all side effects n=36 were mild, n=43 moderate, n=12 severe (mainly dizziness, nausea/vomiting, dyspnea)
* 17 very severe side effects such as dyspnoea, tumor progression, vomiting, deterioration of general well-being, death, pain, fever, diarrhoea, exsiccation; 1 of which were life-threatening, 16 required hospitalization
|Order number=3
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Appetite
|Outcome specification=Change from baseline to week 6
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=After 6 weeks:

No significant differences between the intervention arms and placebo arm for mean improvement (ITT Cannabis extract vs. Placebo p=0.46, THC vs. Placebo p=0.95) or increased appetite (p=0.068)
|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=high risk
|Bias in measurement of the outcome=high risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Change from baseline to week 6, measured with a composite score (mean) of questions 29 (Global Health Status) and 30 (QOL) of the EORTC QLQ-C30, twice a week
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=After 6 weeks:

No significant differences between Cannabis extract arm and Placebo arm (ITT p=0.80) or THC arm and Placebo arm (ITT p=0.43), as well as THC arm and Cannabis extract arm (PP analysis p=0.90)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Mood/Affect
|Outcome specification=Mood, measured daily
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention='''Overall'''

Improvement but without significant differences between arms (p=0.461)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Nausea
|Outcome specification=Measured daily
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention='''Overall'''

Improvement but without significant differences between arm (p=0.367)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Anorexia/Cachexia
|Outcome specification=Measured with the anorexia-cachexia module of the EORTC QLQ-C30
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=After 2 weeks: improvement of all arms by 5% (no statistical values/comparisons)

After 6 weeks: further 5% improvement for Placebo arm, after 2 weeks unchanged for THC arm and decline by 2.5% for Cannabis extract arm (no statistical values/comparisons)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Toxicity
|Outcome specification=Cannabinoid-related toxicity with CannTox module (based on the Drug Reaction Scale of adjectives describing mood, physical feelings, and perceptions of mental or cognitive functions of healthy volunteers under the influence of cannabis);
measured twice a week
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events), Self-developed measurement instrument
|Results during intervention=No significant differences in frequencies between arms for common adverse events, e.g. nausea/vomiting, fatigue, pain, anemia, dizziness, dyspnea, diarrhea, obstipation, vertigo (all p's ≥ .42)

No differences for CannTox scales dizziness, feeling good, feeling high, hallucinations, palpitations, panic attacks, feeling active or unsteady walking

See Arms/Side effects for detailed description
|Results after intervention=NA
|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=high 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=high risk
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=NI
|Outcome name=Functionality
|Outcome specification=Measured with functional scales and individual items of the EORTC QLQ-C30 (physical, role, emotional, cognitive, and social functioning; and dyspnea, diarrhea, and financial problems)
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention='''Overall'''

Steady-state or slight deterioration in all treatment arms (no statistical values/comparisons)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=7
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=NI
|Outcome name=Weight
|Outcome specification=NI
|Type of measurement=Scale
|Results during intervention=No differences for weight or weight loss after 6 weeks (no statistical values)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high 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=high risk
|Order number=8
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Sponsored by the Institute for Clinical Research, Berlin
|Conflicts of Interest=Financial interest: Martin Schnelle and Marcus Reif (Institute for Clinical Research, Berlin)
}}
=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=First unblinded interim analysis showed insufficient differences in the primary end point between placebo and intervention arms (final n=243 out of 445)
|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=NI
|Correction for multiple testing=Yes
|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=NA
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=Independent data review board recommended termination of recruitment because of insufficient differences between study arms in the primary endpoint,
n (power analysis)= 445
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics vote
* Indication of the reliability of the measurement instruments
* Power analysis
* Intent-to-treat analysis (but see CONTRA)
* Very detailed description of the statistics
* Control for compliance and high compliance (44-60%), compliance with treatment was similar between arms (Cannabis extract 49%, THC 44%, and Placebo 60%; p > .15)

CONTRA:
* ITT only for tests between both intervention arm vs. placebo, tests between the 2 intervention arms with PP analysis
* Sample too small according to power analysis, recruitment was stopped after interim analysis due to lack of effects
* 84 patients had severe deviations from the protocol and/or took less than 90% of the intervention, had missing data on the primary endpoint, or had THC in serum at baseline
* Patients in PP analysis mostly male, older with better baseline scores for mood, nausea, daily food intake and QoL
}}

Jatoi et al. (2002): Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study

2024-11-22T13:50:48Z

JDoerfler:

{{Reference
|Reference=Publication: Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study
}}

=Brief summary=
The study included 469 patients with different types of cancer. Randomly divided into three arms, one arm received Megestrol acetate, one arm received Dronabinol and one arm received both drugs. After an estimated two to three months, there was an advantage for the Megestrol arm over the Dronabinol arm for self-assessed/self-measured appetite increase and weight gain at any point in the study. There were no differences between the Megestrol arm and the combined arm. There were also some advantages of Megestrol over Dronabinol in terms of improving quality of life. The study is characterized by a large sample size. However, there are ambiguities in the procedure. For example, no clear end of the study was defined, only average participation times are given in the article, and the reasons and times at which patients withdrew from the study are not clearly stated.

In der Studie wurden 469 Patienten mit verschiedenen Krebsarten eingeschlossen. Zufällig in drei Gruppen eingeteilt, bekam eine Gruppe Megestrol Acetat, eine Gruppe Dronabinol und eine Gruppe beide Mittel. Nach schätzungsweise 2-3 Monaten zeigte sich ein Vorteil für die Megestrol Gruppe gegenüber der Dronabinol Gruppe für selbsteingeschätzte/ selbstgemessene Appetitsteigerung und Gewichtszunahme zu irgendeinem Punkt in der Studie. Zwischen der Megestrol Gruppe und der kombinierten Gruppe zeigten sich keine Unterschiede. Es zeigten sich auch einige Vorteile von Megestrol gegenüber Dronabinol bezüglich der Verbesserung der Lebensqualität. Die Studie zeichnet sich durch eine große Stichprobe aus. Jedoch gibt es Unklarheiten im Ablauf. So wurde kein klares Studienende definiert, im Artikel werden nur mittlere Teilnahmezeiten angegeben, auch sind die Gründe und Zeitpunkte des Ausstiegs von Patienten der Studie nicht deutlich aufgeführt.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Adult patients (≥18 years of age) with histologic evidence of an incurable malignancy other than brain, breast, ovarian, or endometrial cancer; estimated life expectancy of ≥3 months; Eastern Cooperative Oncology Group performance status of 0 to 2, as judged by their primary oncologist; self-reported weight loss of at least 5 pounds (2.3 kg) during the preceding 2 months and/or a physician-estimated caloric intake of less than 20 calories/kg of body weight per day; believe, that loss of appetite or loss of weight was an ongoing problem
|Exclusion criteria=Ongoing use of tube feedings or parenteral nutrition; edema or ascites; treatment with adrenal corticosteroids (except for short-term dexamethasone during the time of chemotherapy), androgens, progestational agents, or other appetite stimulants within the previous month; brain metastases; insulin-requiring diabetes; pregnancy or lactation or unwillingness to use oral contraceptives; anticipated alcohol or barbiturate use during the study period; poorly controlled hypertension or congestive heart failure; history of thromboembolic disease; mechanical obstruction of the alimentary tract, malabsorption, or intractable vomiting
|N randomized=469
|Analysis=ITT Analysis
|Specifications on analyses=No information provided on intent-to-treat analyses, but according to the tables all randomized patients appear to have been included in the analyses.
|Countries of data collection=Canada, Mexico, United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline
T1: end of study (no clear end of study defined)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=Gastrointestinal Cancers, Lung Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy, No therapy
|Specifications on cancer therapies=Planned concurrent chemotherapy, %, per arm
* None: Megestrol Acetate = 30; Dronabinol = 30; Megestrol Acetate + Dronabinol= 30

* With cisplatinum: Megestrol Acetate = 15; Dronabinol = 14; Megestrol Acetate + Dronabinol = 14

* Without cisplatinum: Megestrol Acetate= 55; Dronabinol = 56; Megestrol Acetate + Dronabinol = 56

Planned concurrent radiation, %

* Yes: Megestrol Acetate = 21; Dronabinol = 20; Megestrol Acetate + Dronabinol = 20

* No: Megestrol Acetate = 79; Dronabinol = 80; Megestrol Acetate + Dronabinol = 80
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Sex (%) per arm

* Megestrol Acetate: male = 65; female = 36

* Dronabinol: male = 66; female = 34

* Megestrol Acetate + Dronabinol: male = 66; female = 34
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age per arm:

* Megestrol Acetate = 65 (11) years

* Dronabinol = 67 (10) years

* Megestrol Acetate + Dronabinol = 67 (10) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=159
|Drop-out=106
|Drop-out reasons=Patient refusal and/or toxicity (45%, respectively); patient death (22%, respectively)
|Intervention=Megestrol Acetate
|Dosage and regime=Oral, 800mg/day liquid + placebo
|One-time application=No
|Duration in days=80
|Side Effects / Interactions=Impotence in 18 % of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=152
|Drop-out=111
|Drop-out reasons=Patient refusal and/or toxicity (58%, respectively); patient death (15%, respectively)
|Intervention=Dronabinol
|Dosage and regime=Oral, 2.5mg 2 times a day + liquid placebo
|One-time application=No
|Duration in days=57
|Side Effects / Interactions=Impotence in 4% of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=185
|Drop-out=124
|Drop-out reasons=Patient refusal and/or toxicity (41%, respectively); patient death (26%, respectively)
|Intervention=Megestrol Acetate + Dronabinol
|Dosage and regime=Combination of Megestrol Acetate (oral, 800mg/day liquid) and Dronabinol (oral, 2.5mg 2 times a day)
|One-time application=No
|Duration in days=74
|Side Effects / Interactions=Impotence in 14% of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior
|Order number=3
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Appetite
|Outcome specification=Increase in appetite
|Type of measurement=Observation
|Results during intervention=Patients reporting increase in appetite at any point in the study (6-week median time):

* Significant benefit for Megestrol Acetate arm compared to Dronabinol arm (75% vs. 49%; p=0.0001)

* No differences between Megestrol Acetate + Dronabinol arm (66%) and Megestrol Acetate arm (p=0.17)
|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=high 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=high risk
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Weight
|Outcome specification=Weight gain (10% of own weight)
|Type of measurement=Scale
|Results during intervention=Patients reporting that weight had increased by 10% at any point in the study (6-week median time):
* Significant benefit for Megestrol Acetate arm compared to Dronabinol arm (11% vs. 3%; p=0.02)
* No differences between Megestrol Acetate + Dronabinol arm (8%) and Megestrol Acetate arm (p=0.34)

Physician data:
* Megestrol Acetate arm 14%, Dronabinol arm 5% (Megestrol Acetate arm vs. Dronabinol arm p=0.009)
* Megestrol Acetate + Dronabinol arm 11% (Megestrol Acetate arm vs. Megestrol Acetate + Dronabinol arm, p=0.49)
|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=high 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=high risk
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Quality of life (single Item Uniscale and FAACT-AN)
|Type of measurement=FAACT (Functional Assessment of Anorexia-Cachexia Therapy)
|Results during intervention=Difference baseline to end of study (6-week median time):

* No differences for Uniscale; in the FAACT-AN significant advantage for Megestrol Acetate arm over Dronabinol arm (p=0.002), as well as in individual scales physical and emotional constructs; except for emotional constructs (Megestrol Acetate arm better than Megestrol Acetate + Dronabinol arm)
* No differences between Megestrol Acetate arm and Megestrol Acetate + Dronabinol arm
|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=high 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=high risk
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=OS (Overall Survival)
|Outcome specification=Overall survival rate
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No significant difference (123 vs. 141 vs. 113 days) between the Megestrol Acetate versus Dronabinol versus the combination arm, respectively (log Rank p=0.66)
|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=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Collaborative study by the North Central Cancer Treatment Group and Mayo Clinic.

Dronabinol was provided by Roxane Laboratories,Columbus, OH.
Magestrol acetate was provided by: Bristol-Myers Squibb, princeton, NJ.
|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=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=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* Unclear statistic: Only 45% completed questionnaires after 1 month, no information provided on intent-to-treat analyses, but according to tables all randomized patients appear to have been included in the analyses (patients who dropped out were considered treatment failure)

* Different weights reported by patients and physicians

* No clear indication of time course (end of study), different median times for participation in studies per arm withdrawal due to withdrawal of consent and/or side effect (45%, 58%, and 41%) or death (22%, 15% and 26%)

* No flow chart, so unclear when drop-out/attrition occurred
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=NI
|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=NI
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=No
|Check whether blinding was successful=No
|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
* Stratified randomization
* Power analysis
* Baseline comparability

CONTRA:
* Discrepancies in weight data reported by patients vs. doctors
* No clear timeline for study completion, with varying median participation times across arms (dropouts due to consent withdrawal and/or side effects: 45%, 58%, and 41%; or death: 22%, 15%, and 26%)
* Lack of a flowchart, making the timing of dropouts/attrition unclear
* Only 45% completed questionnaires after one month; no details on intent-to-treat analysis, though tables suggest all randomized patients were included (dropouts were classified as "treatment failure")
}}

Jatoi et al. (2002): Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study

2024-11-22T13:50:31Z

JDoerfler:

{{Reference
|Reference=Publication: Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study
}}
{{Study Note}}
=Brief summary=
The study included 469 patients with different types of cancer. Randomly divided into three arms, one arm received Megestrol acetate, one arm received Dronabinol and one arm received both drugs. After an estimated two to three months, there was an advantage for the Megestrol arm over the Dronabinol arm for self-assessed/self-measured appetite increase and weight gain at any point in the study. There were no differences between the Megestrol arm and the combined arm. There were also some advantages of Megestrol over Dronabinol in terms of improving quality of life. The study is characterized by a large sample size. However, there are ambiguities in the procedure. For example, no clear end of the study was defined, only average participation times are given in the article, and the reasons and times at which patients withdrew from the study are not clearly stated.

In der Studie wurden 469 Patienten mit verschiedenen Krebsarten eingeschlossen. Zufällig in drei Gruppen eingeteilt, bekam eine Gruppe Megestrol Acetat, eine Gruppe Dronabinol und eine Gruppe beide Mittel. Nach schätzungsweise 2-3 Monaten zeigte sich ein Vorteil für die Megestrol Gruppe gegenüber der Dronabinol Gruppe für selbsteingeschätzte/ selbstgemessene Appetitsteigerung und Gewichtszunahme zu irgendeinem Punkt in der Studie. Zwischen der Megestrol Gruppe und der kombinierten Gruppe zeigten sich keine Unterschiede. Es zeigten sich auch einige Vorteile von Megestrol gegenüber Dronabinol bezüglich der Verbesserung der Lebensqualität. Die Studie zeichnet sich durch eine große Stichprobe aus. Jedoch gibt es Unklarheiten im Ablauf. So wurde kein klares Studienende definiert, im Artikel werden nur mittlere Teilnahmezeiten angegeben, auch sind die Gründe und Zeitpunkte des Ausstiegs von Patienten der Studie nicht deutlich aufgeführt.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Adult patients (≥18 years of age) with histologic evidence of an incurable malignancy other than brain, breast, ovarian, or endometrial cancer; estimated life expectancy of ≥3 months; Eastern Cooperative Oncology Group performance status of 0 to 2, as judged by their primary oncologist; self-reported weight loss of at least 5 pounds (2.3 kg) during the preceding 2 months and/or a physician-estimated caloric intake of less than 20 calories/kg of body weight per day; believe, that loss of appetite or loss of weight was an ongoing problem
|Exclusion criteria=Ongoing use of tube feedings or parenteral nutrition; edema or ascites; treatment with adrenal corticosteroids (except for short-term dexamethasone during the time of chemotherapy), androgens, progestational agents, or other appetite stimulants within the previous month; brain metastases; insulin-requiring diabetes; pregnancy or lactation or unwillingness to use oral contraceptives; anticipated alcohol or barbiturate use during the study period; poorly controlled hypertension or congestive heart failure; history of thromboembolic disease; mechanical obstruction of the alimentary tract, malabsorption, or intractable vomiting
|N randomized=469
|Analysis=ITT Analysis
|Specifications on analyses=No information provided on intent-to-treat analyses, but according to the tables all randomized patients appear to have been included in the analyses.
|Countries of data collection=Canada, Mexico, United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline
T1: end of study (no clear end of study defined)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=Gastrointestinal Cancers, Lung Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy, No therapy
|Specifications on cancer therapies=Planned concurrent chemotherapy, %, per arm
* None: Megestrol Acetate = 30; Dronabinol = 30; Megestrol Acetate + Dronabinol= 30

* With cisplatinum: Megestrol Acetate = 15; Dronabinol = 14; Megestrol Acetate + Dronabinol = 14

* Without cisplatinum: Megestrol Acetate= 55; Dronabinol = 56; Megestrol Acetate + Dronabinol = 56

Planned concurrent radiation, %

* Yes: Megestrol Acetate = 21; Dronabinol = 20; Megestrol Acetate + Dronabinol = 20

* No: Megestrol Acetate = 79; Dronabinol = 80; Megestrol Acetate + Dronabinol = 80
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Sex (%) per arm

* Megestrol Acetate: male = 65; female = 36

* Dronabinol: male = 66; female = 34

* Megestrol Acetate + Dronabinol: male = 66; female = 34
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age per arm:

* Megestrol Acetate = 65 (11) years

* Dronabinol = 67 (10) years

* Megestrol Acetate + Dronabinol = 67 (10) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=159
|Drop-out=106
|Drop-out reasons=Patient refusal and/or toxicity (45%, respectively); patient death (22%, respectively)
|Intervention=Megestrol Acetate
|Dosage and regime=Oral, 800mg/day liquid + placebo
|One-time application=No
|Duration in days=80
|Side Effects / Interactions=Impotence in 18 % of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=152
|Drop-out=111
|Drop-out reasons=Patient refusal and/or toxicity (58%, respectively); patient death (15%, respectively)
|Intervention=Dronabinol
|Dosage and regime=Oral, 2.5mg 2 times a day + liquid placebo
|One-time application=No
|Duration in days=57
|Side Effects / Interactions=Impotence in 4% of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=185
|Drop-out=124
|Drop-out reasons=Patient refusal and/or toxicity (41%, respectively); patient death (26%, respectively)
|Intervention=Megestrol Acetate + Dronabinol
|Dosage and regime=Combination of Megestrol Acetate (oral, 800mg/day liquid) and Dronabinol (oral, 2.5mg 2 times a day)
|One-time application=No
|Duration in days=74
|Side Effects / Interactions=Impotence in 14% of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior
|Order number=3
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Appetite
|Outcome specification=Increase in appetite
|Type of measurement=Observation
|Results during intervention=Patients reporting increase in appetite at any point in the study (6-week median time):

* Significant benefit for Megestrol Acetate arm compared to Dronabinol arm (75% vs. 49%; p=0.0001)

* No differences between Megestrol Acetate + Dronabinol arm (66%) and Megestrol Acetate arm (p=0.17)
|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=high 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=high risk
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Weight
|Outcome specification=Weight gain (10% of own weight)
|Type of measurement=Scale
|Results during intervention=Patients reporting that weight had increased by 10% at any point in the study (6-week median time):
* Significant benefit for Megestrol Acetate arm compared to Dronabinol arm (11% vs. 3%; p=0.02)
* No differences between Megestrol Acetate + Dronabinol arm (8%) and Megestrol Acetate arm (p=0.34)

Physician data:
* Megestrol Acetate arm 14%, Dronabinol arm 5% (Megestrol Acetate arm vs. Dronabinol arm p=0.009)
* Megestrol Acetate + Dronabinol arm 11% (Megestrol Acetate arm vs. Megestrol Acetate + Dronabinol arm, p=0.49)
|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=high 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=high risk
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Quality of life (single Item Uniscale and FAACT-AN)
|Type of measurement=FAACT (Functional Assessment of Anorexia-Cachexia Therapy)
|Results during intervention=Difference baseline to end of study (6-week median time):

* No differences for Uniscale; in the FAACT-AN significant advantage for Megestrol Acetate arm over Dronabinol arm (p=0.002), as well as in individual scales physical and emotional constructs; except for emotional constructs (Megestrol Acetate arm better than Megestrol Acetate + Dronabinol arm)
* No differences between Megestrol Acetate arm and Megestrol Acetate + Dronabinol arm
|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=high 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=high risk
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=OS (Overall Survival)
|Outcome specification=Overall survival rate
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No significant difference (123 vs. 141 vs. 113 days) between the Megestrol Acetate versus Dronabinol versus the combination arm, respectively (log Rank p=0.66)
|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=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Collaborative study by the North Central Cancer Treatment Group and Mayo Clinic.

Dronabinol was provided by Roxane Laboratories,Columbus, OH.
Magestrol acetate was provided by: Bristol-Myers Squibb, princeton, NJ.
|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=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=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* Unclear statistic: Only 45% completed questionnaires after 1 month, no information provided on intent-to-treat analyses, but according to tables all randomized patients appear to have been included in the analyses (patients who dropped out were considered treatment failure)

* Different weights reported by patients and physicians

* No clear indication of time course (end of study), different median times for participation in studies per arm withdrawal due to withdrawal of consent and/or side effect (45%, 58%, and 41%) or death (22%, 15% and 26%)

* No flow chart, so unclear when drop-out/attrition occurred
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=NI
|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=NI
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=No
|Check whether blinding was successful=No
|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
* Stratified randomization
* Power analysis
* Baseline comparability

CONTRA:
* Discrepancies in weight data reported by patients vs. doctors
* No clear timeline for study completion, with varying median participation times across arms (dropouts due to consent withdrawal and/or side effects: 45%, 58%, and 41%; or death: 22%, 15%, and 26%)
* Lack of a flowchart, making the timing of dropouts/attrition unclear
* Only 45% completed questionnaires after one month; no details on intent-to-treat analysis, though tables suggest all randomized patients were included (dropouts were classified as "treatment failure")
}}

Grimison et al. (2020): Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial

2024-11-22T13:49:48Z

JDoerfler:

{{Reference
|Reference=Publication: Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial
}}

=Brief summary=
The study included 81 patients with different types of cancer and a history of nausea and vomiting due to chemotherapy. They were randomly divided into tweo arms, one arm received THC and CBD daily and the other arm a placebo. After one cycle of chemotherapy, the arms were switched. At the end of two cycles (so that everyone was in each arm), there was overall less and less severe nausea and vomiting in the THC/CBD arm and an improvement on some quality of life measurement scales. However, the patients receiving THC/CBD had more side effects, such as dizziness and sedation, which were tolerable, according to the authors. The study has an elaborate study design. The statistics seem well thought out and take many factors into account, but a few methodological decisions remain unexplained. It should be noted in particular that many of the people involved in the article have direct contacts with the pharmaceutical industry.

In der Studie wurden 81 Patienten mit verschiedenen Krebsarten und Vorgeschichte von Übelkeit und Erbrechen durch Chemotherapie eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt, eine Gruppe bekam täglich THC und CBD und die andere Gruppe ein Placebo. Nach einem Zyklus Chemotherapie wurden die Gruppen getauscht. Am Ende von zwei Zyklen (sodass jeder in jeder Gruppe war) zeigte sich insgesamt weniger und weniger schwere Übelkeit und Erbrechen in der Gruppe mit THC/CBD und eine Verbesserung auf einigen Skalen der Messung der Lebensqualität. Jedoch hatten die Patienten die THC/CBD bekamen mehr Nebenwirkungen, wie Schwindel und Sedierung, die laut den Autoren jedoch tolerierbar waren. Die Studie hat ein aufwändiges Studiendesign. Die Statistik wirkt gut durchdacht und bezieht viele Faktoren mit ein, jedoch bleiben ein paar methodische Entscheidungen unerklärt. Besonders anzumerken ist, dass viele beteiligten Personen in dem Artikel direkte Kontakte zu Pharmaindustrien aufweisen.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Aged ≥18 years; any malignancy of any stage; receiving intravenous
chemotherapy of moderate or high emetogenic risk; receive at least two more consecutive cycles; refractory CINV (defined as emesis, and/or nausea of moderate severity on a 5-point rating scale, and/or requiring use of rescue medications) in earlier chemotherapy cycles despite guideline-consistent antiemetic prophylaxis consisting of corticosteroids, a 5-HT3 antagonist,
and an NK-1 antagonist with or without olanzapine where indicated
|Exclusion criteria=Eastern Cooperative Oncology Group (ECOG) performance status of >2; a contraindication to medicinal cannabis such as unstable cardiovascular disease, substance use disorder, or significant mental health disorder; experiencing disease-related nausea and vomiting; receiving concomitant oral chemotherapy; had received/were planned to receive radiotherapy to the brain or gastrointestinal tract during the study period
|N randomized=81
|Analysis=PP Analysis
|Specifications on analyses=Only participants who have received both interventions have been included in the efficacy analyses. Data on safety were sourced from the safety population (all participants who received ≥1 dose of study drug). The primary analysis was a comparison of the proportion of participants with complete response between the two treatment arms during two overall phases of treatment (0-120 h) of cycles A and B, using McNemar’s test to account for the within-patient correlation. Continuous outcomes were analysed with a linear model, and accounted for the correlation within a participant. All tests used a two-sided significance level of 10%. Secondary analyses have not been adjusted for multiple comparisons.
|Countries of data collection=Australia
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: one day before chemotherapy

T2: day 8 of each cycle

T3: between 30-42 days after end of intervention
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Palliative
|Types of cancer=Breast Cancer, Colorectal Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Pancreatic Cancer, Genitourinary Cancers - Testicular Cancer, Gynecologic Cancers, Hematologic Cancers, Lung Cancer, Other Cancers
|Stage cancer=NI
|Cancer stage specification=Any malignancy of any stage
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=Moderate-to-high emetogenic intravenous chemotherapy

Chemotherapy regimen, n(%):

Doxorubicin + cyclophosphamide = 20 (26)

FOLFOX ± biological = 13 (17)

Cisplatin based = 12 (15)

FOLFIRINOX = 6 (8)

Other = 27 (35)
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Female : 61 (78%)
Male: 17 (22%)
|Age groups=Adults (18+)
|Age groups specification=Median age (range): 55 (29-80) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=40
|Drop-out=4
|Drop-out reasons=Discontinued after THC:CBD (n = 4):
Death (n = 1); failure to comply (n = 1); chemotherapy stopped (n = 1); patient preference (n = 1)
|Intervention=THC:CBD
|Dosage and regime=1-4 capsules THC 2.5mg/CBD 2.5mg each 3x daily (one day before chemotherapy to day 5)

Median (SD) number of capsules = 2 (1-3)
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Moderate or severe cannabinoid-related side effects in intervention arm (31%) and placebo arm (7%) (p=0.002):
* Significant differences for sedation (19% vs. 4%, p=0.002), dizziness (10% vs. 1%, p=0.03)
* No differences for disorientation (3% vs. 0%, p=0.5), anxiety (1% vs. 1%, p=1.00)
* No cannabinoid-related serious adverse events were reported.

83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001).
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=41
|Drop-out=2
|Drop-out reasons=Discontinued after placebo (n = 2):
chemotherapy stopped (n = 1); patient preference (n = 1)
|Intervention=Placebo
|Dosage and regime=Median (SD) number of capsules = 3 (2-4)
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Moderate or severe cannabinoid-related side effects in intervention arm (31%) and placebo arm (7%) (p=0.002):
* Significant differences for sedation (19% vs. 4%, p=0.002), dizziness (10% vs. 1%, p=0.03)
* No differences for disorientation (3% vs. 0%, p=0.5), anxiety (1% vs. 1%, p=1.00)
* No cannabinoid-related serious adverse events were reported.

83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001).
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=CINV (Chemotherapy-Induced Nausea and Vomiting)
|Outcome specification=Complete response, no vomiting or emergency medication 0-120h of chemotherapy
|Type of measurement=Observation
|Results during intervention=Results after 2 cycles, after switching to the other arm:
* Significant advantage for intervention arm (25%) compared to placebo arm (14%): RR=1.77; 90% CI=1.12,2.79; p=0.041.
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=CINV (Chemotherapy-Induced Nausea and Vomiting)
|Outcome specification=Self-reported "complete response" ("no vomiting", "no clinically significant nausea", defined as nausea <2 on a 10-point scale, and "no use of emergency medication") during the acute (0-24 h), delayed (24-120 h) and general phase (0-120 h) of chemotherapy with diary day -1 to 6 of each cycle)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Results after 2 cycles, after switching to the other arm:
* Advantage for intervention arm for percentage for CR (p=0.04), for scales "no vomiting" (p=0.05), "no emergency medication" p=0.04), "no significant nausea" (p=0.03), mean and maximum number of vomiting per day (p=0.003, p=0.001), mean/maximum nausea values (p's<0.001).
* No difference for complete response and "no significant nausea" (p=0.12)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=high risk
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=Quality of life (nausea & vomiting scales) at baseline, day -1, end of treatment
|Type of measurement=AQoL-8D (Assessment of Quality of Life), FLIE (Functional Living Index for Emesis)
|Results during intervention=FLIE:
* significant advantage for intervention arm for nausea scale (mean difference: 20.9 on 100-point scale, p < 0.001) and vomiting scale (mean difference: 11.9, p < 0.001)

AQOL-8D:
* significant advantage for intervention arm in use-related QoL (mean difference: 0.04, 95% CI 0.01,0.07; p=0.019)
* physical health (mean difference: 0.06, 95% CI 0.03-0.09, p < 0.001)
* mental health (mean difference: 0.04, 95% CI 0.01, 0.06, p=0.004)
* pain (mean difference: 0.08, 95% CI 0.03, 0.13, p=0.003)
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=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 topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Self-developed measurement instrument: structured checklist of cannabinoid-specific adverse events
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events), Self-developed measurement instrument
|Results during intervention=Moderate or severe cannabinoid-related side effects in intervention arm (31%) and placebo arm (7%) (p=0.002):
* Significant differences for sedation (19% vs. 4%, p=0.002), dizziness (10% vs. 1%, p=0.03)
* No differences for disorientation (3% vs. 0%, p=0.5), anxiety (1% vs. 1%, p=1.00)
* No cannabinoid-related serious adverse events were reported.

83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001).
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=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 topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This work was supported by the Department of Health, NSW Government, Australia. Tilray supplied and covered the cost of study treatments and were given the opportunity to review the study protocol and manuscript, but had no role in data analysis.
|Conflicts of Interest=Conflict of interest can be seen in the article, many contacts to pharmaceutical industries.
}}
=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=Knowledge of assignment and believe in positive influence in outcomes assessed with self-report-questionnaires
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=Yes
|Measurement of compliance=Yes
|Consistent reporting in numbers=No
|Comprehensive and coherent reporting=No
|Cross-over=Yes
|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=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=No
|Check whether blinding was successful=No
|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
* Power analysis
* Daily contact with staff on days of administration
* Structured assessment of side effects using a checklist
* Adherence monitored through diary entries and capsule counts
* McNemar’s test used to control for within-patient correlation
* Control for order effects (p=0.29)
* Comparability at baseline ensured by study design

CONTRA:
* Correction for multiple testing only for primary endpoints
* 90% confidence interval (CI) (p=0.1) used for primary endpoints and 95% CI for secondary endpoints due to pilot study design (primary endpoint was also significant at 95%)
* No differentiation of primary endpoint into acute or delayed responses, despite being listed in the methodology
* Unclear presentation of when and how each endpoint is measured
* Numerous interactions with pharmaceutical companies
* Capsule dosing individualized, with no subgroup analyses for high vs. low doses
}}

Côté et al. (2016): Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial

2024-11-22T13:49:21Z

JDoerfler:

{{Reference
|Reference=Publication: Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial
}}

=Brief summary=
In the study, 56 patients with head and neck tumors were randomly divided into two arms, one received nabilone (synthetic THC) every day and the other a placebo. All patients received radiotherapy or a combination of radiotherapy and chemotherapy for seven weeks. At the end of the study, the authors found no differences between the arms for quality of life in general, as well as the symptoms of pain, weight fluctuations, appetite, nausea, mood and sleep. The study sample was small and 24 patients dropped out over the course of the study. The presentation of the results is superficial and inadequate. Without statistical values (mean values), the analysis is not transparent. Further methodological deficiencies in the analysis do not allow any conclusions to be drawn about the results.

In der Studie wurden 56 Patienten mit Kopf-Hals Tumoren zufällig in zwei Gruppen eingeteilt, wovon eine Gruppe jeden Tag Nabilon (synthetisches THC) bekam und die andere ein Placebo. Alle Patienten bekamen für sieben Wochen Radiotherapie oder eine Kombination aus Radio- und Chemotherapie. Am Ende der Studie fanden die Autoren keine Unterschiede zwischen den Gruppen für Lebensqualität allgemein, als auch für die Symptome Schmerz, Gewichtsschwankungen, Appetit, Übelkeit, Stimmung und Schlaf. Die Stichprobe der Studie war klein und es sind über den Verlauf der Studie noch 24 Patienten ausgestiegen. Die Darstellung der Ergebnisse ist oberflächlich und unzureichend. Ohne Angabe von statistischen Werten (Mittelwerte) ist eine Transparenz der Analyse nicht gegeben. Weitere methodische Mängel in der Analyse lassen keine Aussagen zu den Ergebnissen zu.

=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=Histological diagnosis of squamous cell carcinoma of the oral cavity, the oropharynx, the hypopharynx, and/or the larynx; treated by radiotherapy alone, postoperative radiotherapy, radiochemotherapy alone, or postoperative radiochemotherapy; aged 18 to 80 years; no other cancer diagnosis in the past 5 years, except for basal cell and squamous cell carcinoma of the skin
|Exclusion criteria=Metastatic disease; history of radiotherapy in the head and neck region; Karnofsky score <60; cognitive impairment; hepatic insufficiency; pregnant or breastfeeding woman; history of hypersensitivity or adverse reactions to marijuana or other cannabinoids; history of schizophrenia or any other form of psychosis
|N randomized=56
|Analysis=PP Analysis
|Specifications on analyses=Repeated measures analyses of variance (ANOVA), estimated with a linear mixed model, enable us to test the effect of time and treatment on continuous outcomes, while a generalized linear mixed model is used as a logistic regression for dichotomous outcomes. The P-values that are presented are for the interaction term of these models. All the analyses were also carried out while adjusting for site, treatment, and tumor size.
|Countries of data collection=Canada
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline before radiotherapy

T1: first week

T2: second week until

T3: 7th week

Follow-up: between 9th - 11th week
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Neo-adjuvant, Adjuvant
|Types of cancer=Head and Neck Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Radiotherapy only:

intervention arm = 13; placebo arm = 10

Radiotherapy postoperative:

intervention arm = 7; placebo arm = 2

Radiochemotherapy:

intervention arm = 7; placebo arm = 15

Radiochemotherapy postoperative:

intervention arm = 1, placebo arm = 1
|Previous cancer therapies=Surgery, No therapy
|Gender=Mixed
|Gender specifications=Female n = 10 (17.86%); male n = 46 (82.14%)
|Age groups=Adults (18+)
|Age groups specification=Mean age per arm:

intervention arm = 63.5 years

placebo arm = 63.8 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=28
|Drop-out=9
|Drop-out reasons=Not arm specified: severe nausea (n = 5); difficulty swallowing (n = 4); hospitalization (n = 4), pneumonia (n = 1); discontinued RT (n = 1); without reason (n = 9)
|Intervention=Nabilon

+ all patients: additional administration of antiemetics (metoclopramide) and painkillers (acetaminophen (paracetamol), codeine, hydromorphone or transdermal fentanyl) possible
|Dosage and regime=0.5 mg nabilone tablets (from Valeant Canada)

Once a day before radiotherapy in the first week, twice a day in the second week, third week until end of radiotherpy adjusted by radiation oncologist up to maximal 4 tablets
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=No differences for sleepiness (p=0.3166), anxiety (p=0.9163) and xerostomia (p=0.8341)
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=28
|Drop-out=15
|Drop-out reasons=Not arm specified: severe nausea (n = 5); difficulty swallowing (n = 4); hospitalization (n = 4), pneumonia (n = 1); discontinued RT (n = 1); without reason (n = 9)
|Intervention=Placebo

+ all patients: additional administration of antiemetics (metoclopramide) and painkillers (acetaminophen (paracetamol), codeine, hydromorphone or transdermal fentanyl) possible
|Dosage and regime=Once a day before radiotherapy in the first week, twice a day in the second week, third week until end of radiotherpy adjusted by radiation oncologist up to maximal 4 tablets
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=No differences for sleepiness (p=0.3166), anxiety (p=0.9163) and xerostomia (p=0.8341)
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Quality of life (target improvement of 15 points at week 7)
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=No difference between arms (p=0.4270), even after controlling for tumor site, treatment method and cancer stage at week 7 or the entire study period
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Pain with VAS + number of other analgesics used
|Type of measurement=VAS (Visual Analogue Scale), Observation
|Results during intervention=Over the course of the intervention and after: no differences for pain (p=0.6048), analgesic use (p=0.6671), no delay in time to 20% pain increase (p=0.4614) between arms
|Results after intervention=Over the course of the intervention and after: no differences for pain (p=0.6048), analgesic use (p=0.6671), no delay in time to 20% pain increase (p=0.4614) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Weight
|Outcome specification=Weight fluctuations, total days without feeding tube or gastrostomy
|Type of measurement=Scale
|Results during intervention=Over the course of the intervention and after: no difference for weight fluctuations (p=0.1454) or need for a feeding tube (no p-value) between arms.
|Results after intervention=Over the course of the intervention and after: no difference for weight fluctuations (p=0.1454) or need for a feeding tube (no p-value) between arms.
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Appetite
|Outcome specification=Appetite with questionnaire (no further information)
|Type of measurement=Unspecified questionnaire
|Results during intervention=Over the course of the intervention and after: no difference (p=0.3295) between arms
|Results after intervention=Over the course of the intervention and after: no difference (p=0.3295) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Nausea
|Outcome specification=Nausea with questionnaire (no further information) + number of antiemetic drugs used
|Type of measurement=Unspecified questionnaire
|Results during intervention=Over the course of the intervention and after: no difference for nausea (p=0.7105) or antiemetic consumption (p=0.6124) between arms
|Results after intervention=Over the course of the intervention and after: no difference for nausea (p=0.7105) or antiemetic consumption (p=0.6124) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Unspecified effects
|Outcome specification=Sleep quality and mood (no information on survey)
|Type of measurement=NI
|Results during intervention=Over the course of the intervention and after: no differences for mood (p=0.3214) and sleep quality (p=0.4438) between arms
|Results after intervention=Over the course of the intervention and after: no differences for mood (p=0.3214) and sleep quality (p=0.4438) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Toxicity of nabilone
|Type of measurement=NI
|Results during intervention=No differences for sleepiness (p=0.3166), anxiety (p=0.9163) and xerostomia (p=0.8341)
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=7
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=The authors received research grants from the Canadian Institutes of Health Research and the Fonds de recherche en santé du Québec. ICN Valeant Pharmaceuticals provided the nabilone and the placebo pills during the trial.
|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=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=No
|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=Yes
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=Yes
|Check whether blinding was successful=No
|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
* Power analysis
* Intent-to-treat analysis
* Baseline comparability
* Mention of drop-out comparison in the discussion, though no statistical values are provided

CONTRA:

* Lack of blinding control
* No correction for multiple testing
* Superficial and inadequate presentation of results: results are only shown graphically, with no mean/SD values available, lacking transparency
* Very high drop-out rate, with 12 out of 15 participants in placebo arm who dropped out receiving Radiochemotherapy
* Exact dosing from week 3 onward may vary for each participant
* Apart from the primary endpoint, no specific timing provided for final comparisons
}}

Lichtmann et al. (2018): Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain

2024-11-22T13:48:56Z

JDoerfler:

{{Reference
|Reference=Publication: Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain
}}

=Brief summary=
The study included 397 patients with various types of advanced cancer. Randomly divided into two arms, one arm received nabiximol (THC and CBD) and one arm a placebo for five weeks. The daily dose varied from person to person, depending on their needs. All patients also received opioids for pain management. Improvement in pain perception was measured, as well as mean pain scores over the study, extent of sleep disturbance and amount of opioids required. When all patients (including those who dropped out during the study) were included, no benefit was found in the improvement in pain perception. In the analysis with the people, who completed the intervention according to the protocol, there was an advantage for the nabiximol arm. However, the analysis with all patients is more meaningful as it is less susceptible to bias. As no effects were found in the main symptom, the further analyses were only carried out roughly. There was only an advantage for insomnia in the nabiximol arm, but this result should only be taken as information. Furthermore, no difference was found for opioid quantities taken. The study is characterized by a large sample size and a well-designed statistical analysis.

In der Studie wurden 397 mit verschiedenen fortgeschrittenen Krebsarten eingeschlossen. Zufällig in zwei Gruppen eingeteilt, bekam eine Gruppe Nabiximol (THC und CBD) und eine Gruppe ein Placebo für fünf Wochen. Die tägliche Dosis variierte von Person zu Person, je nach Bedürfnissen. Alle Patienten erhielten zusätzlich noch Opioide zur Schmerzbehandlung. Gemessen wurde die Verbesserung des Schmerzempfindens, sowie mittlere Schmerzwerte über die Studie, Ausmaß von Schlafstörung und Menge der benötigten Opioide. Wenn alle Patienten (also auch jene die während der Studie ausstiegen) eingeschlossen wurden, wurde kein Vorteil in der Verbesserung des Schmerzempfindens gefunden. Bei der Analyse mit den Personen, die die Intervention laut Protokoll abgeschlossen hatten, zeigte sich ein Vorteil für die Nabiximol Gruppe. Jedoch ist die Analyse mit allen Patienten aussagekräftiger, da sie weniger verzerrungsanfällig ist. Da im Hauptsymptom keine Effekte gefunden wurden, wurden die weiteren Analysen nur noch grob durchgeführt. Es zeigte sich nur ein Vorteil für Schlafstörungen in der Nabiximol Gruppe, jedoch sollte dieses Ergebnis nur als Information gewertet werden. Es konnte des Weiteren kein Unterschied für eingenommene Opioidmengen gefunden werden. Die Studie zeichnet sich durch eine große Stichprobe aus und durch eine durchdachte statistische Analyse.

=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=Advanced cancer; ≥18 years of age; clinical diagnosis of cancer-related pain that was unalleviated by an optimized maintenance dose of Step 3 opioid therapy (opioid therapy considered optimized if: 1) a dose increase was clinically inappropriate due to opioid-related side effects or 2) further efficacy benefit was not expected at higher doses (for the second definition, patients had to be receiving ≥90 mg morphine equivalents/day, inclusive of maintenance, and breakthrough opioids); each of three consecutive days during the screening period: ≥four opioid breakthrough analgesic episodes per day (averaged over the three days); a stable maintenance opioid therapy dose; average pain ≥four and ≤eight on a 0-10 Numerical Rating Scale (NRS); average pain scores on the NRS that did not change by more than two points (i.e., no more than a two-point difference between the highest and lowest scores, with all scores remaining between four and eight)
|Exclusion criteria=Baseline use of morphine at >500 mg morphine equivalents/day (inclusive of maintenance and breakthrough opioids); current use of more than one type of breakthrough opioid analgesic; planned clinical interventions that would affect pain; any history of schizophrenia or substance abuse
|N randomized=397
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Number of participants evaluated in PP n=291

For the primary efficacy endpoint, that is, percent improvement in average pain NRS score from baseline to end of treatment, the comparison was analyzed using the Wilcoxon rank-sum test. Estimates of the median difference between nabiximols and placebo, together with approximate 95% CI, were calculated using the Hodges-Lehmann approach, and P-values were used for the hierarchical gate-keeping procedure. Other sensitivity analyses for the primary efficacy endpoint included the Wilcoxon rank-sum test based on the PP analysis set, Van der Waerden test, and analysis of covariance with the corresponding baseline value as a covariate and treatment group as a factor, based on the ITT analysis set. Mixed-effect model repeat measurement was also applied with baseline NRS average pain score as a covariate, treatment group as a fixed factor, and the interaction terms for treatment-by-time and baseline-by-time included.

For the key secondary efficacy endpoints (average pain score, worst pain score, and sleep disruption score), analysis of covariance was applied, similar to the primary efficacy endpoint analysis. P-values from these analyses were used for the hierarchical gate-keeping procedure. The time course of the treatment effect on the key secondary endpoints was also evaluated in a similar fashion to the primary efficacy endpoint using model repeat measurement on the ITT analysis set. Analysis of variance was applied on the other secondary endpoints, including PGIC, SGIC, or PSQ, daily total/maintenance/breakthrough opioid dose, except NRS constipation score with ordinal logistic regression.

Subgroup analyses for region (U.S. and rest of the world (ROW)) were performed for the primary and key secondary efficacy endpoints using the ITT set at the 0.05 level, without formal adjustment for multiplicity.
|Countries of data collection=Belgium, Bulgaria, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Romania, United Kingdom, United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: after 3 weeks (21 days)

T2: after 5 weeks (35 days)

T3: after 7 weeks follow-up (up to day 43)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative, NI
|Types of cancer=Bone and Soft Tissue Cancers, Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Esophageal Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Gastrointestinal Cancers - Liver Cancer, Genitourinary Cancers, Genitourinary Cancers - Bladder Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Uterine Cancer, Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Thyroid Cancer, Hematologic Cancers, Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid), Lung Cancer, Prostate Cancer, Skin Cancer, Stomach Cancer, Other Cancers, Gastrointestinal Cancers - Gallbladder Cancer, Eye Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8); mostly mixed pain
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Intervention arm: female n = 95 (48%)

Placebo arm: female n = 88 (44.2%)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age per arm:

Intervention arm = 59.2 (12) years

Placebo arm = 60.7 (11.1) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=199
|Drop-out=85
|Drop-out reasons=Side effects (n=40); consent withdrawn (n=18); death (n=27)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, 27 mg/ml THC and 25mg/ml CBD)

Week 1: dose finding; week 2-5: stable dose, maximum 10 sprays

Mean number of spray bursts in the 1st week: 3.7 and then stabilized: 6.4
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Most frequently nausea (n=17) and dizziness (n=15); 1 case of disorientation and 1 case of visual hallucinations
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=198
|Drop-out=75
|Drop-out reasons=Side effects (n=35); consent withdrawn (n = 13); death (n=27)
|Intervention=Placebo
|Dosage and regime=Oral spray (self-applied by patient)

Week 1: dose finding; week 2-5: stable dose, maximum 10 sprays

Mean number of spray bursts in the 1st week: 3.8 and then stabilized: 7.3
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Most frequently nausea (n=10) and dizziness (n=5); 1 case of vomiting
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Median improvement in pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significant difference in median improvement for ITT after 5 weeks:

* Intervention 10.7% vs. placebo 4.5%; treatment difference = 3.41%, 95% CI: 0.00% - 8.16%; p=0.0854;

Significant difference for per protocol analysis after 5 weeks:

* Intervention 15.5% vs. placebo 6.3%; treatment difference = 5.49%, 95% CI: 0.00% - 11.11%; p=0.0378
|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=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for mean pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significance calculated as primary endpoint showed no effects (to control for alpha error).
|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=some concerns
|Overall RoB judgment=high risk
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for the worst pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significance calculated as primary endpoint showed no effects (to control for alpha error).
|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=some concerns
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Sleep
|Outcome specification=Extent of sleep disturbance
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significance calculated as primary endpoint showed no effects (to control for alpha error).

Only unadjusted values: advantage for intervention arm over placebo arm for sleep disturbance
|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=some concerns
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=General intake, intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Results during intervention=No significant differences between arms after 3 weeks and 5 weeks (p=0.6410; p=0.4217).
|Results after intervention=No significant arm differences after 7 weeks (p=0.9328).
|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=some concerns
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Unspecified effects
|Outcome specification=Specification NRS: Constipation NRS
|Type of measurement=NRS (Numeric Rating Scale), SGIC (Subject Global Impression of Change), PSQ (Patient Satisfaction Questionnaire), PGIC (Physician Global Impression of Change)
|Results during intervention=Higher improvement in intervention arm compared to placebo arm after 3 weeks for SGIC, PSQ and after 5 weeks for SGIC, PGIC, PSQ.
|Results after intervention=At week 7 no significant difference for SGIC, PGIC and PSQ.
|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=some concerns
|Overall RoB judgment=high risk
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This work was supported by Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA. The efforts of A.H. Lichtman were supported by the Virginia Commonwealth University School of Pharmacy start-up 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=NI
|Samples sufficiently large=Yes
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=Unclear if centres were comparable and what "optimized opioid therapy" looked like in every country
|Possibility of placebo effects=NA
|Other reasons=Unclear if centres were comparable and what "optimized opioid therapy" looked like in every country
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=Yes
|Measurement of compliance=NI
|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=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=NI
|Check whether blinding was successful=No
|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
* Intent-to-treat analysis (primary endpoint)
* Multiple testing controlled for endpoints pain and sleep disturbance
* Arms comparable at baseline

CONTRA:
* No information on whether centers were comparable in patient treatment; particularly as “optimal” opioid treatment may vary by country.
* No power analysis
* No details provided on how randomization was conducted or how blinding was ensured
* Correction for multiple testing only for primary endpoint
}}

Lichtmann et al. (2018): Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain

2024-11-22T13:48:49Z

JDoerfler:

{{Reference
|Reference=Publication: Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain
}}
{{Study Note}}
=Brief summary=
The study included 397 patients with various types of advanced cancer. Randomly divided into two arms, one arm received nabiximol (THC and CBD) and one arm a placebo for five weeks. The daily dose varied from person to person, depending on their needs. All patients also received opioids for pain management. Improvement in pain perception was measured, as well as mean pain scores over the study, extent of sleep disturbance and amount of opioids required. When all patients (including those who dropped out during the study) were included, no benefit was found in the improvement in pain perception. In the analysis with the people, who completed the intervention according to the protocol, there was an advantage for the nabiximol arm. However, the analysis with all patients is more meaningful as it is less susceptible to bias. As no effects were found in the main symptom, the further analyses were only carried out roughly. There was only an advantage for insomnia in the nabiximol arm, but this result should only be taken as information. Furthermore, no difference was found for opioid quantities taken. The study is characterized by a large sample size and a well-designed statistical analysis.

In der Studie wurden 397 mit verschiedenen fortgeschrittenen Krebsarten eingeschlossen. Zufällig in zwei Gruppen eingeteilt, bekam eine Gruppe Nabiximol (THC und CBD) und eine Gruppe ein Placebo für fünf Wochen. Die tägliche Dosis variierte von Person zu Person, je nach Bedürfnissen. Alle Patienten erhielten zusätzlich noch Opioide zur Schmerzbehandlung. Gemessen wurde die Verbesserung des Schmerzempfindens, sowie mittlere Schmerzwerte über die Studie, Ausmaß von Schlafstörung und Menge der benötigten Opioide. Wenn alle Patienten (also auch jene die während der Studie ausstiegen) eingeschlossen wurden, wurde kein Vorteil in der Verbesserung des Schmerzempfindens gefunden. Bei der Analyse mit den Personen, die die Intervention laut Protokoll abgeschlossen hatten, zeigte sich ein Vorteil für die Nabiximol Gruppe. Jedoch ist die Analyse mit allen Patienten aussagekräftiger, da sie weniger verzerrungsanfällig ist. Da im Hauptsymptom keine Effekte gefunden wurden, wurden die weiteren Analysen nur noch grob durchgeführt. Es zeigte sich nur ein Vorteil für Schlafstörungen in der Nabiximol Gruppe, jedoch sollte dieses Ergebnis nur als Information gewertet werden. Es konnte des Weiteren kein Unterschied für eingenommene Opioidmengen gefunden werden. Die Studie zeichnet sich durch eine große Stichprobe aus und durch eine durchdachte statistische Analyse.

=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=Advanced cancer; ≥18 years of age; clinical diagnosis of cancer-related pain that was unalleviated by an optimized maintenance dose of Step 3 opioid therapy (opioid therapy considered optimized if: 1) a dose increase was clinically inappropriate due to opioid-related side effects or 2) further efficacy benefit was not expected at higher doses (for the second definition, patients had to be receiving ≥90 mg morphine equivalents/day, inclusive of maintenance, and breakthrough opioids); each of three consecutive days during the screening period: ≥four opioid breakthrough analgesic episodes per day (averaged over the three days); a stable maintenance opioid therapy dose; average pain ≥four and ≤eight on a 0-10 Numerical Rating Scale (NRS); average pain scores on the NRS that did not change by more than two points (i.e., no more than a two-point difference between the highest and lowest scores, with all scores remaining between four and eight)
|Exclusion criteria=Baseline use of morphine at >500 mg morphine equivalents/day (inclusive of maintenance and breakthrough opioids); current use of more than one type of breakthrough opioid analgesic; planned clinical interventions that would affect pain; any history of schizophrenia or substance abuse
|N randomized=397
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Number of participants evaluated in PP n=291

For the primary efficacy endpoint, that is, percent improvement in average pain NRS score from baseline to end of treatment, the comparison was analyzed using the Wilcoxon rank-sum test. Estimates of the median difference between nabiximols and placebo, together with approximate 95% CI, were calculated using the Hodges-Lehmann approach, and P-values were used for the hierarchical gate-keeping procedure. Other sensitivity analyses for the primary efficacy endpoint included the Wilcoxon rank-sum test based on the PP analysis set, Van der Waerden test, and analysis of covariance with the corresponding baseline value as a covariate and treatment group as a factor, based on the ITT analysis set. Mixed-effect model repeat measurement was also applied with baseline NRS average pain score as a covariate, treatment group as a fixed factor, and the interaction terms for treatment-by-time and baseline-by-time included.

For the key secondary efficacy endpoints (average pain score, worst pain score, and sleep disruption score), analysis of covariance was applied, similar to the primary efficacy endpoint analysis. P-values from these analyses were used for the hierarchical gate-keeping procedure. The time course of the treatment effect on the key secondary endpoints was also evaluated in a similar fashion to the primary efficacy endpoint using model repeat measurement on the ITT analysis set. Analysis of variance was applied on the other secondary endpoints, including PGIC, SGIC, or PSQ, daily total/maintenance/breakthrough opioid dose, except NRS constipation score with ordinal logistic regression.

Subgroup analyses for region (U.S. and rest of the world (ROW)) were performed for the primary and key secondary efficacy endpoints using the ITT set at the 0.05 level, without formal adjustment for multiplicity.
|Countries of data collection=Belgium, Bulgaria, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Romania, United Kingdom, United States
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: after 3 weeks (21 days)

T2: after 5 weeks (35 days)

T3: after 7 weeks follow-up (up to day 43)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative, NI
|Types of cancer=Bone and Soft Tissue Cancers, Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Esophageal Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Gastrointestinal Cancers - Liver Cancer, Genitourinary Cancers, Genitourinary Cancers - Bladder Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Uterine Cancer, Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Thyroid Cancer, Hematologic Cancers, Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid), Lung Cancer, Prostate Cancer, Skin Cancer, Stomach Cancer, Other Cancers, Gastrointestinal Cancers - Gallbladder Cancer, Eye Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8); mostly mixed pain
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Intervention arm: female n = 95 (48%)

Placebo arm: female n = 88 (44.2%)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age per arm:

Intervention arm = 59.2 (12) years

Placebo arm = 60.7 (11.1) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=199
|Drop-out=85
|Drop-out reasons=Side effects (n=40); consent withdrawn (n=18); death (n=27)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, 27 mg/ml THC and 25mg/ml CBD)

Week 1: dose finding; week 2-5: stable dose, maximum 10 sprays

Mean number of spray bursts in the 1st week: 3.7 and then stabilized: 6.4
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Most frequently nausea (n=17) and dizziness (n=15); 1 case of disorientation and 1 case of visual hallucinations
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=198
|Drop-out=75
|Drop-out reasons=Side effects (n=35); consent withdrawn (n = 13); death (n=27)
|Intervention=Placebo
|Dosage and regime=Oral spray (self-applied by patient)

Week 1: dose finding; week 2-5: stable dose, maximum 10 sprays

Mean number of spray bursts in the 1st week: 3.8 and then stabilized: 7.3
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Most frequently nausea (n=10) and dizziness (n=5); 1 case of vomiting
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Median improvement in pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significant difference in median improvement for ITT after 5 weeks:

* Intervention 10.7% vs. placebo 4.5%; treatment difference = 3.41%, 95% CI: 0.00% - 8.16%; p=0.0854;

Significant difference for per protocol analysis after 5 weeks:

* Intervention 15.5% vs. placebo 6.3%; treatment difference = 5.49%, 95% CI: 0.00% - 11.11%; p=0.0378
|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=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for mean pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significance calculated as primary endpoint showed no effects (to control for alpha error).
|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=some concerns
|Overall RoB judgment=high risk
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for the worst pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significance calculated as primary endpoint showed no effects (to control for alpha error).
|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=some concerns
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Sleep
|Outcome specification=Extent of sleep disturbance
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significance calculated as primary endpoint showed no effects (to control for alpha error).

Only unadjusted values: advantage for intervention arm over placebo arm for sleep disturbance
|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=some concerns
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=General intake, intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Results during intervention=No significant differences between arms after 3 weeks and 5 weeks (p=0.6410; p=0.4217).
|Results after intervention=No significant arm differences after 7 weeks (p=0.9328).
|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=some concerns
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Unspecified effects
|Outcome specification=Specification NRS: Constipation NRS
|Type of measurement=NRS (Numeric Rating Scale), SGIC (Subject Global Impression of Change), PSQ (Patient Satisfaction Questionnaire), PGIC (Physician Global Impression of Change)
|Results during intervention=Higher improvement in intervention arm compared to placebo arm after 3 weeks for SGIC, PSQ and after 5 weeks for SGIC, PGIC, PSQ.
|Results after intervention=At week 7 no significant difference for SGIC, PGIC and PSQ.
|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=some concerns
|Overall RoB judgment=high risk
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This work was supported by Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA. The efforts of A.H. Lichtman were supported by the Virginia Commonwealth University School of Pharmacy start-up 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=NI
|Samples sufficiently large=Yes
|Ethnicity mentioned=Yes
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=Unclear if centres were comparable and what "optimized opioid therapy" looked like in every country
|Possibility of placebo effects=NA
|Other reasons=Unclear if centres were comparable and what "optimized opioid therapy" looked like in every country
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=Yes
|Measurement of compliance=NI
|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=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=NI
|Check whether blinding was successful=No
|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
* Intent-to-treat analysis (primary endpoint)
* Multiple testing controlled for endpoints pain and sleep disturbance
* Arms comparable at baseline

CONTRA:
* No information on whether centers were comparable in patient treatment; particularly as “optimal” opioid treatment may vary by country.
* No power analysis
* No details provided on how randomization was conducted or how blinding was ensured
* Correction for multiple testing only for primary endpoint
}}

Portenoy et al. (2012): Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial

2024-11-22T13:48:06Z

JDoerfler:

{{Reference
|Reference=Publication: Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial
}}

=Brief summary=
In this study, the effect of nabiximol, a cannabis-containing oral spray, on the personal perception of pain in patients with various advanced cancers and moderate to severe tumor pain was investigated as a function of dose. The study compared four different arms, namely three different nabiximols arms (low dose, medium dose, high dose) and a placebo arm. With regard to the primary endpoint, namely the number of patients in whom treatment with nabiximols led to a significant improvement in pain perception (≥30%), there were no significant differences between the arms. However, it was found that patients with the low dose in particular, but in some cases also with the medium dose, responded better overall to the treatment compared to the placebo arm and reported a significantly greater improvement in pain and sleep disturbances on average over the course of the study. In addition, patients with the low dose of nabiximols required less opioids depending on the pain compared to the placebo arm.The large international sample was a positive aspect of this study, but there are also some points of criticism. In particular, the differences in treatment adherence between the arms, the lack of clarity as to whether the arms were comparable at the start of the study and the high drop-out rate during the course of the study should be mentioned. For this reason, the results of this study can only be interpreted with caution.

In dieser Studie wurde in Abhängigkeit der Dosis die Wirkung von Nabiximol, einem cannabishaltigen Mundspray, hinsichtlich der persönlichen Wahrnehmung von Schmerzen bei Patienten mit verschiedenen, vorangeschrittenen Krebserkrankungen und mittleren bis schweren Tumorschmerzen untersucht. In der Studie wurden vier verschiedene Gruppen verglichen, nämlich drei verschiedene Nabiximol-Arme (niedrige Dosis, mittlere Dosis, hohe Dosis) und eine Placebogruppe. Hinsichtlich des primären Endpunkts, nämlich der Anzahl an Patienten, bei denen die Behandlung mit Nabiximol zu einer deutlichen Verbesserung der Schmerzwahrnehmung (≥30%) geführt hat, zeigten sich keine bedeutsamen Unterschiede zwischen den Gruppen. Es wurde jedoch gefunden, dass vor allem Patienten mit der niedrigen Dosis, teilweise aber auch mit der mittleren Dosis im Vergleich zur Placebogruppe insgesamt besser auf die Behandlung ansprachen und im Mittel eine bedeutsam stärkere Verbesserung der Schmerzen und der Schlafstörungen im Verlauf der Studie berichteten. Zudem benötigen Patienten mit der niedrigen Nabiximoldosis weniger Opiode in Abhängigkeit der Schmerzen im Vergleich zur Placebogruppe. Positiv an dieser Studie war die große internationale Stichprobe, es lassen sich jedoch auch einige Kritikpunkte nennen. Dabei sind vor allem die Unterschiede in der Therapietreue zwischen den Armen, die Unklarkeit, ob die Gruppen zum Beginn der Studie vergleichbar waren zu nennen und die hohe Ausfallrate im Verlauf der Studie zu nennen. Deswegen lassen sich die Ergebnisse dieser Studie nur mit Vorsicht interpretieren.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=4
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Adult patients with active cancer and chronic pain (moderate or severe despite a stable opioid regimen that could not be made more effective by further opioid dose titration); stable, average pain: NRS: ≥4≤ 8 (no change in 3 days > 2 points)
|Exclusion criteria=Patients receiving long-term methadone therapy for pain; major psychiatric or cardiovascular disorder; epilepsy; significant renal or hepatic impairment; pregnant, lactating or not using adequate contraception; patients, who had received or who were due to receive therapies expected to change the pain (such as radiotherapy, or chemotherapy or hormonal therapy); marijuana use, cannabinoid-based medications or rimonabant within 30 days of study entry, and unwilling to abstain for the duration of the study
|N randomized=360
|Analysis=ITT Analysis
|Specifications on analyses=Missing data for the efficacy endpoints were imputed using the last observation carry forward (LOCF) method.

The proportions of responders were compared between the treatments using logistic regression, with region (North America/Rest of the World) and treatment used as factors.

The cumulative response to treatment was shown by plotting cumulative response rates against increasing thresholds for response, ie, percentage changes from baseline in the mean 11-point NRS pain score that defined a response. The cumulative response curves for each of the active treatment groups were compared with placebo using pairwise Wilcoxon rank-sum tests. The Hodges-Lehmann estimates and 95% CI for the median also were performed.

The analysis of all the secondary efficacy assessments was considered supportive and no formal adjustments for multiple comparisons were made. The change in mean pain NRS scores, BPI-SF, sleep disruption NRS, PAC-QoL questionnaire, and MADRS were all analyzed using analysis of covariance (ANCOVA), with the baseline value as a covariate and region and treatment group as factors. An analysis also was performed on the mean pain NRS scores to assess the time course of the treatment effect using repeated measure analysis. Additionally, the difference in time required to establish baseline was investigated as a possible moderator of treatment effect by using the number of days until the patient became eligible for randomization and total number of days in the baseline period as covariates in the analysis of change in the mean daily NRS score for
average pain.
|Countries of data collection=Europe, South Africa, North America, Latin America
|LoE=Level 2 Oxford 2011
|Outcome timeline=T1: baseline (3 days)

T2: day 21

T3: day 35 (end of intervention)

T4: 14 days after treatment
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative, NI
|Types of cancer=Breast Cancer, Gastrointestinal Cancers, Lung Cancer, Prostate Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=Mean (SD) duration = 3.6 (4.8) years
|Comorbidity=Chronic, therapy-resistant tumor pain (treated with opioids)
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Female n (%): 174 (48.3)
Male n (%): 186 (51.7)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age = 58 (12.2) years

Range = 20-93 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=91
|Drop-out=20
|Drop-out reasons=Side effects (n=5); consent withdrawn (n=1); progression of the disease (n=7); other reasons (n=3)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: 1-4 (low dose)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis; weight loss
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=88
|Drop-out=21
|Drop-out reasons=Side effects (n=6); consent withdrawn (n=5); progression of the disease (n=7); other reasons (n=3)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: 6-10 (medium dose)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis; weight loss
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=90
|Drop-out=31
|Drop-out reasons=Side effects (n=20); consent withdrawn (n=4); progression of the disease (n=7)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: 11-16 (high dose)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis weight loss
|Order number=3
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=91
|Drop-out=25
|Drop-out reasons=Side effects (n=9); consent withdrawn (n=6); progression of the disease (n=7): no effect (n=1); other reasons (n=1); no follow-up (n=1)
|Intervention=Placebo
|Dosage and regime=Placebo via oral spray (self-applied by patient)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: variable (1-4, 6-10, 11-16)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=NI
|Order number=4
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Number of responders (≥ 30% pain reduction Numeric Rating Scale for average pain during the last 3 days of week 5 compared with the mean during the 3-day baseline period)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Baseline to 5 weeks: no group differences; OR in each case

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.59

* Nabiximol (1-4 sprays) vs. placebo: 1.37; p=0.33

* Nabiximol (6-10 sprays) vs. placebo: 1.19, p=0.61

* Nabiximol (11-16 sprays) vs. placebo: 0.9, p=0.76
|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=NA
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Number per improvement level (10%, 20% etc.-100%)
|Type of measurement=Observation
|Results during intervention=Over the course of the sudy significant difference between intervention combined arms and placebo: full spectrum 0-100% responders (OR in each case):

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.035

* Nabiximol (1-4 sprays) vs. placebo: p=0.008

* Nabiximol (6-10 sprays) vs. placebo: p=0.038

* Nabiximol (11-16 sprays) vs. placebo: p=0.68
|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=NA
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for moderate pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Baseline to 5 weeks:

No significant group differences between intervention groups combined and placebo:

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.072

Mean:

* Nabiximol (1-4 sprays): baseline = 5.8, day 35 = 4.3

* Nabiximol (6-10 sprays): baseline = 5.8, day 35 = 4.7

* Nabiximol (11-16 sprays): NI

* Placebo: baseline = 5.7, day 35 = 4.9

Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI)

* Nabiximol (1-4 sprays) vs. placebo = -0.75 (-1.28, 0.22), p=0.006

Otherwise no differences:

* Nabiximol (6-10 sprays) vs. placebo = -0.36 (-0.89, 0.18), p=0.19

* Nabiximol (11-16 sprays) vs. placebo = -0.09 (-0.62, 0.44), p=0.75
|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=NA
|Overall RoB judgment=some concerns
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for the worst pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Baseline to 5 weeks:

Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI)

* Nabiximol (1-4 sprays) vs. placebo =- 0.73 (-1.30, -0.17), p=0.011

Otherwise no significant differences:

* Nabiximol (6-10 sprays) vs. placebo = -0.24 (-0.8, 0.3), p=0.4

* Nabiximol (11-16 sprays) vs. placebo = -0.6 (-0.6, 0.5), p=0.83
|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=NA
|Overall RoB judgment=some concerns
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Sleep
|Outcome specification=Extent of sleep disturbance
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI)

* Nabiximol (1-4 sprays) vs. placebo = -0.88 (-1.45, -0.31), p = 0.003

Otherwise no differences:

* Nabiximol (6-10 sprays)/nabiximol (11-16 sprays) alone vs. placebo: not significant

Combining low and high dose group:

* Significant difference vs. placebo in favor of nabiximols (p = .016)
|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=NA
|Overall RoB judgment=some concerns
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=NI
|Outcome name=Pain
|Outcome specification=Opiod consumption: score from change in self-assessed pain in relation to opiod consumption in morphine-equivalent milligrams)
|Type of measurement=Observation
|Results during intervention=No significant group differences between intervention groups combined and placebo: OR (95% CI)

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo =1.54 (0.95, 2.50), p = 0.077

* Significant difference for nabiximol (1-4 sprays) vs. placebo = 1.87, p=0.038

Otherwise no differences:

* Nabiximol (6-10 sprays)/nabiximol (11-16 sprays) vs. placebo: not significant
|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=NA
|Overall RoB judgment=some concerns
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Pain
|Outcome specification=NA
|Type of measurement=BPI-SF (Brief Pain Inventory - Short Form)
|Results during intervention=After 5 weeks: 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)=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=NA
|Overall RoB judgment=some concerns
|Order number=7
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|Outcome specification=NA
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire), MADRS (Montgomery-Asberg Depression Rating Scale), PAC-QoL (Patient Assessment of Constipation - Quality of Life)
|Results during intervention=After 5 weeks: Small effect of nabiximol on EORTC-QCQ-C30 (no values given), otherwise no significant differences for questionnaires.
|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=high risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=8
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported in part by the Huntsman Cancer Foundation (S.W.). GW Pharmaceuticals produces nabiximols, which is licensed in Canada as an adjunctive analgesic treatment in adult patients with advanced cancer.

This study was funded by GW Pharmaceuticals and Otsuka.
|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=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=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=Compliance different in arms 94.5%, 85.1%, 62.2%, placebo NI

Post-hoc analyses show confounding variables that lead to increased deaths in intervention arms: High level of white blood cells, low level of calcium, hemoglobin and lymphocytes --> doubts about comparability of the arms

In the analyses of subjective perception of pain, no control of changes in opiod consumption
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=Yes
|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=NI
|Ethics / CoI / Funding=Yes
|Blinding reliable=No
|Check whether blinding was successful=NI
|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
* Intent-to-treat analysis
* Power analysis

CONTRA:
* Differences in treatment adherence
* Some descriptive differences at baseline without p-values provided (e.g., pain duration)
* Post-hoc analyses reveal confounding variables associated with higher mortality rates in intervention arms: high white blood cell count, low calcium, hemoglobin, and lymphocyte levels, raising doubts about group comparability.
* In analyses of subjective pain perception, changes in opioid consumption were not controlled for.
* Mostly one-dimensional pain parameters were considered.
* Results in the text are reported unclearly, with some values missing or not precisely specified.
* No information on cancer stage.
* Poor reporting quality.
* Correction for multiple comparison only for primary endpoints
}}

Portenoy et al. (2012): Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial

2024-11-22T13:47:59Z

JDoerfler:

{{Reference
|Reference=Publication: Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial
}}
{{Study Note}}
=Brief summary=
In this study, the effect of nabiximol, a cannabis-containing oral spray, on the personal perception of pain in patients with various advanced cancers and moderate to severe tumor pain was investigated as a function of dose. The study compared four different arms, namely three different nabiximols arms (low dose, medium dose, high dose) and a placebo arm. With regard to the primary endpoint, namely the number of patients in whom treatment with nabiximols led to a significant improvement in pain perception (≥30%), there were no significant differences between the arms. However, it was found that patients with the low dose in particular, but in some cases also with the medium dose, responded better overall to the treatment compared to the placebo arm and reported a significantly greater improvement in pain and sleep disturbances on average over the course of the study. In addition, patients with the low dose of nabiximols required less opioids depending on the pain compared to the placebo arm.The large international sample was a positive aspect of this study, but there are also some points of criticism. In particular, the differences in treatment adherence between the arms, the lack of clarity as to whether the arms were comparable at the start of the study and the high drop-out rate during the course of the study should be mentioned. For this reason, the results of this study can only be interpreted with caution.

In dieser Studie wurde in Abhängigkeit der Dosis die Wirkung von Nabiximol, einem cannabishaltigen Mundspray, hinsichtlich der persönlichen Wahrnehmung von Schmerzen bei Patienten mit verschiedenen, vorangeschrittenen Krebserkrankungen und mittleren bis schweren Tumorschmerzen untersucht. In der Studie wurden vier verschiedene Gruppen verglichen, nämlich drei verschiedene Nabiximol-Arme (niedrige Dosis, mittlere Dosis, hohe Dosis) und eine Placebogruppe. Hinsichtlich des primären Endpunkts, nämlich der Anzahl an Patienten, bei denen die Behandlung mit Nabiximol zu einer deutlichen Verbesserung der Schmerzwahrnehmung (≥30%) geführt hat, zeigten sich keine bedeutsamen Unterschiede zwischen den Gruppen. Es wurde jedoch gefunden, dass vor allem Patienten mit der niedrigen Dosis, teilweise aber auch mit der mittleren Dosis im Vergleich zur Placebogruppe insgesamt besser auf die Behandlung ansprachen und im Mittel eine bedeutsam stärkere Verbesserung der Schmerzen und der Schlafstörungen im Verlauf der Studie berichteten. Zudem benötigen Patienten mit der niedrigen Nabiximoldosis weniger Opiode in Abhängigkeit der Schmerzen im Vergleich zur Placebogruppe. Positiv an dieser Studie war die große internationale Stichprobe, es lassen sich jedoch auch einige Kritikpunkte nennen. Dabei sind vor allem die Unterschiede in der Therapietreue zwischen den Armen, die Unklarkeit, ob die Gruppen zum Beginn der Studie vergleichbar waren zu nennen und die hohe Ausfallrate im Verlauf der Studie zu nennen. Deswegen lassen sich die Ergebnisse dieser Studie nur mit Vorsicht interpretieren.

=Study Design=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=4
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Adult patients with active cancer and chronic pain (moderate or severe despite a stable opioid regimen that could not be made more effective by further opioid dose titration); stable, average pain: NRS: ≥4≤ 8 (no change in 3 days > 2 points)
|Exclusion criteria=Patients receiving long-term methadone therapy for pain; major psychiatric or cardiovascular disorder; epilepsy; significant renal or hepatic impairment; pregnant, lactating or not using adequate contraception; patients, who had received or who were due to receive therapies expected to change the pain (such as radiotherapy, or chemotherapy or hormonal therapy); marijuana use, cannabinoid-based medications or rimonabant within 30 days of study entry, and unwilling to abstain for the duration of the study
|N randomized=360
|Analysis=ITT Analysis
|Specifications on analyses=Missing data for the efficacy endpoints were imputed using the last observation carry forward (LOCF) method.

The proportions of responders were compared between the treatments using logistic regression, with region (North America/Rest of the World) and treatment used as factors.

The cumulative response to treatment was shown by plotting cumulative response rates against increasing thresholds for response, ie, percentage changes from baseline in the mean 11-point NRS pain score that defined a response. The cumulative response curves for each of the active treatment groups were compared with placebo using pairwise Wilcoxon rank-sum tests. The Hodges-Lehmann estimates and 95% CI for the median also were performed.

The analysis of all the secondary efficacy assessments was considered supportive and no formal adjustments for multiple comparisons were made. The change in mean pain NRS scores, BPI-SF, sleep disruption NRS, PAC-QoL questionnaire, and MADRS were all analyzed using analysis of covariance (ANCOVA), with the baseline value as a covariate and region and treatment group as factors. An analysis also was performed on the mean pain NRS scores to assess the time course of the treatment effect using repeated measure analysis. Additionally, the difference in time required to establish baseline was investigated as a possible moderator of treatment effect by using the number of days until the patient became eligible for randomization and total number of days in the baseline period as covariates in the analysis of change in the mean daily NRS score for
average pain.
|Countries of data collection=Europe, South Africa, North America, Latin America
|LoE=Level 2 Oxford 2011
|Outcome timeline=T1: baseline (3 days)

T2: day 21

T3: day 35 (end of intervention)

T4: 14 days after treatment
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative, NI
|Types of cancer=Breast Cancer, Gastrointestinal Cancers, Lung Cancer, Prostate Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=Mean (SD) duration = 3.6 (4.8) years
|Comorbidity=Chronic, therapy-resistant tumor pain (treated with opioids)
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Female n (%): 174 (48.3)
Male n (%): 186 (51.7)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age = 58 (12.2) years

Range = 20-93 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=91
|Drop-out=20
|Drop-out reasons=Side effects (n=5); consent withdrawn (n=1); progression of the disease (n=7); other reasons (n=3)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: 1-4 (low dose)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis; weight loss
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=88
|Drop-out=21
|Drop-out reasons=Side effects (n=6); consent withdrawn (n=5); progression of the disease (n=7); other reasons (n=3)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: 6-10 (medium dose)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis; weight loss
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=90
|Drop-out=31
|Drop-out reasons=Side effects (n=20); consent withdrawn (n=4); progression of the disease (n=7)
|Intervention=Nabiximol
|Dosage and regime=Nabiximol via oral spray (self-applied by patient, one spray 2.7 mg THC and 2.5 mg CBD)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: 11-16 (high dose)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=Cognitive functions: negative effect of nabiximols (no values given); nausea and vomiting; dizziness; drowsiness; disorientation; anorexia, constipation; dry mouth; anemia; diarrhea; dysgeusia headache; asthenia hallucinations; reduced appetite; fatigue; pain; insomnia; stomatitis weight loss
|Order number=3
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=91
|Drop-out=25
|Drop-out reasons=Side effects (n=9); consent withdrawn (n=6); progression of the disease (n=7): no effect (n=1); other reasons (n=1); no follow-up (n=1)
|Intervention=Placebo
|Dosage and regime=Placebo via oral spray (self-applied by patient)

Week 1: dose finding; week 2-5: stable dose

Maximal number of sprays: variable (1-4, 6-10, 11-16)
|One-time application=No
|Duration in days=35
|Side Effects / Interactions=NI
|Order number=4
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Number of responders (≥ 30% pain reduction Numeric Rating Scale for average pain during the last 3 days of week 5 compared with the mean during the 3-day baseline period)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Baseline to 5 weeks: no group differences; OR in each case

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.59

* Nabiximol (1-4 sprays) vs. placebo: 1.37; p=0.33

* Nabiximol (6-10 sprays) vs. placebo: 1.19, p=0.61

* Nabiximol (11-16 sprays) vs. placebo: 0.9, p=0.76
|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=NA
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Number per improvement level (10%, 20% etc.-100%)
|Type of measurement=Observation
|Results during intervention=Over the course of the sudy significant difference between intervention combined arms and placebo: full spectrum 0-100% responders (OR in each case):

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.035

* Nabiximol (1-4 sprays) vs. placebo: p=0.008

* Nabiximol (6-10 sprays) vs. placebo: p=0.038

* Nabiximol (11-16 sprays) vs. placebo: p=0.68
|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=NA
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for moderate pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Baseline to 5 weeks:

No significant group differences between intervention groups combined and placebo:

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo: p=0.072

Mean:

* Nabiximol (1-4 sprays): baseline = 5.8, day 35 = 4.3

* Nabiximol (6-10 sprays): baseline = 5.8, day 35 = 4.7

* Nabiximol (11-16 sprays): NI

* Placebo: baseline = 5.7, day 35 = 4.9

Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI)

* Nabiximol (1-4 sprays) vs. placebo = -0.75 (-1.28, 0.22), p=0.006

Otherwise no differences:

* Nabiximol (6-10 sprays) vs. placebo = -0.36 (-0.89, 0.18), p=0.19

* Nabiximol (11-16 sprays) vs. placebo = -0.09 (-0.62, 0.44), p=0.75
|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=NA
|Overall RoB judgment=some concerns
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Change in NRS value for the worst pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Baseline to 5 weeks:

Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI)

* Nabiximol (1-4 sprays) vs. placebo =- 0.73 (-1.30, -0.17), p=0.011

Otherwise no significant differences:

* Nabiximol (6-10 sprays) vs. placebo = -0.24 (-0.8, 0.3), p=0.4

* Nabiximol (11-16 sprays) vs. placebo = -0.6 (-0.6, 0.5), p=0.83
|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=NA
|Overall RoB judgment=some concerns
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Sleep
|Outcome specification=Extent of sleep disturbance
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Significant difference between nabiximol (1-4 sprays) and placebo: mean difference (95% CI)

* Nabiximol (1-4 sprays) vs. placebo = -0.88 (-1.45, -0.31), p = 0.003

Otherwise no differences:

* Nabiximol (6-10 sprays)/nabiximol (11-16 sprays) alone vs. placebo: not significant

Combining low and high dose group:

* Significant difference vs. placebo in favor of nabiximols (p = .016)
|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=NA
|Overall RoB judgment=some concerns
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=NI
|Outcome name=Pain
|Outcome specification=Opiod consumption: score from change in self-assessed pain in relation to opiod consumption in morphine-equivalent milligrams)
|Type of measurement=Observation
|Results during intervention=No significant group differences between intervention groups combined and placebo: OR (95% CI)

* Nabiximol (1-4 sprays) + nabiximol (6-10 sprays) + nabiximol (11-16 sprays) vs. placebo =1.54 (0.95, 2.50), p = 0.077

* Significant difference for nabiximol (1-4 sprays) vs. placebo = 1.87, p=0.038

Otherwise no differences:

* Nabiximol (6-10 sprays)/nabiximol (11-16 sprays) vs. placebo: not significant
|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=NA
|Overall RoB judgment=some concerns
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Pain
|Outcome specification=NA
|Type of measurement=BPI-SF (Brief Pain Inventory - Short Form)
|Results during intervention=After 5 weeks: 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)=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=NA
|Overall RoB judgment=some concerns
|Order number=7
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|Outcome specification=NA
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire), MADRS (Montgomery-Asberg Depression Rating Scale), PAC-QoL (Patient Assessment of Constipation - Quality of Life)
|Results during intervention=After 5 weeks: Small effect of nabiximol on EORTC-QCQ-C30 (no values given), otherwise no significant differences for questionnaires.
|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=high risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=8
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Supported in part by the Huntsman Cancer Foundation (S.W.). GW Pharmaceuticals produces nabiximols, which is licensed in Canada as an adjunctive analgesic treatment in adult patients with advanced cancer.

This study was funded by GW Pharmaceuticals and Otsuka.
|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=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=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=Compliance different in arms 94.5%, 85.1%, 62.2%, placebo NI

Post-hoc analyses show confounding variables that lead to increased deaths in intervention arms: High level of white blood cells, low level of calcium, hemoglobin and lymphocytes --> doubts about comparability of the arms

In the analyses of subjective perception of pain, no control of changes in opiod consumption
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=Yes
|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=NI
|Ethics / CoI / Funding=Yes
|Blinding reliable=No
|Check whether blinding was successful=NI
|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
* Intent-to-treat analysis
* Power analysis

CONTRA:
* Differences in treatment adherence
* Some descriptive differences at baseline without p-values provided (e.g., pain duration)
* Post-hoc analyses reveal confounding variables associated with higher mortality rates in intervention arms: high white blood cell count, low calcium, hemoglobin, and lymphocyte levels, raising doubts about group comparability.
* In analyses of subjective pain perception, changes in opioid consumption were not controlled for.
* Mostly one-dimensional pain parameters were considered.
* Results in the text are reported unclearly, with some values missing or not precisely specified.
* No information on cancer stage.
* Poor reporting quality.
* Correction for multiple comparison only for primary endpoints
}}

Johnson et al. (2010): Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain

2024-11-22T13:46:36Z

JDoerfler:

{{Reference
|Reference=Publication: Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain
}}

=Brief summary=
In this study, 177 patients with advanced cancer were randomly divided into three arms. One arm received THC and CBD for two weeks, the other arm only THC and the third arm a placebo. The daily dose varied from person to person depending on their needs. All patients also received opioids for pain management. After two weeks, the THC plus CBD arm showed an advantage in general pain perception compared to the placebo arm. Measured with a different instrument, the THC arm showed an advantage over the placebo arm for pain in the last 24 hours. No differences were found between the THC arm and the placebo arm. There were no differences for number of days or dose of opioid use, as well as sleep quality or nausea. There was a deterioration in appetite, memory and concentration in the THC plus CBD and THC arms compared to the placebo arm. For the measurement of quality of life, there was also an advantage for the placebo arm over the other two arms in the categories "cognitive functions" and an advantage for the placebo arm over the THC plus CBD arm for "nausea and vomiting". A large number of symptoms were recorded in this study, but no correction was made in the analysis. This increases the risk of finding an effect even though it is not there. This alone means, that the results should be interpreted with caution. This is also supported by the fact, that the results for the same symptoms such as nausea and pain differ depending on the measurement instrument. In addition, little information is given about the patients.

In dieser Studie wurden 177 Patienten mit fortgeschrittenen Krebserkrankungen zufällig in drei Gruppen eingeteilt. Die eine Gruppe erhielt über zwei Wochen THC und CBD, die andere Gruppe nur THC und die dritte Gruppe ein Placebo. Die tägliche Dosis variierte von Person zu Person je nach Bedürfnissen. Alle Patienten erhielten zusätzlich noch Opioide zur Schmerzbehandlung. Nach zwei Wochen zeigte sich ein Vorteil für das allgemeine Schmerzempfinden für die THC plus CBD Gruppe im Vergleich zur Placebogruppe. Gemessen mit einem anderen Instrument zeigte sich ein Vorteil der THC Gruppe gegenüber der Placebogruppe für Schmerz in den letzten 24 Stunden. Keine Unterschiede wurden gefunden zwischen der THC Gruppe und der Placebogruppe. Es gab keine Unterschiede für Anzahl der Tage oder Dosis von Opioidnutzung, sowie Schlafqualität oder Übelkeit. Bezüglich Appetit, Gedächtnis und Konzentration zeigte sich eine Verschlechterung in der THC plus CBD Gruppe und THC Gruppe im Vergleich zur Placebogruppe. Für die Messung der Lebensqualität zeigte sich in den Kategorien „kognitive Funktionen“ ebenfalls ein Vorteil für die Placebogruppe gegenüber den anderen beiden Gruppen und für „Übelkeit und Erbrechen“ ein Vorteil für die Placebogruppe gegenüber der THC plus CBD Gruppe. In dieser Studie wurden sehr viele Symptome erhoben, jedoch keine Korrektur dessen in der Analyse vorgenommen. Dies erhöht die Gefahr, einen Effekt zu finden, obwohl dieser nicht da ist. Dies allein führt dazu, dass die Ergebnisse mit Vorsicht interpretiert werden sollten. Gestützt wird dieses auch dadurch, dass sich die Ergebnisse für gleiche Symptome wie Übelkeit und Schmerz je nach Messinstrument unterscheiden. Zudem werden wenig Informationen zu den Patienten gegeben.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Adult male or female patients, who had been using strong opioids for at least one week to relieve pain associated with incurable malignancy; pain severity score of 4 or above on a 0-10 Numerical Rating Scale (NRS) on both days of the two-day baseline period
|Exclusion criteria=Cancers affecting the oral cavity; radiotherapy to the floor of the mouth; major psychiatric or cardiovascular disorders; epilepsy; renal or hepatic impairment; pregnant, lactating, or not using adequate contraception; therapies expected to confound the study outcome (epidural analgesia within 48 hours of screening; palliative radio-, chemo-, or hormonal therapy within two weeks of screening; CBs within seven days of randomization); use of levodopa, sildenafil, or fentanyl; hypersensitivity to CBs
|N randomized=177
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=For the two coprimary efficacy variables (NRS pain score and use of break-through medication), the Hochberg method was used to test the global hypothesis for a treatment effect on pain.
The daily pain NRS score was the mean of the three daily assessments. The change in mean NRS pain score from baseline (all days in run-in period) to the end of treatment (last three days on treatment) was analyzed using analysis of covariance (ANCOVA), with baseline pain as a covariate and grouped study center and treatment as factors. The proportions of responders (patients with ≥30% improvement from baseline to end of study NRS pain score) were compared between treatments. Use of breakthrough medication (number of days of use during last three days on treatment) was analyzed using logistic regression with a cumulative logit model. In addition, the change from baseline in mean number of doses of escape medication was analyzed using ANCOVA.
|Countries of data collection=Europe
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline (2 days)

T1: after 7-10 days

T2: after 14-20 days
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=Breast Cancer, Lung Cancer, Prostate Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=Mean (SD) duration of cancer: 3.5 (4.4) years
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=No therapy in the last 2 weeks
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Female n (%): 82 (46)

Male n (%): 95 (54)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) Age: 60.2 (12.3) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=60
|Drop-out=12
|Drop-out reasons=Adverse event (n=10); consent withdrawal (n=1); other (n=1)
|Intervention=THC:CBD
|Dosage and regime=THC:CBD via oral spray (self-applied by patient, one dose 2.7mg THC and 2.5mg CBD)

Week 1: dose finding

Week 2: stable dose, maximum of 8 sprays every 3 hours and 48 sprays in 24 hours: dose was determined by patients themselves
|One-time application=No
|Duration in days=14
|Side Effects / Interactions=Intervention-associated events in n=106 (60%): drowsiness, dizziness, nausea, confusion, vomiting, hypotension, hypercalcemia, increased gamma GT

Most side effects were mild/moderate; no statistical comparisons given; one case of syncope probably related to THC; other events not associated with intervention
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=58
|Drop-out=13
|Drop-out reasons=Adverse event (n=7); consent withdrawal (n=2); sponsor decision (n=1); protocol violation (n=1); other (n=2)
|Intervention=THC
|Dosage and regime=THC extract via oral spray (2.7 mg), dosage variable;
Week 1: dose finding

Week 2: stable dose, maximum of 8 sprays every 3 hours and 48 sprays in 24 hours: dose was determined by patients themselves
|One-time application=No
|Duration in days=14
|Side Effects / Interactions=Intervention-associated events in n=106 (60%): drowsiness, dizziness, nausea, confusion, vomiting, hypotension, hypercalcemia, increased gamma GT;

Most side effects were mild/moderate; no statistical comparisons given; one case of syncope probably related to THC; other events not associated with intervention
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=59
|Drop-out=8
|Drop-out reasons=Adverse event (n=3); consent withdrawal (n=2); other (n=3)
|Intervention=Placebo
|Dosage and regime=NI
|One-time application=No
|Duration in days=14
|Side Effects / Interactions=NI
|Order number=3
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Number of responders (≥ 30% pain reduction NRS scale baseline vs. 14-20 days)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Significant advantage for THC:CBD arm compared to placebo arm after 14-20 days (mean improvement = -1.37 vs. -0.69; p=0.014), no significant difference between THC arm and placebo arm after 14-20 days (mean improvement = -1.01 vs. -0.69; p=0.245)

Same results for median differences (THC:CBD arm vs. placebo arm = 0.55, p=0.024; THC arm vs. placebo arm = 0.24, p=0.204)

Responders:

More patients in THC:CBD arm compared to placebo arm showed improvement of more than 30% from baseline to 14-20 days (n=23 (43%) vs. n=12 (21%); Odds Ratio = 2.81; 95% CI=1.22, 6.50; p=0.006).

No difference between THC arm and placebo arm (n=12 (23%) vs. n=12 (21%); Odds Ratio 1.10 (95% CI=0.44, 2.73; p=0.28).

No data for comparison between THC:CBD arm and THC arm.
|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=Cannabinoids
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Breakthrough pain and corresponding opioid intake and daily opioid use with diary Numeric Rating Scale (NRS) over the last 24h
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Background medication opioids baseline to 14-21 days (median to baseline 271mg daily morphine equivalents): no significant changes in dosage

Breakthrough pain and corresponding opioid use at 14-21 days:

No difference between arms for number of days used (THC:CBD arm vs. placebo arm, p=0.697; THC arm vs. placebo arm, p=0.555); non-significant reduction in each arm (THC:CBD arm = -0.19 vs. THC arm = -0.14; placebo arm = -0.15) with no difference between arms (THC:CBD arm vs. placebo arm, p=0.688; THC arm vs. placebo arm; p=0.899); more patients in placebo arm (n=7) with increased dosage compared to THC:CBD arm (p=0.004)
|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=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Sleep
|Outcome specification=Sleep quality
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significant differences between THC:CBD arm/THC arm and placebo arm.
|Results after intervention=NA
|Bias arising from the randomization process=low risk
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Nausea
|Outcome specification=Nausea
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significant differences between THC:CBD arm/THC arm and placebo arm
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Cognitive functioning
|Outcome specification=Memory
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Placebo arm with no change (0.01), THC:CBD arm and THC arm with deterioration compared to placebo arm (THC:CBD arm = 0.63 vs. placebo arm = 0.01, p=0.045; THC arm = 0.66 vs. placebo arm = 0.01, p=0.053).
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Cognitive functioning
|Outcome specification=Concentration
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Placebo arm with improvement, THC:CBD arm and THC arm with deterioration (placebo arm = -0.35 vs. THC:CBD arm = 0.33, p=0.021; placebo arm = -0.35 vs. THC arm = 0.29, p=0.028)
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Appetite
|Outcome specification=Appetite
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Improvement in placebo arm, deterioration in THC:CBD arm and THC arm (placebo arm = -0.59 vs. THC:CBD arm = 0.24, p=0.016; placebo group = -0.59 vs. THC group = 0.06, p=0.056).
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=7
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=Quality of life at baseline and 14-21 days after
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=At days 14-21: Effects for reduction of "cognitive function" in THC:CBD arm and THC arm compared to placebo arm (THC:CBD arm = -5.33 vs. placebo arm = 3.68, p=0.02; THC arm = -6.77 vs. placebo arm = 3.68, p=0.01)

Worsening of "nausea and vomiting" in THC:CBD arm compared to placebo arm (THC:CBD arm = 5.13 vs. placebo arm = -3.43, p=0.02; THC arm = -3.41 vs. placebo arm = -3.43; p=1.0).

For "pain" no difference between THC:CBD arm/THC arm and placebo arm.

For "social function" significant advantage for THC arm over placebo arm (9.66 vs. 1.58; p=0.038).
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=8
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Pain at baseline and 14-21 days after
|Type of measurement=BPI-SF (Brief Pain Inventory - Short Form)
|Results during intervention=Pain in the last 24h: significant advantage for THC arm over placebo arm (-3.20 vs. 0.87; p=0.048), no difference for interference pain.
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Order number=9
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This study was sponsored by GW Pharma Ltd. All study medication was supplied by GW Pharma Ltd., and it also funded all sites involved in the study by means of per-patient payments based on recruitment. GW Pharma Ltd. has funded J. R. Johnson (primary author) to attend two conferences to present the results of this study.
|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=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=Yes
|Possibility of attention effects=No information whether centers were comparable in treatment of patients; especially “optimized” opioid treatment may vary from country to country
|Possibility of placebo effects=NA
|Other reasons=No information whether centers were comparable in treatment of patients; especially “optimized” opioid treatment may vary from country to country
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|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=Yes
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=Yes
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethical approval
* Intent-to-treat analysis
* Power analysis
* Arms comparable at baseline

CONTRA:
* No information on whether centers were comparable in patient treatment; especially as “optimal” opioid treatment may vary from country to country.
* Baseline data: cancer type not specified for 104 patients.
* No control for multiple testing.
* Reported results in the text are unclear.
* No information on cancer stage.
* No explanation of how randomization was conducted or how blinding was ensured.
* Most comparisons are between the interventionarms and the placeboarm, but there are few comparisons between the interventionarms
* No elaboration of the intent-to-treat analysis in the methodology
}}
=Additional Notes=

Cruciani et al. (2009): L-Carnitine Supplementation in Patients with Advanced Cancer and Carnitine Deficiency: A Double-Blind, Placebo-Controlled Study

2024-11-21T08:14:28Z

JDoerfler:

{{Reference
|Reference=Publication: L-Carnitine Supplementation in Patients with Advanced Cancer and Carnitine Deficiency: A Double-Blind, Placebo-Controlled Study
}}

=Brief summary=
The study investigated the impact of carnitine on fatigue/exhaustion caused by cancer and the associated chemotherapy and medication. A total of 33 patients with various cancers and a carnitine deficiency caused by the treatment were randomly assigned to two groups. One group received 2g of carnitine daily for 4 weeks, while the other group received a placebo for 2 weeks and then 2g of carnitine daily for the next 2 weeks. At the beginning of the study, none of the participants knew whether they were receiving carnitine or a placebo. After 2 weeks, this information was disclosed, so both groups knew they were either receiving carnitine or had previously received a placebo and were now also receiving carnitine. The resutls of the analysis after 2 weeks showed no significant results.
After 4 weeks, the results of an exploratory analysis showed a greater improvement in fatigue in the group that received carnitine from the start. Additionally, it showed a deterioration in quality of life in terms of functionality for the initial placebo group and a general improvement in physical functionality in the group that received carnitine from the beginning. In summary, the improvement in fatigue is not interpretable as the effect only occurred when the participants knew which group they were originally assigned to. Similarly, the effect of better physical functionality or worse functional quality of life only appeared after 4 weeks, and thus under the knowledge of group assignment.

Die Studie untersuchte den Einfluss von Carnitin auf Müdigkeit/ Erschöpfung verursacht durch eine Krebserkrankung bzw. die damit verbundene Chemotherapie und Medikation. Insgesamt 33 Patienten mit verschiedenen Krebserkrankungen und einem Carnitindefizit, verursacht durch die Behandlung wurden zufällig 2 Gruppen zugeordnet. Die eine Gruppe erhielt über 4 Wochen 2g Carnitin täglich, während die andere Gruppe 2 Wochen ein Placebo erhielt und erst dann für die nächsten 2 Wochen auch 2g Carnitin täglich. Zu Beginn der Studie wusste keiner der Probanden ob er Carnitin oder ein Placebo erhielt, nach 2 Wochen wurde dies offen gelegt, sodass beide Gruppen wussten, dass sie Carnitin erhielten oder zuvor ein Placebo erhielten und nun aber auch Carnitin bekommen. In den Auswertungen nach 2 Wochen zeigten sich keine bedeutsamen Effekte.
In einer explorativen Analyse zeigte sich nach 4 Wochen eine stärkere Besserung der Müdigkeit in der Gruppe, die von Anfang an Carnitin erhielt. Zudem zeigten die Ergebnisse eine Verschlechterung der Lebensqualität im Sinne der Funktionalität für die anfängliche Placebogruppe und eine generelle bessere körperliche Funktionalität in der Gruppe, die von Anfang an Carnitin erhielt. Zusammenfassend ist das Ergebnis der Besserung der Müdigkeit allerdings nicht interpretierbar, da der Effekt erst auftrat, als die Probanden wussten, welcher Gruppe sie ursprünglich zugeordnet waren. Auch der Effekt der besseren körperlichen Funktionalität bzw. schlechteren funktionalen Lebensqualität tritt erst nach 4 Wochen und damit unter dem Wissen der Gruppenzugehörigkeit auf.

=Study Design=
1. Phase of the study: double-blind (randomized)

2. Phase of the study: open-label (both arms received carnitine)

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Moderate to severe fatigue, a Karnofsky Performance Status (KPS) score 14 of 50 or more, and carnitine deficiency; carnitine deficiency was defined as free carnitine less than 35 µmol/L for males or less than 25 µmol/L for females (normal range 35-67 and 25-55, respectively), or an acyl-carnitine ratio of more than 0.4 (acylcarnitine ratio 0.4 total acyl-carnitine - free acyl-carnitine/free acyl-carnitine)
|Exclusion criteria=Uncontrolled or severe cardiovascular, pulmonary, or renal disease; current treatment with either chemotherapy or radiation therapy; encephalopathy or psychiatric disorder sufficient to compromise adherence to study methods or data collection; history of stroke, seizure, or primary or metastatic brain tumor; fewer than 60 days of concurrent use of recombinant erythropoietin, and known sensitivity to carnitine
|N randomized=29
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=ITT-Analyse n=29
Per Protocol Analyse n= 27

An exploratory analysis was performed in which the data (all 17 patients who started on L-carnitine plus 10 patients who started on placebo, inkluding two protocol violators) was supplemented by the scores recorded at the end of the open-label phase. The pattern mixture analysis used three measurements over time and accounted for missing data.
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=T0: before intervention (baseline)
T1: 2 weeks (end of phase 1)
T2: 1 week after the start of the intervention
T3: 4 weeks (end of phase 2)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer, Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal Cancer, Gastrointestinal Cancers - Esophageal Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Gastrointestinal Cancers - Liver Cancer, Genitourinary Cancers - Bladder Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Head and Neck Cancers, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Lung Cancer, Prostate Cancer, Stomach Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Carnitine deficiency; carnitine deficiency was defined as free carnitine less than 35 µmol/L for males or less than 25 µmol/L for females (normal range 35-67 and 25-55, respectively), or an acyl-carnitine ratio of more than 0.4 (acylcarnitine ratio 0.4 total acyl-carnitine - free acyl-carnitine/free acyl-carnitine)
|Current cancer therapy=Chemotherapy, NI, Radiation therapy
|Specifications on cancer therapies=The protocol was amended during the course of the study, and patients receiving chemotherapy or radiation therapy were allowed under the modified protocol.
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=55% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 66–70 (13) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=17
|Drop-out=Phase 1 n=7
Phase 2 n=1
|Drop-out reasons=Phase 1: n=2 death, n=3 deteriorations, n=1 diarrhea, n=1 missed follow-up
Phase 2: no reasons given
|Intervention=L-Carnitine
|Dosage and regime=0.5 g/day for 2 days, then 1 g/day for 2 days, and then 2 g (2x1g) daily for 10 days in 10 ml syrup = 14 days + 14 days after unblinding
|One-time application=No
|Duration in days=28
|Side Effects / Interactions=1 case of constipation and 1 case of diarrhea were reported by the authors to be associated with carnitine
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=12
|Drop-out=Phase 1 n=5
Phase 2 n=1
|Drop-out reasons=Phase 1: n=1 death, n=2 deteriorations, n=2 with low fatigue
Phase 2: no reasons given
|Intervention=Placebo
|Dosage and regime=14 days, then L-Carnitine 2g (2x 1g) daily for 14 days
|One-time application=No
|Duration in days=28
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Fatigue
|Outcome specification=NA
|Type of measurement=FACT (Functional Assessment of Cancer Therapy)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
After 4 weeks (end of phase II; PMA, pattern mixture analysis): greater change for the intervention arm compared to the placebo arm (b=2.6; p=0.03; adjusted), Intervention arm: Baseline: Mean (SD) = 16.0 (8.5) – 4 weeks: Mean (SD) = 22.4 (10.7), Placebo arm: Baseline: Mean (SD) = 11.8 (6.1) – 4 weeks: Mean (SD) = 15.1 (4.8)
|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=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Quality of Life and Well-being
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), LASA (Linear Analogue Self-Assessment)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
After 4 weeks (end of phase II, PMA Analysis): significant difference for the functional subscale (b=1.9; p=0.03; unadjusted; b=2.0; p=0.002; adjusted); Intervention arm: Baseline: Mean (SD) = 11.4 (5.1) – 4 weeks: Mean (SD) = 11.0 (3.2), Placebo arm: Baseline: Mean (SD) = 10.8 (6.0) – 4 weeks: Mean (SD) = 9.2 (3.8); this difference is due to the decrease in values in the placebo arm; no direct comparison was conducted
|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=Primary
|Outcome name=Mental status/ function
|Outcome specification=NA
|Type of measurement=MMSE (Mini-Mental State Exam)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
No differences between arms and/or time points for PMA-Analysis
|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=Primary
|Outcome name=Physical functioning
|Outcome specification=NA
|Type of measurement=KPS (Karnofsky Performance Status)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
After 4 weeks (end of phase II, PMA Analysis): significant difference between the arms (b=2.58; p=0.003, unadjusted; b=2.7; p=0.002, adjusted), Intervention arm: Baseline: Mean (SD) = 58.2 (8.8) – 4 weeks: Mean (SD) = 64.2 (9.0), Placebo arm: Baseline: Mean (SD) = 57.0 (4.8) – 4 weeks: Mean (SD) = 50.0 (15.5); with higher values for the intervention arm and lower values for the placebo arm
|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=Primary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Interview
|Results during intervention=Adverse events were observed in 21 out of 29 patients (hospice patients); 7 were hospitalized (intervention arm: 4 times, placebo arm: 3 times). Fifteen hospice patients and eight non-hospice patients reported adverse events, including:
Nausea/vomiting (intervention arm: 2 times); Stomach problems (intervention arm: 2 times); Increased pain (placebo arm: 2 times); Diarrhea (intervention arm: 2 times); Confusion (placebo arm: 1 time); Tinnitus (placebo arm: 1 time)

According to the authors, only one case of constipation and one case of diarrhea were associated with carnitine.
|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 Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=“The study was funded by grant # R21AT01025 from the National Institutes of Health.”
|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=?
|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.
* Intention-to-treat analysis.
* Block randomization according to RTX or CTX, gender, and hemoglobin level.
* Power analysis conducted.
* Explanation provided for unequal group sizes (block randomization).
* Critical discussion of results.

CONTRA:
* Inclusion of baseline values only in an additional secondary analysis (PPA).
* Effects in PPA only for control of baseline values and age.
* Small sample size.
* Differing reports of required free carnitine for men in the abstract and main text.
}}

Cruciani et al. (2009): L-Carnitine Supplementation in Patients with Advanced Cancer and Carnitine Deficiency: A Double-Blind, Placebo-Controlled Study

2024-11-21T08:14:18Z

JDoerfler:

{{Reference
|Reference=Publication: L-Carnitine Supplementation in Patients with Advanced Cancer and Carnitine Deficiency: A Double-Blind, Placebo-Controlled Study
}}
{{Study Note}}
=Brief summary=
The study investigated the impact of carnitine on fatigue/exhaustion caused by cancer and the associated chemotherapy and medication. A total of 33 patients with various cancers and a carnitine deficiency caused by the treatment were randomly assigned to two groups. One group received 2g of carnitine daily for 4 weeks, while the other group received a placebo for 2 weeks and then 2g of carnitine daily for the next 2 weeks. At the beginning of the study, none of the participants knew whether they were receiving carnitine or a placebo. After 2 weeks, this information was disclosed, so both groups knew they were either receiving carnitine or had previously received a placebo and were now also receiving carnitine. The resutls of the analysis after 2 weeks showed no significant results.
After 4 weeks, the results of an exploratory analysis showed a greater improvement in fatigue in the group that received carnitine from the start. Additionally, it showed a deterioration in quality of life in terms of functionality for the initial placebo group and a general improvement in physical functionality in the group that received carnitine from the beginning. In summary, the improvement in fatigue is not interpretable as the effect only occurred when the participants knew which group they were originally assigned to. Similarly, the effect of better physical functionality or worse functional quality of life only appeared after 4 weeks, and thus under the knowledge of group assignment.

Die Studie untersuchte den Einfluss von Carnitin auf Müdigkeit/ Erschöpfung verursacht durch eine Krebserkrankung bzw. die damit verbundene Chemotherapie und Medikation. Insgesamt 33 Patienten mit verschiedenen Krebserkrankungen und einem Carnitindefizit, verursacht durch die Behandlung wurden zufällig 2 Gruppen zugeordnet. Die eine Gruppe erhielt über 4 Wochen 2g Carnitin täglich, während die andere Gruppe 2 Wochen ein Placebo erhielt und erst dann für die nächsten 2 Wochen auch 2g Carnitin täglich. Zu Beginn der Studie wusste keiner der Probanden ob er Carnitin oder ein Placebo erhielt, nach 2 Wochen wurde dies offen gelegt, sodass beide Gruppen wussten, dass sie Carnitin erhielten oder zuvor ein Placebo erhielten und nun aber auch Carnitin bekommen. In den Auswertungen nach 2 Wochen zeigten sich keine bedeutsamen Effekte.
In einer explorativen Analyse zeigte sich nach 4 Wochen eine stärkere Besserung der Müdigkeit in der Gruppe, die von Anfang an Carnitin erhielt. Zudem zeigten die Ergebnisse eine Verschlechterung der Lebensqualität im Sinne der Funktionalität für die anfängliche Placebogruppe und eine generelle bessere körperliche Funktionalität in der Gruppe, die von Anfang an Carnitin erhielt. Zusammenfassend ist das Ergebnis der Besserung der Müdigkeit allerdings nicht interpretierbar, da der Effekt erst auftrat, als die Probanden wussten, welcher Gruppe sie ursprünglich zugeordnet waren. Auch der Effekt der besseren körperlichen Funktionalität bzw. schlechteren funktionalen Lebensqualität tritt erst nach 4 Wochen und damit unter dem Wissen der Gruppenzugehörigkeit auf.

=Study Design=
1. Phase of the study: double-blind (randomized)

2. Phase of the study: open-label (both arms received carnitine)

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=Yes
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|Inclusion criteria=Moderate to severe fatigue, a Karnofsky Performance Status (KPS) score 14 of 50 or more, and carnitine deficiency; carnitine deficiency was defined as free carnitine less than 35 µmol/L for males or less than 25 µmol/L for females (normal range 35-67 and 25-55, respectively), or an acyl-carnitine ratio of more than 0.4 (acylcarnitine ratio 0.4 total acyl-carnitine - free acyl-carnitine/free acyl-carnitine)
|Exclusion criteria=Uncontrolled or severe cardiovascular, pulmonary, or renal disease; current treatment with either chemotherapy or radiation therapy; encephalopathy or psychiatric disorder sufficient to compromise adherence to study methods or data collection; history of stroke, seizure, or primary or metastatic brain tumor; fewer than 60 days of concurrent use of recombinant erythropoietin, and known sensitivity to carnitine
|N randomized=29
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=ITT-Analyse n=29
Per Protocol Analyse n= 27

An exploratory analysis was performed in which the data (all 17 patients who started on L-carnitine plus 10 patients who started on placebo, inkluding two protocol violators) was supplemented by the scores recorded at the end of the open-label phase. The pattern mixture analysis used three measurements over time and accounted for missing data.
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=T0: before intervention (baseline)
T1: 2 weeks (end of phase 1)
T2: 1 week after the start of the intervention
T3: 4 weeks (end of phase 2)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer, Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal Cancer, Gastrointestinal Cancers - Esophageal Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Gastrointestinal Cancers - Liver Cancer, Genitourinary Cancers - Bladder Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Head and Neck Cancers, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Lung Cancer, Prostate Cancer, Stomach Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Carnitine deficiency; carnitine deficiency was defined as free carnitine less than 35 µmol/L for males or less than 25 µmol/L for females (normal range 35-67 and 25-55, respectively), or an acyl-carnitine ratio of more than 0.4 (acylcarnitine ratio 0.4 total acyl-carnitine - free acyl-carnitine/free acyl-carnitine)
|Current cancer therapy=Chemotherapy, NI, Radiation therapy
|Specifications on cancer therapies=The protocol was amended during the course of the study, and patients receiving chemotherapy or radiation therapy were allowed under the modified protocol.
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=55% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 66–70 (13) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=17
|Drop-out=Phase 1 n=7
Phase 2 n=1
|Drop-out reasons=Phase 1: n=2 death, n=3 deteriorations, n=1 diarrhea, n=1 missed follow-up
Phase 2: no reasons given
|Intervention=L-Carnitine
|Dosage and regime=0.5 g/day for 2 days, then 1 g/day for 2 days, and then 2 g (2x1g) daily for 10 days in 10 ml syrup = 14 days + 14 days after unblinding
|One-time application=No
|Duration in days=28
|Side Effects / Interactions=1 case of constipation and 1 case of diarrhea were reported by the authors to be associated with carnitine
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=12
|Drop-out=Phase 1 n=5
Phase 2 n=1
|Drop-out reasons=Phase 1: n=1 death, n=2 deteriorations, n=2 with low fatigue
Phase 2: no reasons given
|Intervention=Placebo
|Dosage and regime=14 days, then L-Carnitine 2g (2x 1g) daily for 14 days
|One-time application=No
|Duration in days=28
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Fatigue
|Outcome specification=NA
|Type of measurement=FACT (Functional Assessment of Cancer Therapy)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
After 4 weeks (end of phase II; PMA, pattern mixture analysis): greater change for the intervention arm compared to the placebo arm (b=2.6; p=0.03; adjusted), Intervention arm: Baseline: Mean (SD) = 16.0 (8.5) – 4 weeks: Mean (SD) = 22.4 (10.7), Placebo arm: Baseline: Mean (SD) = 11.8 (6.1) – 4 weeks: Mean (SD) = 15.1 (4.8)
|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=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Quality of Life and Well-being
|Type of measurement=FACT (Functional Assessment of Cancer Therapy), LASA (Linear Analogue Self-Assessment)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
After 4 weeks (end of phase II, PMA Analysis): significant difference for the functional subscale (b=1.9; p=0.03; unadjusted; b=2.0; p=0.002; adjusted); Intervention arm: Baseline: Mean (SD) = 11.4 (5.1) – 4 weeks: Mean (SD) = 11.0 (3.2), Placebo arm: Baseline: Mean (SD) = 10.8 (6.0) – 4 weeks: Mean (SD) = 9.2 (3.8); this difference is due to the decrease in values in the placebo arm; no direct comparison was conducted
|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=Primary
|Outcome name=Mental status/ function
|Outcome specification=NA
|Type of measurement=MMSE (Mini-Mental State Exam)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
No differences between arms and/or time points for PMA-Analysis
|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=Primary
|Outcome name=Physical functioning
|Outcome specification=NA
|Type of measurement=KPS (Karnofsky Performance Status)
|Results during intervention=After 2 weeks (end of phase I, ITT-Analysis and PP-Analysis): No differences between arms and/or time points
|Results after intervention=Exploratory analysis:
After 4 weeks (end of phase II, PMA Analysis): significant difference between the arms (b=2.58; p=0.003, unadjusted; b=2.7; p=0.002, adjusted), Intervention arm: Baseline: Mean (SD) = 58.2 (8.8) – 4 weeks: Mean (SD) = 64.2 (9.0), Placebo arm: Baseline: Mean (SD) = 57.0 (4.8) – 4 weeks: Mean (SD) = 50.0 (15.5); with higher values for the intervention arm and lower values for the placebo arm
|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=Primary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Interview
|Results during intervention=Adverse events were observed in 21 out of 29 patients (hospice patients); 7 were hospitalized (intervention arm: 4 times, placebo arm: 3 times). Fifteen hospice patients and eight non-hospice patients reported adverse events, including:
Nausea/vomiting (intervention arm: 2 times); Stomach problems (intervention arm: 2 times); Increased pain (placebo arm: 2 times); Diarrhea (intervention arm: 2 times); Confusion (placebo arm: 1 time); Tinnitus (placebo arm: 1 time)

According to the authors, only one case of constipation and one case of diarrhea were associated with carnitine.
|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 Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=“The study was funded by grant # R21AT01025 from the National Institutes of Health.”
|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=?
|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.
* Intention-to-treat analysis.
* Block randomization according to RTX or CTX, gender, and hemoglobin level.
* Power analysis conducted.
* Explanation provided for unequal group sizes (block randomization).
* Critical discussion of results.

CONTRA:
* Inclusion of baseline values only in an additional secondary analysis (PPA).
* Effects in PPA only for control of baseline values and age.
* Small sample size.
* Differing reports of required free carnitine for men in the abstract and main text.
}}

Stratton et al. (2010): Oral Selenium Supplementation Has No Effect on Prostate- Specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer

2024-11-21T08:13:45Z

JDoerfler:

{{Reference
|Reference=Publication: Oral Selenium Supplementation Has No Effect on Prostate- Specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer
}}

=Brief summary=
In this study, data from 140 men with low-grade non-metastatic prostate cancer were included, who had decided against active therapy and instead opted for a watchful waiting therapy. The participants were randomly assigned to three arms, in which they received either 200 μg or 800 μg of selenium daily, or a placebo. The study investigated whether the PSA value, as an indicator for the development and thus worsening of the participants' prostate cancer, changed over the following years. After five years, no difference in the PSA value was found between the arms. Neither between the selenium arms and the placebo arm, nor between the two selenium arms. It was only shown that men who already had a high selenium plasma level at the start of the study and then took 800 μg daily over the course of the study showed a significantly higher PSA value after five years compared to the placebo arm. However, this is a very small subgroup of the original sample, so the result should be interpreted with caution. Overall, the study shows great statistical and planning care, but fails to provide important information about the randomization and blinding process, which could call the study's framework into question. It is also noteworthy that the selenium concentration of the participants at baseline was already on average (SD) 134.5 (41.5) ng/mL, which is considered very high. Therefore, a dose of 200 or even 800 μg daily can be considered an overdose of selenium.

In dieser Studie wurden die Daten von 140 Männern mit niedrig-gradigem nicht metastasierendem Prostatakrebs eingeschlossen, welche sich gegen eine aktive Therapie und stattdessen für eine abwartende Überwachungs-Therapie entschieden haben. Die Probanden wurden zufällig in drei Gruppen eingeteilt, in derer sie entweder täglich 200 μg oder 800 μg Selen bekamen, oder ein Placebo. Untersucht wurde, ob sich der PSA Wert, als Indikator für die Entwicklung und damit Verschlechterung des Prostatakrebses der Probanden über die kommenden Jahre verändert. Nach fünf Jahren konnte zwischen den Gruppen kein Unterschied bezüglich der Höhe des PSA-Wertes festgestellt werden. Weder zwischen den Selen-Gruppen und der Placebo-Gruppe, noch zwischen den beiden Selen-Gruppen. Es konnte nur gezeigt werden, dass Männer, welche schon zu Beginn der Studie einen hohen Selen-Plasma-Wert hatten und dann über die Zeit der Studie täglich 800 μg zu sich nahmen nach fünf Jahren einen bedeutsam höheren PSA-Wert aufzeigten als die Placebo-Gruppe. Doch hier handelt es sich um eine sehr kleine Untergruppe der ursprünglichen Stichprobe, weshalb das Ergebnis mit Vorsicht zu interpretieren ist. Insgesamt wartet die Studie mit großer statistischer und planungsmäßiger Sorgfalt auf, versäumt hingegen wichtige Informationen über den Randomisierungs- und Verblindungsprozess zu liefern, womit die Rahmenbedingungen der Studie in Frage gestellt werden könnten. Es zudem anzumerken, dass die Selenkonzentration der Probanden zur Baseline bereits im Mittel (SD) bei 134.5 (41.5) ng/mL lag, was schon als sehr hoch anzusehen ist. Wodurch eine Gabe von 200 oder sogar 800µg täglich als eine Überdosierung von Selen zu werten ist.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Biopsy-proven localized (nonmetastatic) prostate cancer documented within 48 months before enrolling in the trial, Gleason score of <8, serum PSA level of <50 ng/mL, age <85 years, life expectancy of ≥3 years, elected to forgo front-line therapy and chose to be followed by active surveillance, limited daily selenium supplementation to no more than 50 μg from non-study sources
|Exclusion criteria=NI
|N randomized=140
|Analysis=ITT Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=Baseline; then every 3 months for 5 years
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Active surveillance
|Types of cancer=Prostate Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Biopsy-proven localized (nonmetastatic) prostate cancer
|Comorbidity=NI
|Current cancer therapy=Active surveillance
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=Mean: 72.8 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=47
|Drop-out=38
|Drop-out reasons=9 completed study; 18 reached study endpoint, 7 on study at study end, 2 died, 2 concurrent illness, 4 withdrew for reasons not study-related, 5 withdrew for other study-related reasons
|Intervention=Selenium
|Dosage and regime=200 μg selenium per day (yeast selenium); Follow-up duration (mean (SD); median): 33.4 (20.3); 33.3 years
|One-time application=No
|Duration in days=1.826
|Side Effects / Interactions=The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 6 (12.8%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 0 (0.0%), no significant difference between arms
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=47
|Drop-out=35
|Drop-out reasons=12 completed study; 13 reached study endpoint, 6 on study at study end, 2 died, 2 concurrent illness, 6 withdrew for reasons not study-related, 6 withdrew for other study-related reasons
|Intervention=Selenium
|Dosage and regime=800 μg selenium per day (yeast selenium); Follow-up duration (mean (SD); median): 33.3 (23.3); 33.8 years
|One-time application=No
|Duration in days=1.826
|Side Effects / Interactions=The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 8 (17.0%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 4 (8.5%); no significant difference between the arms
|Order number=2
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=46
|Drop-out=38
|Drop-out reasons=8 completed study; 14 reached study endpoint, 14 on study at study end, 1 died, 2 concurrent illness, 4 withdrew for reasons not study-related, 3 withdrew for other study-related reasons
|Intervention=Placebo
|Dosage and regime=Placebo; Follow-up duration (mean (SD); median): 36.3 (20.7); 38.4 years
|One-time application=No
|Duration in days=1.826
|Side Effects / Interactions=The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 10 (21.7%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 5 (10.9%), no significant difference between arms
|Order number=3
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=PSA level (Prostate-Specific Antigen)
|Outcome specification=Change over 5 years
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=After 5 years: selenium arms not significantly different to placebo arm (p=0.32 and p=0.61) or to each other

Subgroup of high-selenium arm with high selenium value at baseline shows higher PSA values than placebo arm (p=0.018)
|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=some concerns
|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=“Public Health Service grants CA079080 and CA023074. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.“
|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=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=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=Yes
|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
|Additional Notes=PRO:

* Ethics approval obtained.
* Participants were tested for 30 days to assess adherence to the intake protocol before randomization.
* Only those with over 80% adherence were randomized.
* Extensive prior questioning and recording of all medical factors related to potential selenium risk.
* Detailed information on expected side effects provided.
* Use of a "Data and Safety Monitoring Committee" to monitor protocols, side effects, etc.
* Intent-to-treat analysis conducted.
* Adequate and participant-adjusted analysis considering: Duration of participation in the study, Skin color, Baseline plasma selenium, Age, BMI, Nicotine consumption, PSA assay, Gleason score
* Power analysis performed.
* Arm comparability achieved except for BMI, which was adjusted in the analysis.

CONTRA:

* Participants could still take 50 μg of selenium outside of the study.
* Unclear if baseline blood samples were taken before the test run of pill intake.
* Baseline selenium differences between arms with p=0.07 were already close to significance.
* The 800 μg selenium arm had a significantly higher descriptive level at 146 ng/mL compared to 128 ng/mL in the placebo arm.
* Unclear randomization and blinding process.
* Analysis of a subgroup from the 800 μg selenium arm resulted in very few participants.
}}

Stratton et al. (2010): Oral Selenium Supplementation Has No Effect on Prostate- Specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer

2024-11-21T08:13:24Z

JDoerfler:

{{Reference
|Reference=Publication: Oral Selenium Supplementation Has No Effect on Prostate- Specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer
}}
{{Study Note}}
=Brief summary=
In this study, data from 140 men with low-grade non-metastatic prostate cancer were included, who had decided against active therapy and instead opted for a watchful waiting therapy. The participants were randomly assigned to three arms, in which they received either 200 μg or 800 μg of selenium daily, or a placebo. The study investigated whether the PSA value, as an indicator for the development and thus worsening of the participants' prostate cancer, changed over the following years. After five years, no difference in the PSA value was found between the arms. Neither between the selenium arms and the placebo arm, nor between the two selenium arms. It was only shown that men who already had a high selenium plasma level at the start of the study and then took 800 μg daily over the course of the study showed a significantly higher PSA value after five years compared to the placebo arm. However, this is a very small subgroup of the original sample, so the result should be interpreted with caution. Overall, the study shows great statistical and planning care, but fails to provide important information about the randomization and blinding process, which could call the study's framework into question. It is also noteworthy that the selenium concentration of the participants at baseline was already on average (SD) 134.5 (41.5) ng/mL, which is considered very high. Therefore, a dose of 200 or even 800 μg daily can be considered an overdose of selenium.

In dieser Studie wurden die Daten von 140 Männern mit niedrig-gradigem nicht metastasierendem Prostatakrebs eingeschlossen, welche sich gegen eine aktive Therapie und stattdessen für eine abwartende Überwachungs-Therapie entschieden haben. Die Probanden wurden zufällig in drei Gruppen eingeteilt, in derer sie entweder täglich 200 μg oder 800 μg Selen bekamen, oder ein Placebo. Untersucht wurde, ob sich der PSA Wert, als Indikator für die Entwicklung und damit Verschlechterung des Prostatakrebses der Probanden über die kommenden Jahre verändert. Nach fünf Jahren konnte zwischen den Gruppen kein Unterschied bezüglich der Höhe des PSA-Wertes festgestellt werden. Weder zwischen den Selen-Gruppen und der Placebo-Gruppe, noch zwischen den beiden Selen-Gruppen. Es konnte nur gezeigt werden, dass Männer, welche schon zu Beginn der Studie einen hohen Selen-Plasma-Wert hatten und dann über die Zeit der Studie täglich 800 μg zu sich nahmen nach fünf Jahren einen bedeutsam höheren PSA-Wert aufzeigten als die Placebo-Gruppe. Doch hier handelt es sich um eine sehr kleine Untergruppe der ursprünglichen Stichprobe, weshalb das Ergebnis mit Vorsicht zu interpretieren ist. Insgesamt wartet die Studie mit großer statistischer und planungsmäßiger Sorgfalt auf, versäumt hingegen wichtige Informationen über den Randomisierungs- und Verblindungsprozess zu liefern, womit die Rahmenbedingungen der Studie in Frage gestellt werden könnten. Es zudem anzumerken, dass die Selenkonzentration der Probanden zur Baseline bereits im Mittel (SD) bei 134.5 (41.5) ng/mL lag, was schon als sehr hoch anzusehen ist. Wodurch eine Gabe von 200 oder sogar 800µg täglich als eine Überdosierung von Selen zu werten ist.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Biopsy-proven localized (nonmetastatic) prostate cancer documented within 48 months before enrolling in the trial, Gleason score of <8, serum PSA level of <50 ng/mL, age <85 years, life expectancy of ≥3 years, elected to forgo front-line therapy and chose to be followed by active surveillance, limited daily selenium supplementation to no more than 50 μg from non-study sources
|Exclusion criteria=NI
|N randomized=140
|Analysis=ITT Analysis
|Specifications on analyses=NI
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=Baseline; then every 3 months for 5 years
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Active surveillance
|Types of cancer=Prostate Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Biopsy-proven localized (nonmetastatic) prostate cancer
|Comorbidity=NI
|Current cancer therapy=Active surveillance
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=Mean: 72.8 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=47
|Drop-out=38
|Drop-out reasons=9 completed study; 18 reached study endpoint, 7 on study at study end, 2 died, 2 concurrent illness, 4 withdrew for reasons not study-related, 5 withdrew for other study-related reasons
|Intervention=Selenium
|Dosage and regime=200 μg selenium per day (yeast selenium); Follow-up duration (mean (SD); median): 33.4 (20.3); 33.3 years
|One-time application=No
|Duration in days=1.826
|Side Effects / Interactions=The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 6 (12.8%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 0 (0.0%), no significant difference between arms
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=47
|Drop-out=35
|Drop-out reasons=12 completed study; 13 reached study endpoint, 6 on study at study end, 2 died, 2 concurrent illness, 6 withdrew for reasons not study-related, 6 withdrew for other study-related reasons
|Intervention=Selenium
|Dosage and regime=800 μg selenium per day (yeast selenium); Follow-up duration (mean (SD); median): 33.3 (23.3); 33.8 years
|One-time application=No
|Duration in days=1.826
|Side Effects / Interactions=The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 8 (17.0%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 4 (8.5%); no significant difference between the arms
|Order number=2
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=46
|Drop-out=38
|Drop-out reasons=8 completed study; 14 reached study endpoint, 14 on study at study end, 1 died, 2 concurrent illness, 4 withdrew for reasons not study-related, 3 withdrew for other study-related reasons
|Intervention=Placebo
|Dosage and regime=Placebo; Follow-up duration (mean (SD); median): 36.3 (20.7); 38.4 years
|One-time application=No
|Duration in days=1.826
|Side Effects / Interactions=The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 10 (21.7%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 5 (10.9%), no significant difference between arms
|Order number=3
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=PSA level (Prostate-Specific Antigen)
|Outcome specification=Change over 5 years
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=After 5 years: selenium arms not significantly different to placebo arm (p=0.32 and p=0.61) or to each other

Subgroup of high-selenium arm with high selenium value at baseline shows higher PSA values than placebo arm (p=0.018)
|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=some concerns
|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=“Public Health Service grants CA079080 and CA023074. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.“
|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=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=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=Yes
|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
|Additional Notes=PRO:

* Ethics approval obtained.
* Participants were tested for 30 days to assess adherence to the intake protocol before randomization.
* Only those with over 80% adherence were randomized.
* Extensive prior questioning and recording of all medical factors related to potential selenium risk.
* Detailed information on expected side effects provided.
* Use of a "Data and Safety Monitoring Committee" to monitor protocols, side effects, etc.
* Intent-to-treat analysis conducted.
* Adequate and participant-adjusted analysis considering: Duration of participation in the study, Skin color, Baseline plasma selenium, Age, BMI, Nicotine consumption, PSA assay, Gleason score
* Power analysis performed.
* Arm comparability achieved except for BMI, which was adjusted in the analysis.

CONTRA:

* Participants could still take 50 μg of selenium outside of the study.
* Unclear if baseline blood samples were taken before the test run of pill intake.
* Baseline selenium differences between arms with p=0.07 were already close to significance.
* The 800 μg selenium arm had a significantly higher descriptive level at 146 ng/mL compared to 128 ng/mL in the placebo arm.
* Unclear randomization and blinding process.
* Analysis of a subgroup from the 800 μg selenium arm resulted in very few participants.
}}

Côté et al. (2016): Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial

2024-11-07T13:51:12Z

JDoerfler:

{{Reference
|Reference=Publication: Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial
}}

=Brief summary=
In the study, 56 patients with head and neck tumors were randomly divided into two arms, one received nabilone (synthetic THC) every day and the other a placebo. All patients received radiotherapy or a combination of radiotherapy and chemotherapy for seven weeks. At the end of the study, the authors found no differences between the arms for quality of life in general, as well as the symptoms of pain, weight fluctuations, appetite, nausea, mood and sleep. The study sample was small and 24 patients dropped out over the course of the study. The presentation of the results is superficial and inadequate. Without statistical values (mean values), the analysis is not transparent. Further methodological deficiencies in the analysis do not allow any conclusions to be drawn about the results.

In der Studie wurden 56 Patienten mit Kopf-Hals Tumoren zufällig in zwei Gruppen eingeteilt, wovon eine Gruppe jeden Tag Nabilon (synthetisches THC) bekam und die andere ein Placebo. Alle Patienten bekamen für sieben Wochen Radiotherapie oder eine Kombination aus Radio- und Chemotherapie. Am Ende der Studie fanden die Autoren keine Unterschiede zwischen den Gruppen für Lebensqualität allgemein, als auch für die Symptome Schmerz, Gewichtsschwankungen, Appetit, Übelkeit, Stimmung und Schlaf. Die Stichprobe der Studie war klein und es sind über den Verlauf der Studie noch 24 Patienten ausgestiegen. Die Darstellung der Ergebnisse ist oberflächlich und unzureichend. Ohne Angabe von statistischen Werten (Mittelwerte) ist eine Transparenz der Analyse nicht gegeben. Weitere methodische Mängel in der Analyse lassen keine Aussagen zu den Ergebnissen zu.

=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=Histological diagnosis of squamous cell carcinoma of the oral cavity, the oropharynx, the hypopharynx, and/or the larynx; treated by radiotherapy alone, postoperative radiotherapy, radiochemotherapy alone, or postoperative radiochemotherapy; aged 18 to 80 years; no other cancer diagnosis in the past 5 years, except for basal cell and squamous cell carcinoma of the skin
|Exclusion criteria=Metastatic disease; history of radiotherapy in the head and neck region; Karnofsky score <60; cognitive impairment; hepatic insufficiency; pregnant or breastfeeding woman; history of hypersensitivity or adverse reactions to marijuana or other cannabinoids; history of schizophrenia or any other form of psychosis
|N randomized=56
|Analysis=PP Analysis
|Specifications on analyses=Repeated measures analyses of variance (ANOVA), estimated with a linear mixed model, enable us to test the effect of time and treatment on continuous outcomes, while a generalized linear mixed model is used as a logistic regression for dichotomous outcomes. The P-values that are presented are for the interaction term of these models. All the analyses were also carried out while adjusting for site, treatment, and tumor size.
|Countries of data collection=Canada
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline before radiotherapy

T1: first week

T2: second week until

T3: 7th week

Follow-up: between 9th - 11th week
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Neo-adjuvant, Adjuvant
|Types of cancer=Head and Neck Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Radiotherapy only:

intervention arm = 13; placebo arm = 10

Radiotherapy postoperative:

intervention arm = 7; placebo arm = 2

Radiochemotherapy:

intervention arm = 7; placebo arm = 15

Radiochemotherapy postoperative:

intervention arm = 1, placebo arm = 1
|Previous cancer therapies=Surgery, No therapy
|Gender=Mixed
|Gender specifications=Female n = 10 (17.86%); male n = 46 (82.14%)
|Age groups=Adults (18+)
|Age groups specification=Mean age per arm:

intervention arm = 63.5 years

placebo arm = 63.8 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=28
|Drop-out=9
|Drop-out reasons=Not arm specified: severe nausea (n = 5); difficulty swallowing (n = 4); hospitalization (n = 4), pneumonia (n = 1); discontinued RT (n = 1); without reason (n = 9)
|Intervention=Nabilon

+ all patients: additional administration of antiemetics (metoclopramide) and painkillers (acetaminophen (paracetamol), codeine, hydromorphone or transdermal fentanyl) possible
|Dosage and regime=0.5 mg nabilone tablets (from Valeant Canada)

Once a day before radiotherapy in the first week, twice a day in the second week, third week until end of radiotherpy adjusted by radiation oncologist up to maximal 4 tablets
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=No differences for sleepiness (p=0.3166), anxiety (p=0.9163) and xerostomia (p=0.8341)
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=28
|Drop-out=15
|Drop-out reasons=Not arm specified: severe nausea (n = 5); difficulty swallowing (n = 4); hospitalization (n = 4), pneumonia (n = 1); discontinued RT (n = 1); without reason (n = 9)
|Intervention=Placebo

+ all patients: additional administration of antiemetics (metoclopramide) and painkillers (acetaminophen (paracetamol), codeine, hydromorphone or transdermal fentanyl) possible
|Dosage and regime=Once a day before radiotherapy in the first week, twice a day in the second week, third week until end of radiotherpy adjusted by radiation oncologist up to maximal 4 tablets
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=No differences for sleepiness (p=0.3166), anxiety (p=0.9163) and xerostomia (p=0.8341)
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Quality of life (target improvement of 15 points at week 7)
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=No difference between arms (p=0.4270), even after controlling for tumor site, treatment method and cancer stage at week 7 or the entire study period
|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=some concerns
|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=Pain
|Outcome specification=Pain with VAS + number of other analgesics used
|Type of measurement=VAS (Visual Analogue Scale), Observation
|Results during intervention=Over the course of the intervention and after: no differences for pain (p=0.6048), analgesic use (p=0.6671), no delay in time to 20% pain increase (p=0.4614) between arms
|Results after intervention=Over the course of the intervention and after: no differences for pain (p=0.6048), analgesic use (p=0.6671), no delay in time to 20% pain increase (p=0.4614) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Weight
|Outcome specification=Weight fluctuations, total days without feeding tube or gastrostomy
|Type of measurement=Scale
|Results during intervention=Over the course of the intervention and after: no difference for weight fluctuations (p=0.1454) or need for a feeding tube (no p-value) between arms.
|Results after intervention=Over the course of the intervention and after: no difference for weight fluctuations (p=0.1454) or need for a feeding tube (no p-value) between arms.
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Appetite
|Outcome specification=Appetite with questionnaire (no further information)
|Type of measurement=Unspecified questionnaire
|Results during intervention=Over the course of the intervention and after: no difference (p=0.3295) between arms
|Results after intervention=Over the course of the intervention and after: no difference (p=0.3295) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Nausea
|Outcome specification=Nausea with questionnaire (no further information) + number of antiemetic drugs used
|Type of measurement=Unspecified questionnaire
|Results during intervention=Over the course of the intervention and after: no difference for nausea (p=0.7105) or antiemetic consumption (p=0.6124) between arms
|Results after intervention=Over the course of the intervention and after: no difference for nausea (p=0.7105) or antiemetic consumption (p=0.6124) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=5
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Unspecified effects
|Outcome specification=Sleep quality and mood (no information on survey)
|Type of measurement=NI
|Results during intervention=Over the course of the intervention and after: no differences for mood (p=0.3214) and sleep quality (p=0.4438) between arms
|Results after intervention=Over the course of the intervention and after: no differences for mood (p=0.3214) and sleep quality (p=0.4438) between arms
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=6
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Toxicity of nabilone
|Type of measurement=NI
|Results during intervention=No differences for sleepiness (p=0.3166), anxiety (p=0.9163) and xerostomia (p=0.8341)
|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=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=7
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=The authors received research grants from the Canadian Institutes of Health Research and the Fonds de recherche en santé du Québec. ICN Valeant Pharmaceuticals provided the nabilone and the placebo pills during the trial.
|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=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=No
|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=Yes
|Side effects taken into account in the interpretation of the results=Yes
|Ethics / CoI / Funding=Yes
|Blinding reliable=Yes
|Check whether blinding was successful=No
|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
* Power analysis
* Intent-to-treat analysis
* Baseline comparability
* Mention of drop-out comparison in the discussion, though no statistical values are provided

CONTRA:

* Lack of blinding control
* No correction for multiple testing
* Superficial and inadequate presentation of results: results are only shown graphically, with no mean/SD values available, lacking transparency
* Very high drop-out rate, with 12 out of 15 participants in placebo arm who dropped out receiving Radiochemotherapy
* Exact dosing from week 3 onward may vary for each participant
* Apart from the primary endpoint, no specific timing provided for final comparisons
}}

Project:About

2024-11-07T13:43:22Z

JDoerfler:

<html>
=What is CAMIH?=

CAMIH, short for Complementary and Alternative Medicine Insights Hub, is a database offering up-to-date evidence from randomized controlled trials on complementary approaches and methods for treating oncology patients. Each study has been meticulously reviewed and critically evaluated for methodological rigor using the ''Cochrane Risk of Bias Tool 2.0''. This approach ensures that the database not only provides a comprehensive collection of evidence but also contextualizes these findings within a framework of methodological quality.

Study searches can be conducted directly via the search bar, but we also offer a thematically organized overview of all studies. Additionally, CAMIH provides an option for specific, customized search queries (via the CAMIH Helper) to generate a targeted summary on the topic of interest.

CAMIH is designed to promote transparency in medical research by offering a clear view of current evidence while emphasizing the importance of interpreting findings in relation to each study’s methodological quality. Every study entry and methodological evaluation in CAMIH has been developed by expert methodologists, using rigorous standards based on the published study details (and, where available, associated protocols or registrations). Drawing on years of expertise in study evaluation, additional assessment criteria were also developed and applied to each study in the database.

Each study page includes a reference page summarizing key information from the publication, along with dedicated author pages that link to the authors' publications. CAMIH aims to serve as a valuable resource for clinicians and researchers, helping them navigate and assess evidence with precision.

''Disclaimer'': The Brief Summary provided on each study page was prepared by our methodology experts, taking into account study quality, and may therefore differ in content or in interpretation of the results from the original publication. In contrast, each study’s Reference page contains only information directly sourced from the publication itself.

The database was developed by a team of methodological experts in study evaluation, led by XX, in collaboration with computer scientists under the direction XX.

Main Page

2024-11-07T13:32:54Z

JDoerfler:

<html>
== Welcome to CAMIH, the Complementary and Alternative Medicine Insights Hub! ==

CAMIH is a database offering up-to-date evidence from randomized controlled trials on complementary approaches and methods for treating oncology patients. Each study has been meticulously reviewed and critically evaluated for methodological rigor using the Cochrane Risk of Bias Tool 2.0. This approach ensures that the database not only provides a comprehensive collection of evidence but also contextualizes these findings within a framework of methodological quality.
 
 
Study searches can be conducted directly via the search bar, but we also offer a thematically organized overview of all studies. Additionally, CAMIH provides an option for specific, customized search queries (via the Query Helper) to generate a targeted summary on the topic of interest.
 
 
Via FAQ you can get information on the Level of Evidence, the RoB Tool 2.0. and types of analyses.

== Important Links ==
 
<gallery mode=nolines>
File:studies_by_type.png |'''Studies by study type'''|link=Category:Study
File:studies_by_topic.png |'''Studies by topic'''|link=Study_Overview
File:all_publications.png |'''All available publications'''|link=Category:Publication
File:faq.png |'''FAQ'''|link=FAQ
File:helper.png |'''Query helper'''|link=https://camih.med.uni-jena.de/helper
</gallery>

== Creator Tools ==
* [[Form:Author|Create a new Author]] (optional)
* [[Form:Publication|Create a new Publication]]
* [[Form:RCT_Study|Create a new RCT Study]]
* [[Form:SR_Study|Create a new SR Study]]

Main Page

2024-11-07T13:32:02Z

JDoerfler:

<html>
== Welcome to CAMIH, the Complementary and Alternative Medicine Insights Hub! ==

CAMIH is a database offering up-to-date evidence from randomized controlled trials on complementary approaches and methods for treating oncology patients. Each study has been meticulously reviewed and critically evaluated for methodological rigor using the Cochrane Risk of Bias Tool 2.0. This approach ensures that the database not only provides a comprehensive collection of evidence but also contextualizes these findings within a framework of methodological quality.
 
Study searches can be conducted directly via the search bar, but we also offer a thematically organized overview of all studies. Additionally, CAMIH provides an option for specific, customized search queries (via the Query Helper) to generate a targeted summary on the topic of interest.
 
Via FAQ you can get information on the Level of Evidence, the RoB Tool 2.0. and types of analyses.

== Important Links ==
 
<gallery mode=nolines>
File:studies_by_type.png |'''Studies by study type'''|link=Category:Study
File:studies_by_topic.png |'''Studies by topic'''|link=Study_Overview
File:all_publications.png |'''All available publications'''|link=Category:Publication
File:faq.png |'''FAQ'''|link=FAQ
File:helper.png |'''Query helper'''|link=https://camih.med.uni-jena.de/helper
</gallery>

== Creator Tools ==
* [[Form:Author|Create a new Author]] (optional)
* [[Form:Publication|Create a new Publication]]
* [[Form:RCT_Study|Create a new RCT Study]]
* [[Form:SR_Study|Create a new SR Study]]

Main Page

2024-11-07T13:28:33Z

JDoerfler:

<html>
== Welcome to CAMIH, the Complementary and Alternative Medicine Insights Hub! ==

CAMIH is a database offering up-to-date evidence from randomized controlled trials on complementary approaches and methods for treating oncology patients. Each study has been meticulously reviewed and critically evaluated for methodological rigor using the Cochrane Risk of Bias Tool 2.0. This approach ensures that the database not only provides a comprehensive collection of evidence but also contextualizes these findings within a framework of methodological quality.
 
Study searches can be conducted directly via the search bar, but we also offer a thematically organized overview of all studies. Additionally, CAMIH provides an option for specific, customized search queries (via the Query Helper) to generate a targeted summary on the topic of interest.

Via FAQ you can get information on the Level of Evidence, the RoB Tool 2.0. and types of analyses.

== Important Links ==
 
<gallery mode=nolines>
File:studies_by_type.png |'''Studies by study type'''|link=Category:Study
File:studies_by_topic.png |'''Studies by topic'''|link=Study_Overview
File:all_publications.png |'''All available publications'''|link=Category:Publication
File:faq.png |'''FAQ'''|link=FAQ
File:helper.png |'''Query helper'''|link=https://camih.med.uni-jena.de/helper
</gallery>

== Creator Tools ==
* [[Form:Author|Create a new Author]] (optional)
* [[Form:Publication|Create a new Publication]]
* [[Form:RCT_Study|Create a new RCT Study]]
* [[Form:SR_Study|Create a new SR Study]]

Karp et al. (2012): Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597

2024-11-07T12:51:19Z

JDoerfler:

{{Reference
|Reference=Publication: Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597
}}

=Brief summary=
In this study, 1561 participants with resected non-small cell lung cancer were included. They were randomly divided into two arms and were each to take 200 µg of yeast selenium (1040 participants) or a placebo (521 participants) every day. However, the study was terminated early, as an interim analysis after a study period of around nine years showed that no benefit could be achieved for the selenium arm; instead, there was a positive trend for the placebo arm. In a final analysis another two years later, there were no significant differences in the incidence of secondary tumors, lung cancer or other cancer recurrence, time to recurrence or overall survival of the patients. However, it was shown that participants who had never smoked had a higher survival time after three and five years than those who were current smokers or had only quit in the last year. The study leaves out basic framework descriptions. A promising subgroup analysis between different selenium concentrations and their effects on the cancer-free time interval remains without statistical value and thus cannot be clearly interpreted.

In dieser Studie wurden 1561 Probanden mit reseziertem nicht-kleinzelligem Lungenkarzinom eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt und sollten jeweils jeden Tag 200 µg Hefeselen (1040 Probanden) oder ein Placebo (521 Probanden) zu sich nehmen. Die Studie wurde allerdings frühzeitig abgebrochen, da sich in einer Zwischenanalyse nach etwa neun Jahren Studienlaufzeit abzeichnete, dass kein Vorteil für die Selengruppe erzielt werden könne, stattdessen gab es einen positiven Trend für die Placebogruppe. In einer abschließenden Analyse weitere zwei Jahre später zeigten sich keine bedeutsamen Unterschiede bezüglich des Auftretens von sekundären Tumoren, Lungenkrebs oder sonstiger Rückkehr von Krebs, sowie der Zeit bis zur Rückkehr oder dem Gesamtüberleben der Patienten. Allerdings wurde gezeigt, dass Personen, die nie geraucht haben, eine höhere Überlebenszeit nach drei und fünf Jahren zeigten, als Probanden die aktuell rauchten, oder erst im letzten Jahr aufgehört hatten. Die Studie vernachlässigt grundlegende Rahmenbeschreibungen. Eine vielversprechende Subgruppenanalyse zwischen verschieden hohen Selenkonzentration und deren Auswirkungen auf das Krebsfreie-Zeitintervall bleibt ohne statistische Wertangabe und kann damit nicht eindeutig interpretiert werden.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=36 months from complete resection of histologically proven stage IA (pT1N0) or stage IB (pT2N0) NSCLC (carcinoid tumors were excluded); pathologic stage N0 confirmed by sampling at least one mediastinal lymph node at resection; chest x-ray or computed tomography scan ≤ 8 weeks before registration without sign of new or recurrent lung cancer; no concurrent cancers or any other prior cancer history within the past 5 years, except localized nonmelanoma skin cancer; no synchronous lesions (lung + nonlung) or metastasis, even if resectable; no history of greater than one lung cancer primary tumor at any time; normal hepatic function (total bilirubin and Aspartat-Aminotransferase or Alanin-Aminotransferase ≤ institutional upper limit of normal); laboratory values (incl. Complete Blood Count) obtained within 8 weeks before registration; and Eastern Cooperative Oncology Group performance status of 0 or 1.

Patients with stage IA Non-Small Cell Lung Cancer should not have received any therapy other than surgery. Patients with stage IB Non-Small Cell Lung Cancer were allowed to have received other primary therapy (chemotherapy, radiotherapy, or biologic therapy) provided this was completed at least 6 months before study registration and all treatment-related symptoms had subsided before study registration.

Supplements were defined as any nonfood compound taken by mouth or injection to provide dietary factors. Supplements containing ≥ 70 µg of selenium taken regularly (≥ three times per week for ≥ 4 consecutive weeks during the prior year) were required to be discontinued ≥ 1 month before registration. Supplements containing ≤ 70 µg of selenium were continued throughout study participation. Supplements not containing selenium were either discontinued ≥ 2 weeks before study entry or continued throughout study participation.
|Exclusion criteria=NI
|N randomized=1561
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=Study period: October 6, 2000 - November 5, 2009
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage
|Cancer stage specification=IA (pT1N0) or IB (pT2N0)
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Mixed
|Gender specifications=Female: intervention arm 51%, placebo arm 52%
|Age groups=Adults (18+)
|Age groups specification=Age (median): 66 years; range: intervention arm 24-94 years; placebo arm 38-86 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=1040
|Drop-out=N=817
|Drop-out reasons=Ineligible (n = 10);
No therapy (n = 12)

Discontinued treatment:
Completed (n = 238);
Progression (n = 117);
Toxicity (n = 20);
Death (n = 18);
Withdrawal (n = 157);
Nonprotocol treatment (n = 1);
Complicating disease (n = 30);
Maximum dose (n = 2);
Other (n = 212)
|Intervention=Selenium
|Dosage and regime=200 µg daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=26 in intervention arm had a diabetes diagnosis
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=521
|Drop-out=N=406
|Drop-out reasons=Ineligible (n = 6);
No therapy (n = 2)

Discontinued treatment:
Completed (n = 134);
Progression (n = 52);
Toxicity (n = 8);
Death (n = 12);
Withdrawal (n = 67);
Nonprotocol treatment (n = 3);
Complicating disease (n = 17);
Other (n = 105)
|Intervention=Placebo
|Dosage and regime=Daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=12 in placebo arm had a diabetes diagnosis
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=DFS Randomization until secondary tumors or recurrence and 5-year DFS
|Type of measurement=Observation
|Results during intervention=During study: n=44 non-melanoma skin cancers, (n=14 and n=13 basal cell carcinoma and n=11 and n=6 squamous cell carcinoma in intervention and placebo arm), no significant values given
|Results after intervention=Interim analysis October 2009:
N=83 secondary lung tumors; Rate intervention arm: 1.91 per 100 persons per year vs. 1.36 in placebo arm; p=ns

June 2011:
N=252 secondary tumors in 224 patients, of which 98 (out of 97 patients) were lung cancer (38.9%); Lung cancer and other cancers (SPT) in intervention arm: 1.62 and 3.54 per 100 persons per year vs. placebo arm: 1.30 and 3.39 per 100 persons per year; p=0.294

5-year DFS:
October 2009:
Intervention arm: 72% vs. placebo arm: 78%, no significance values given

June 2011:
Intervention arm: 74.4% vs. placebo arm: 79.6%; p=0.69

Note: 5-year DFS rates with subdivision into low, average and high selenium concentration intervention vs. placebo: 75.5% (SE, 10.3%) vs. 72.9% (SE, 12.7%), 75.6% (SE, 2.27%) vs. 78.2% (SE, 3.3%), and 72.9% (SE, 4.5%) vs. 80.9% (SE, 5.2%)
|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=some concerns
|Overall RoB judgment=low risk
|Order number=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=5-year OS
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Intervention arm: 76.8% (SE, 1.6%) vs. placebo arm: 79.9% (SE, 2.1%); p=0.154

Note: Distribution significantly different for smoking status (p=0.027): active smokers or those who had quit within one year showed a 3-year OS of 85.5% (SE, 1.7%) and 5-year OS of 74.9% (SE, 2.4%), whereas participants who had never smoked showed a 3-year OS of 90% (SE, 2.8%) and a 5-year OS of 83.6% (SE, 3.6%); no difference for DFS; p=0.245
|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=some concerns
|Overall RoB judgment=low risk
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Collected in 865 patients in intervention arm and 477 in placebo arm:
* Grade 1-2 toxicity in intervention arm: 31% and placebo arm: 26% of subjects
* Grade ≥ 3 toxicity occurred in less than 2% of subjects in intervention arm and 3% in placebo arm
* n=1 patient in placebo arm had constitutional lethal toxicity
* no arm comparison performed
|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=some concerns
|Overall RoB judgment=low risk
|Order number=3
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Selenium level at baseline (n=1,022), year 2 (n=375), and year 4 (n=194): at baseline selenium level mostly in normal range, after 2 and 4 years significantly increased selenium concentration in the intervention arm
|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=some concerns
|Overall RoB judgment=low risk
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=According to authors none.
|Conflicts of Interest=“Employment or Leadership Position: None; Consultant or Advisory Role: David H. Johnson, Peloton Therapeutics (C), Mirna Therapeutics (C) Stock Ownership: None; Honoraria: None; research; Expert Testimony: None; Patents: None Other Remuneration: None“
}}
=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=No
|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=* Subjects could continue to take supplements that contained ≤70 µg selenium and also others that did not contain selenium
|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=NA
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=Note: Interim analysis in October 2009 (46% of endpoints reached with 1561 patients randomized), study was stopped by DMC on November 5, 2009 as a trend for a placebo arm benefit was found; June 2011 update with 54% of the endpoints

PRO:
* Prior testing of compliance in a 4-week phase and then testing every 3 months.
* Stratification by demographic variables.
* Power analysis conducted.
* Intent-to-treat analysis performed.
* Measurement of selenium concentration.
* Very detailed presentation of data.

CONTRA:
* Participants could continue taking supplements containing ≤70 µg of selenium and others containing no selenium.
* Subgroup analysis based on selenium concentration level but without significance values.
* No mention of ethics approval.
* Confusing description of DFS (disease-free survival).
* Figure 2b describes OS (overall survival) in days (typographical error).
* OS curves diverge significantly after approximately 7.5 years, but no explanation of these data is provided.
}}

Karp et al. (2012): Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597

2024-11-07T12:50:52Z

JDoerfler:

{{Reference
|Reference=Publication: Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597
}}

=Brief summary=
In this study, 1561 participants with resected non-small cell lung cancer were included. They were randomly divided into two arms and were each to take 200 µg of yeast selenium (1040 participants) or a placebo (521 participants) every day. However, the study was terminated early, as an interim analysis after a study period of around nine years showed that no benefit could be achieved for the selenium arm; instead, there was a positive trend for the placebo arm. In a final analysis another two years later, there were no significant differences in the incidence of secondary tumors, lung cancer or other cancer recurrence, time to recurrence or overall survival of the patients. However, it was shown that participants who had never smoked had a higher survival time after three and five years than those who were current smokers or had only quit in the last year. The study leaves out basic framework descriptions. A promising subgroup analysis between different selenium concentrations and their effects on the cancer-free time interval remains without statistical value and thus cannot be clearly interpreted.

In dieser Studie wurden 1561 Probanden mit reseziertem nicht-kleinzelligem Lungenkarzinom eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt und sollten jeweils jeden Tag 200 µg Hefeselen (1040 Probanden) oder ein Placebo (521 Probanden) zu sich nehmen. Die Studie wurde allerdings frühzeitig abgebrochen, da sich in einer Zwischenanalyse nach etwa neun Jahren Studienlaufzeit abzeichnete, dass kein Vorteil für die Selengruppe erzielt werden könne, stattdessen gab es einen positiven Trend für die Placebogruppe. In einer abschließenden Analyse weitere zwei Jahre später zeigten sich keine bedeutsamen Unterschiede bezüglich des Auftretens von sekundären Tumoren, Lungenkrebs oder sonstiger Rückkehr von Krebs, sowie der Zeit bis zur Rückkehr oder dem Gesamtüberleben der Patienten. Allerdings wurde gezeigt, dass Personen, die nie geraucht haben, eine höhere Überlebenszeit nach drei und fünf Jahren zeigten, als Probanden die aktuell rauchten, oder erst im letzten Jahr aufgehört hatten. Die Studie vernachlässigt grundlegende Rahmenbeschreibungen. Eine vielversprechende Subgruppenanalyse zwischen verschieden hohen Selenkonzentration und deren Auswirkungen auf das Krebsfreie-Zeitintervall bleibt ohne statistische Wertangabe und kann damit nicht eindeutig interpretiert werden.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=36 months from complete resection of histologically proven stage IA (pT1N0) or stage IB (pT2N0) NSCLC (carcinoid tumors were excluded); pathologic stage N0 confirmed by sampling at least one mediastinal lymph node at resection; chest x-ray or computed tomography scan ≤ 8 weeks before registration without sign of new or recurrent lung cancer; no concurrent cancers or any other prior cancer history within the past 5 years, except localized nonmelanoma skin cancer; no synchronous lesions (lung + nonlung) or metastasis, even if resectable; no history of greater than one lung cancer primary tumor at any time; normal hepatic function (total bilirubin and Aspartat-Aminotransferase or Alanin-Aminotransferase ≤ institutional upper limit of normal); laboratory values (incl. Complete Blood Count) obtained within 8 weeks before registration; and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients with stage IA Non-Small Cell Lung Cancer should not have received any therapy other than surgery. Patients with stage IB Non-Small Cell Lung Cancer were allowed to have received other primary therapy (chemotherapy, radiotherapy, or biologic therapy) provided this was completed at least 6 months before study registration and all treatment-related symptoms had subsided before study registration.

Supplements were defined as any nonfood compound taken by mouth or injection to provide dietary factors. Supplements containing ≥ 70 µg of selenium taken regularly (≥ three times per week for ≥ 4 consecutive weeks during the prior year) were required to be discontinued ≥ 1 month before registration. Supplements containing ≤ 70 µg of selenium were continued throughout study participation. Supplements not containing selenium were either discontinued ≥ 2 weeks before study entry or continued throughout study participation.
|Exclusion criteria=NI
|N randomized=1561
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=Study period: October 6, 2000 - November 5, 2009
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage
|Cancer stage specification=IA (pT1N0) or IB (pT2N0)
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Mixed
|Gender specifications=Female: intervention arm 51%, placebo arm 52%
|Age groups=Adults (18+)
|Age groups specification=Age (median): 66 years; range: intervention arm 24-94 years; placebo arm 38-86 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=1040
|Drop-out=N=817
|Drop-out reasons=Ineligible (n = 10);
No therapy (n = 12)

Discontinued treatment:
Completed (n = 238);
Progression (n = 117);
Toxicity (n = 20);
Death (n = 18);
Withdrawal (n = 157);
Nonprotocol treatment (n = 1);
Complicating disease (n = 30);
Maximum dose (n = 2);
Other (n = 212)
|Intervention=Selenium
|Dosage and regime=200 µg daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=26 in intervention arm had a diabetes diagnosis
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=521
|Drop-out=N=406
|Drop-out reasons=Ineligible (n = 6);
No therapy (n = 2)

Discontinued treatment:
Completed (n = 134);
Progression (n = 52);
Toxicity (n = 8);
Death (n = 12);
Withdrawal (n = 67);
Nonprotocol treatment (n = 3);
Complicating disease (n = 17);
Other (n = 105)
|Intervention=Placebo
|Dosage and regime=Daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=12 in placebo arm had a diabetes diagnosis
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=DFS Randomization until secondary tumors or recurrence and 5-year DFS
|Type of measurement=Observation
|Results during intervention=During study: n=44 non-melanoma skin cancers, (n=14 and n=13 basal cell carcinoma and n=11 and n=6 squamous cell carcinoma in intervention and placebo arm), no significant values given
|Results after intervention=Interim analysis October 2009:
N=83 secondary lung tumors; Rate intervention arm: 1.91 per 100 persons per year vs. 1.36 in placebo arm; p=ns

June 2011:
N=252 secondary tumors in 224 patients, of which 98 (out of 97 patients) were lung cancer (38.9%); Lung cancer and other cancers (SPT) in intervention arm: 1.62 and 3.54 per 100 persons per year vs. placebo arm: 1.30 and 3.39 per 100 persons per year; p=0.294

5-year DFS:
October 2009:
Intervention arm: 72% vs. placebo arm: 78%, no significance values given

June 2011:
Intervention arm: 74.4% vs. placebo arm: 79.6%; p=0.69

Note: 5-year DFS rates with subdivision into low, average and high selenium concentration intervention vs. placebo: 75.5% (SE, 10.3%) vs. 72.9% (SE, 12.7%), 75.6% (SE, 2.27%) vs. 78.2% (SE, 3.3%), and 72.9% (SE, 4.5%) vs. 80.9% (SE, 5.2%)
|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=some concerns
|Overall RoB judgment=low risk
|Order number=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=5-year OS
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Intervention arm: 76.8% (SE, 1.6%) vs. placebo arm: 79.9% (SE, 2.1%); p=0.154

Note: Distribution significantly different for smoking status (p=0.027): active smokers or those who had quit within one year showed a 3-year OS of 85.5% (SE, 1.7%) and 5-year OS of 74.9% (SE, 2.4%), whereas participants who had never smoked showed a 3-year OS of 90% (SE, 2.8%) and a 5-year OS of 83.6% (SE, 3.6%); no difference for DFS; p=0.245
|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=some concerns
|Overall RoB judgment=low risk
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Collected in 865 patients in intervention arm and 477 in placebo arm:
* Grade 1-2 toxicity in intervention arm: 31% and placebo arm: 26% of subjects
* Grade ≥ 3 toxicity occurred in less than 2% of subjects in intervention arm and 3% in placebo arm
* n=1 patient in placebo arm had constitutional lethal toxicity
* no arm comparison performed
|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=some concerns
|Overall RoB judgment=low risk
|Order number=3
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Selenium level at baseline (n=1,022), year 2 (n=375), and year 4 (n=194): at baseline selenium level mostly in normal range, after 2 and 4 years significantly increased selenium concentration in the intervention arm
|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=some concerns
|Overall RoB judgment=low risk
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=According to authors none.
|Conflicts of Interest=“Employment or Leadership Position: None; Consultant or Advisory Role: David H. Johnson, Peloton Therapeutics (C), Mirna Therapeutics (C) Stock Ownership: None; Honoraria: None; research; Expert Testimony: None; Patents: None Other Remuneration: None“
}}
=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=No
|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=* Subjects could continue to take supplements that contained ≤70 µg selenium and also others that did not contain selenium
|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=NA
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=Note: Interim analysis in October 2009 (46% of endpoints reached with 1561 patients randomized), study was stopped by DMC on November 5, 2009 as a trend for a placebo arm benefit was found; June 2011 update with 54% of the endpoints

PRO:
* Prior testing of compliance in a 4-week phase and then testing every 3 months.
* Stratification by demographic variables.
* Power analysis conducted.
* Intent-to-treat analysis performed.
* Measurement of selenium concentration.
* Very detailed presentation of data.

CONTRA:
* Participants could continue taking supplements containing ≤70 µg of selenium and others containing no selenium.
* Subgroup analysis based on selenium concentration level but without significance values.
* No mention of ethics approval.
* Confusing description of DFS (disease-free survival).
* Figure 2b describes OS (overall survival) in days (typographical error).
* OS curves diverge significantly after approximately 7.5 years, but no explanation of these data is provided.
}}

Karp et al. (2012): Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597

2024-11-07T12:50:17Z

JDoerfler:

{{Reference
|Reference=Publication: Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597
}}
{{Study Note}}
=Brief summary=
In this study, 1561 participants with resected non-small cell lung cancer were included. They were randomly divided into two arms and were each to take 200 µg of yeast selenium (1040 participants) or a placebo (521 participants) every day. However, the study was terminated early, as an interim analysis after a study period of around nine years showed that no benefit could be achieved for the selenium arm; instead, there was a positive trend for the placebo arm. In a final analysis another two years later, there were no significant differences in the incidence of secondary tumors, lung cancer or other cancer recurrence, time to recurrence or overall survival of the patients. However, it was shown that participants who had never smoked had a higher survival time after three and five years than those who were current smokers or had only quit in the last year. The study leaves out basic framework descriptions. A promising subgroup analysis between different selenium concentrations and their effects on the cancer-free time interval remains without statistical value and thus cannot be clearly interpreted.

In dieser Studie wurden 1561 Probanden mit reseziertem nicht-kleinzelligem Lungenkarzinom eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt und sollten jeweils jeden Tag 200 µg Hefeselen (1040 Probanden) oder ein Placebo (521 Probanden) zu sich nehmen. Die Studie wurde allerdings frühzeitig abgebrochen, da sich in einer Zwischenanalyse nach etwa neun Jahren Studienlaufzeit abzeichnete, dass kein Vorteil für die Selengruppe erzielt werden könne, stattdessen gab es einen positiven Trend für die Placebogruppe. In einer abschließenden Analyse weitere zwei Jahre später zeigten sich keine bedeutsamen Unterschiede bezüglich des Auftretens von sekundären Tumoren, Lungenkrebs oder sonstiger Rückkehr von Krebs, sowie der Zeit bis zur Rückkehr oder dem Gesamtüberleben der Patienten. Allerdings wurde gezeigt, dass Personen, die nie geraucht haben, eine höhere Überlebenszeit nach drei und fünf Jahren zeigten, als Probanden die aktuell rauchten, oder erst im letzten Jahr aufgehört hatten. Die Studie vernachlässigt grundlegende Rahmenbeschreibungen. Eine vielversprechende Subgruppenanalyse zwischen verschieden hohen Selenkonzentration und deren Auswirkungen auf das Krebsfreie-Zeitintervall bleibt ohne statistische Wertangabe und kann damit nicht eindeutig interpretiert werden.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=36 months from complete resection of histologically proven stage IA (pT1N0) or stage IB (pT2N0) NSCLC (carcinoid tumors were excluded); pathologic stage N0 confirmed by sampling at least one mediastinal lymph node at resection; chest x-ray or computed tomography scan ≤ 8 weeks before registration without sign of new or recurrent lung cancer; no concurrent cancers or any other prior cancer history within the past 5 years, except localized nonmelanoma skin cancer; no synchronous lesions (lung + nonlung) or metastasis, even if resectable; no history of greater than one lung cancer primary tumor at any time; normal hepatic function (total bilirubin and Aspartat-Aminotransferase or Alanin-Aminotransferase ≤ institutional upper limit of normal); laboratory values (including Complete Blood Count) obtained within 8 weeks before registration; and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients with stage IA Non-Small Cell Lung Cancer should not have received any therapy other than surgery. Patients with stage IB Non-Small Cell Lung Cancer were allowed to have received other primary therapy (chemotherapy, radiotherapy, or biologic therapy) provided this was completed at least 6 months before study registration and all treatment-related symptoms had subsided before study registration.

Supplements were defined as any nonfood compound taken by mouth or injection to provide dietary factors. Supplements containing ≥ 70 µg of selenium taken regularly (≥ three times per week for ≥ 4 consecutive weeks during the prior year) were required to be discontinued ≥ 1 month before registration. Supplements containing ≤ 70 µg of selenium were continued throughout study participation. Supplements not containing selenium were either discontinued ≥ 2 weeks before study entry or continued throughout study participation.
|Exclusion criteria=NI
|N randomized=1561
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=Study period: October 6, 2000 - November 5, 2009
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage
|Cancer stage specification=IA (pT1N0) or IB (pT2N0)
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Mixed
|Gender specifications=Female: intervention arm 51%, placebo arm 52%
|Age groups=Adults (18+)
|Age groups specification=Age (median): 66 years; range: intervention arm 24-94 years; placebo arm 38-86 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=1040
|Drop-out=N=817
|Drop-out reasons=Ineligible (n = 10);
No therapy (n = 12)

Discontinued treatment:
Completed (n = 238);
Progression (n = 117);
Toxicity (n = 20);
Death (n = 18);
Withdrawal (n = 157);
Nonprotocol treatment (n = 1);
Complicating disease (n = 30);
Maximum dose (n = 2);
Other (n = 212)
|Intervention=Selenium
|Dosage and regime=200 µg daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=26 in intervention arm had a diabetes diagnosis
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=521
|Drop-out=N=406
|Drop-out reasons=Ineligible (n = 6);
No therapy (n = 2)

Discontinued treatment:
Completed (n = 134);
Progression (n = 52);
Toxicity (n = 8);
Death (n = 12);
Withdrawal (n = 67);
Nonprotocol treatment (n = 3);
Complicating disease (n = 17);
Other (n = 105)
|Intervention=Placebo
|Dosage and regime=Daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=12 in placebo arm had a diabetes diagnosis
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=DFS Randomization until secondary tumors or recurrence and 5-year DFS
|Type of measurement=Observation
|Results during intervention=During study: n=44 non-melanoma skin cancers, (n=14 and n=13 basal cell carcinoma and n=11 and n=6 squamous cell carcinoma in intervention and placebo arm), no significant values given
|Results after intervention=Interim analysis October 2009:
N=83 secondary lung tumors; Rate intervention arm: 1.91 per 100 persons per year vs. 1.36 in placebo arm; p=ns

June 2011:
N=252 secondary tumors in 224 patients, of which 98 (out of 97 patients) were lung cancer (38.9%); Lung cancer and other cancers (SPT) in intervention arm: 1.62 and 3.54 per 100 persons per year vs. placebo arm: 1.30 and 3.39 per 100 persons per year; p=0.294

5-year DFS:
October 2009:
Intervention arm: 72% vs. placebo arm: 78%, no significance values given

June 2011:
Intervention arm: 74.4% vs. placebo arm: 79.6%; p=0.69

Note: 5-year DFS rates with subdivision into low, average and high selenium concentration intervention vs. placebo: 75.5% (SE, 10.3%) vs. 72.9% (SE, 12.7%), 75.6% (SE, 2.27%) vs. 78.2% (SE, 3.3%), and 72.9% (SE, 4.5%) vs. 80.9% (SE, 5.2%)
|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=some concerns
|Overall RoB judgment=low risk
|Order number=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=5-year OS
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Intervention arm: 76.8% (SE, 1.6%) vs. placebo arm: 79.9% (SE, 2.1%); p=0.154

Note: Distribution significantly different for smoking status (p=0.027): active smokers or those who had quit within one year showed a 3-year OS of 85.5% (SE, 1.7%) and 5-year OS of 74.9% (SE, 2.4%), whereas participants who had never smoked showed a 3-year OS of 90% (SE, 2.8%) and a 5-year OS of 83.6% (SE, 3.6%); no difference for DFS; p=0.245
|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=some concerns
|Overall RoB judgment=low risk
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Collected in 865 patients in intervention arm and 477 in placebo arm:
* Grade 1-2 toxicity in intervention arm: 31% and placebo arm: 26% of subjects
* Grade ≥ 3 toxicity occurred in less than 2% of subjects in intervention arm and 3% in placebo arm
* n=1 patient in placebo arm had constitutional lethal toxicity
* no arm comparison performed
|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=some concerns
|Overall RoB judgment=low risk
|Order number=3
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Selenium level at baseline (n=1,022), year 2 (n=375), and year 4 (n=194): at baseline selenium level mostly in normal range, after 2 and 4 years significantly increased selenium concentration in the intervention arm
|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=some concerns
|Overall RoB judgment=low risk
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=According to authors none.
|Conflicts of Interest=“Employment or Leadership Position: None; Consultant or Advisory Role: David H. Johnson, Peloton Therapeutics (C), Mirna Therapeutics (C) Stock Ownership: None; Honoraria: None; research; Expert Testimony: None; Patents: None Other Remuneration: None“
}}
=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=No
|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=* Subjects could continue to take supplements that contained ≤70 µg selenium and also others that did not contain selenium
|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=NA
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=Note: Interim analysis in October 2009 (46% of endpoints reached with 1561 patients randomized), study was stopped by DMC on November 5, 2009 as a trend for a placebo arm benefit was found; June 2011 update with 54% of the endpoints

PRO:
* Prior testing of compliance in a 4-week phase and then testing every 3 months.
* Stratification by demographic variables.
* Power analysis conducted.
* Intent-to-treat analysis performed.
* Measurement of selenium concentration.
* Very detailed presentation of data.

CONTRA:
* Participants could continue taking supplements containing ≤70 µg of selenium and others containing no selenium.
* Subgroup analysis based on selenium concentration level but without significance values.
* No mention of ethics approval.
* Confusing description of DFS (disease-free survival).
* Figure 2b describes OS (overall survival) in days (typographical error).
* OS curves diverge significantly after approximately 7.5 years, but no explanation of these data is provided.
}}

Azizi et al. (2015): Efficacy of Topical and Systemic Vitamin E in Preventing Chemotherapy-induced Oral Mucositis

2024-11-07T12:29:41Z

JDoerfler:

{{Reference
|Reference=Publication: Efficacy of Topical and Systemic Vitamin E in Preventing Chemotherapy-induced Oral Mucositis
}}
{{Study Note}}
=Brief summary=
This study investigated the efficacy of vitamin E in preventing oral mucositis (i.e. inflammation of the oral mucosa, a common side effect of chemotherapy) in patients with hematologic cancers such as leukemia and lymphoma. The patients were divided into three different arms, one of which coated the mouth twice daily with a vitamin E paste (arm A), one arm took a vitamin E tablet twice daily (arm B) and the control arm received a placebo paste (arm C). While there were no differences in the number of patients with severe mucositis after the first and second chemotherapy cycles, there were significantly fewer patients in arm A than in the other two arms after the third and fourth cycles. Comparable results were seen in the patients' self-assessment of pain. Here, too, the patients reported comparable pain in the first two cycles and in the other two cycles the pain in arm A was felt to be less than in the other two arms. There are numerous criticisms of this study. Among other things, only a very small sample with a high drop-out rate over the course of the study was examined. In addition, this study lacks numerous details, such as the values of the variables examined at the start of the study and other important demographic variables.

Diese Studie untersuchte die Wirksamkeit von Vitamin E bei der Vorbeugung von oraler Mukositis (d. h. Entzündung der Mundschleimhaut, eine häufige Nebenwirkung der Chemotherapie) bei Patienten mit hämatologischen Krebsarten wie Leukämie und Lymphomen. Die Patienten wurden in drei verschiedene Arme eingeteilt, von denen einer den Mund zweimal täglich mit einer Vitamin-E-Paste bestrich (Arm A), ein Arm nahm zweimal täglich eine Vitamin-E-Tablette ein (Arm B) und der Kontrollarm erhielt eine Placebopaste (Arm C). Während es nach dem ersten und zweiten Chemotherapiezyklus keine Unterschiede in der Zahl der Patienten mit schwerer Mukositis gab, waren es nach dem dritten und vierten Zyklus deutlich weniger Patienten in Arm A als in den beiden anderen Armen. Vergleichbare Ergebnisse ergaben sich bei der Selbsteinschätzung der Patienten bezüglich ihrer Schmerzen. Auch hier gaben die Patienten in den ersten beiden Zyklen vergleichbare Schmerzen an, in den beiden anderen Zyklen wurden die Schmerzen in Arm A als geringer empfunden als in den beiden anderen Armen. Es gibt zahlreiche Kritikpunkte an dieser Studie. Unter anderem wurde nur eine sehr kleine Stichprobe mit einer hohen Abbrecherquote im Verlauf der Studie untersucht. Außerdem fehlen in dieser Studie zahlreiche Details, wie z. B. die Werte der untersuchten Variablen zu Beginn der Studie und andere wichtige demografische Variablen.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=At least 18 years of age, diagnosis of a hematologic cancer (leukemia or lymphoma), and non-smoker and non-alcoholic.
|Exclusion criteria=Patients who were supposed to receive head and neck radiotherapy as part of their treatment, patients who were taking anticoagulant therapy, as some studies have shown that vitamin E may increase the bleeding tendency.
|N randomized=76
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline
T1: after first cycle
T2: after second cycle
T3: after third cycle
T4: after fourth cycle
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid), Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin)
|Stage cancer=NA
|Cancer stage specification=NA
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=46% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) = 30.72 (8.41) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=26
|Drop-out=7 (3 after third cycle, 4 after fourth cycle)
|Drop-out reasons=Various reasons (death, severe mucositis, noncompliance, etc.)
|Intervention=Vitamin E paste
|Dosage and regime=1g; 2x daily

Duration: day -2 chemotherapy until 20 days after the end of the chemotherapy cycle for 4 chemotherapy cycles
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=24
|Drop-out=8 (3 after third cycle, 5 after fourth cycle)
|Drop-out reasons=Various reasons (death, severe mucositis, noncompliance, etc.)
|Intervention=Vitamin E tablets
|Dosage and regime=oral, 200mg, 2x daily

Duration: day -2 chemotherapy until 20 days after the end of the chemotherapy cycle for 4 chemotherapy cycles
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=26
|Drop-out=12 (4 after third cycle, 8 after fourth cycle)
|Drop-out reasons=Various reasons (death, severe mucositis, noncompliance, etc.)
|Intervention=Placebo paste
|Dosage and regime=1g; 2x daily

Duration: day -2 chemotherapy until 20 days after the end of the chemotherapy cycle for 4 chemotherapy cycles
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=3
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Oral mucositis
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Number in % with grade 3-4

After 1st cycle
intervention arm (paste): 7.6, intervention arm (tablets): 8.3, placebo arm: 7.6; p = ns

After 2nd cycle
intervention arm (paste): 11.5, intervention arm (tablets): 12.5, placebo arm: 15.3; p = ns

After 3rd cycle
intervention arm (paste): 21.7, intervention arm (tablets): 33.3, placebo arm: 31.8; p = 0.01
|Results after intervention=Number in % with grade 3-4

After 4th cycle
intervention arm (paste): 26.3, intervention arm (tablets): 43.7, placebo arm: 42.8; p = 0.01
|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=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=NA
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=Mean value

After the 1st cycle
Intervention arm (paste): 1.2, intervention arm (tablets): 1.3, placebo arm: 1; p = ns

After 2nd cycle
Intervention arm (paste): 2, intervention arm (tablets): 1.9, placebo arm: 2.2; p = ns

After 3rd cycle
Intervention arm (paste): 2.43, intervention arm (tablets): 3.8, placebo arm: 4.4; p = 0.05
|Results after intervention=Mean value

After 4th cycle
Intervention arm (paste): 2.9, intervention arm (tablets): 4.33, placebo arm: 4.86; p = 0.001
|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=NI
|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=?
|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:
* Blinding of investigators.

CONTRA:
* Unclear randomization.
* No blinding of patients.
* Small sample size without power analysis.
* Very high dropout rate (after the fourth CTX cycle: Vitamin E paste: 27%, Vitamin E oral: 33%, Placebo: 46%).
* No information on compliance.
* Multiple testing without time-based models.
* Poor reporting quality (e.g., no information on cancer types or stages, no standard deviations or 95% confidence intervals, no baseline values of the variables studied).
}}

Büntzel et al. (2010): Selenium Substitution During Radiotherapy of Solid Tumours - Laboratory Data from Two Observation Studies in Gynaecological and Head and Neck Cancer Patients

2024-11-07T07:53:57Z

JDoerfler:

{{Reference
|Reference=Publication: Selenium Substitution During Radiotherapy of Solid Tumours Laboratory Data from Two Observation Studies in Gynaecological and Head and Neck Cancer Patients
}}
{{Study Note
|Study Note=This study includes the samples of 2 studies ([[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]], [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]]), reporting the outcome of change in selenium concentration in the blood as a result of selenium administration.
}}
=Brief summary=
This study includes the samples of two studies, each with a sample of head and neck patients [[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]] or gynecological cancer patients [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] who were randomly divided into two arms and received or did not receive additional selenium during the period of radiotherapy. All subjects had a proven selenium deficiency. This study served only to demonstrate the change in selenium concentration in the blood as a result of selenium administration. Both arms had comparable selenium levels at the beginning of the study. There was a significantly higher selenium concentration in the blood of the arm that received selenium halfway through radiotherapy (around week four) and at the end of radiotherapy. This difference was no longer significant six weeks after radiotherapy. This study can be seen more as an addition to the two studies by Büntzel et al. (2008) and Mücke et al. (2008) than as an independent study. Very little marginal information is given here about the patients or the course of treatment and no details are given about the drop-outs that obviously took place.

Diese Studie umfasst die Stichproben von zwei Studien mit jeweils einer Stichprobe von Hals-Nasen-Kopf Tumorpatienten [[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]] oder gynäkologischen Krebspatienten [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]], welche zufällig in zwei Gruppen eingeteilt wurden und während der Zeit der Radiotherapie zusätzlich Selen erhielten oder nicht. Alle Probanden hatten ein nachgewiesenes Selendefizit. Diese Studie diente nur zur Darstellung der Veränderung der Selenkonzentration im Blut durch die Selengabe. Beide Gruppen hatten zu Beginn der Studie einen vergleichbaren Selenspiegel. Es zeigte sich jeweils zur Hälfte der Radiotherapie (etwa vierte Woche) und zu dessen Ende eine bedeutsam höhere Selenkonzentration im Blut der Gruppe welche Selen erhalten hatten. Dieser Unterschied war sechs Wochen nach der Radiotherapie nicht mehr bedeutsam. Diese Studie kann eher als Zusatz zu den beiden Studien von Büntzel et al. (2008) und Mücke et al. (2008) gesehen werden, als eine eigenständige Studie. Es wird hier sehr wenig Randinformation zu den Patienten oder den Ablauf der Behandlung gegeben und es werden keine Angaben zu den offensichtlich stattgefundenen Drop-Outs gemacht.

=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=Patients suffering from gynaecological or head and neck cancer who were irradiated because of their disease
|Exclusion criteria=NI
|N randomized=128
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=Germany
|LoE=2b Oxford 2009
|Outcome timeline=Selenium concentration measured at baseline, after 4 weeks, after the end of radiotherapy and 6 weeks after the end of radiotherapy

Overall duration: 7 weeks of radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Gynecologic Cancers, Head and Neck Cancers
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Head and Neck cancer - Advanced Stage
Gynecologic cancer - FIGO Stadium I-IV
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=NI
|Age groups=Adults (18+)
|Age groups specification=Mean(SD)

Intervention arm: 63.83(9.2) years

Control arm: 63.03(10.5) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=63
|Drop-out=Not seperated by arm n=7
|Drop-out reasons=NI
|Intervention=Sodium selenite
|Dosage and regime=500µg sodium selenite 2 days before the start of radiotherapy and on days with radiotherapy; and 300 µg sodium selenite on days without radiotherapy (weekends and vacations), orally as a liquid 1 hour before radiotherapy
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=-999
|Drop-out=Not seperated by arm n=7
|Drop-out reasons=NI
|Intervention=Usual Care
|Dosage and regime=NA
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Selenium level
|Outcome specification=Serum concentration and whole blood concentration
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=At baseline no significant differences;

Significant differences in selenium concentrations (serum and blood) at half of radiotherapy (p<0.0001)
|Results after intervention=At 6 weeks after irradiation no significant differences;

Significant differences in selenium concentrations (serum and blood) at the end of radiotherapy (p<0.0001)
|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
}}

{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained.

CONTRA:
* Arm comparability tested only for age.
* No demographic information provided.
* No information on the dropout of 7 participants.
* Few conditions given.
}}

Büntzel et al. (2010): Selenium Substitution During Radiotherapy of Solid Tumours - Laboratory Data from Two Observation Studies in Gynaecological and Head and Neck Cancer Patients

2024-11-07T07:53:26Z

JDoerfler:

{{Reference
|Reference=Publication: Selenium Substitution During Radiotherapy of Solid Tumours Laboratory Data from Two Observation Studies in Gynaecological and Head and Neck Cancer Patients
}}
{{Study Note
|Study Note=This study includes the samples of 2 studies ([[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]], [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]]), reporting the outcome of change in selenium concentration in the blood as a result of selenium administration.
}}
=Brief summary=
This study includes the samples of two studies, each with a sample of head and neck patients [[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]] or gynecological cancer patients [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] who were randomly divided into two arms and received or did not receive additional selenium during the period of radiotherapy. All subjects had a proven selenium deficiency. This study served only to demonstrate the change in selenium concentration in the blood as a result of selenium administration. Both arms had comparable selenium levels at the beginning of the study. There was a significantly higher selenium concentration in the blood of the arm that received selenium halfway through radiotherapy (around week four) and at the end of radiotherapy. This difference was no longer significant six weeks after radiotherapy. This study can be seen more as an addition to the two studies by Büntzel et al. (2008) and Mücke et al. (2008) than as an independent study. Very little marginal information is given here about the patients or the course of treatment and no details are given about the drop-outs that obviously took place.

Diese Studie umfasst die Stichproben von zwei Studien mit jeweils einer Stichprobe von Hals-Nasen-Kopf Tumorpatienten [[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]] oder gynäkologischen Krebspatienten [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]], welche zufällig in zwei Gruppen eingeteilt wurden und während der Zeit der Radiotherapie zusätzlich Selen erhielten oder nicht. Alle Probanden hatten ein nachgewiesenes Selendefizit. Diese Studie diente nur zur Darstellung der Veränderung der Selenkonzentration im Blut durch die Selengabe. Beide Gruppen hatten zu Beginn der Studie einen vergleichbaren Selenspiegel. Es zeigte sich jeweils zur Hälfte der Radiotherapie (etwa vierte Woche) und zu dessen Ende eine bedeutsam höhere Selenkonzentration im Blut der Gruppe welche Selen erhalten hatten. Dieser Unterschied war sechs Wochen nach der Radiotherapie nicht mehr bedeutsam. Diese Studie kann eher als Zusatz zu den beiden Studien von Büntzel et al. (2008) und Mücke et al. (2008) gesehen werden, als eine eigenständige Studie. Es wird hier sehr wenig Randinformation zu den Patienten oder den Ablauf der Behandlung gegeben und es werden keine Angaben zu den offensichtlich stattgefundenen Drop-Outs gemacht.

=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=Patients suffering from gynaecological or head and neck cancer who were irradiated because of their disease
|Exclusion criteria=NI
|N randomized=128
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=Germany
|LoE=2b Oxford 2009
|Outcome timeline=Selenium concentration measured at baseline, after 4 weeks, after the end of radiotherapy and 6 weeks after the end of radiotherapy

Overall duration: 7 weeks of radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Gynecologic Cancers, Head and Neck Cancers
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Head and Neck cancer - Advanced Stage
Gynecologic cancer - FIGO Stadium I-IV
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=NI
|Age groups=Adults (18+)
|Age groups specification=Mean(SD)

Intervention arm: 63.83(9.2) years

Control arm: 63.03(10.5) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=63
|Drop-out=Not seperated by arm n=7
|Drop-out reasons=NI
|Intervention=Sodium selenite
|Dosage and regime=500µg sodium selenite 2 days before the start of radiotherapy and on days with radiotherapy; and 300 µg sodium selenite on days without radiotherapy (weekends and vacations), orally as a liquid 1 hour before radiotherapy
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=-999
|Drop-out=Not seperated by arm n=7
|Drop-out reasons=NI
|Intervention=Usual Care
|Dosage and regime=NA
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Selenium level
|Outcome specification=Serum concentration and whole blood concentration
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=At baseline no significant differences;

Significant differences in selenium concentrations (serum and blood) at half of radiotherapy (p<0.0001)
|Results after intervention=At 6 weeks after irradiation no significant differences;

Significant differences in selenium concentrations (serum and blood) at the end of radiotherapy (p<0.0001)
|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=?
|Sample size corresponds to power analysis=NA
|Reasons given for samples being too small according to power analysis=ag
|Samples sufficiently large=NA
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=s
|Possibility of placebo effects=d
|Other reasons=sdg
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=NA
|Measurement of compliance=NA
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=NA
|Were side effects systematically recorded=NA
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=?
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained.

CONTRA:
* Arm comparability tested only for age.
* No demographic information provided.
* No information on the dropout of 7 participants.
* Few conditions given.
}}

Laali et al. (2020): Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer

2024-11-07T07:47:22Z

JDoerfler:

{{Reference
|Reference=Publication: Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer
}}

=Brief summary=
In this study, 84 patients with pre-existing head and neck tumours were included. These patients were randomly divided into two arms. One arm (37 patients) received 400 micrograms of selenium daily while the other arm (34 patients) received placebo tablets. Both arms received the regular combined radiochemotherapy in addition to the tablets. The occurrence of inflammation of the oral mucosa, which is a common side effect of radiochemotherapy, was investigated. For this purpose, both the blood selenium level and the current condition of the oral mucosa were recorded at the beginning of the study. While taking the tablets, the oral cavity was examined weekly and the degree of inflammation of the mucous membranes was assessed. No significant difference was found between the two arms with regard to the occurrence of oral mucosal inflammation. No differences between the selenium levels of the two arms were found at the end of the study either. Overall, the study had a small number of participants and the number of patients included in the final analysis is not clearly presented.

In dieser Studie wurden 84 Patienten mit bereits bestehenden Kopf-Hals-Tumoren eingeschlossen. Diese Patienten wurden zufällig in zwei Gruppen eingeteilt. Die eine Gruppe (37 Patienten) erhielt täglich 400 Mikrogramm Selen während die andere Gruppe (34 Patienten) Placebotabletten bekam. Beide Gruppen erhielten neben den Tabletten die reguläre kombinierte Radiochemotherapie. Untersucht wurde das Auftreten von Entzündungen der Mundschleimhaut, welche eine häufige Nebenwirkung der Radiochemotherapie darstellt. Dazu wurden am Anfang der Studie sowohl der Blutselenspiegel als auch der aktuelle Zustand der Mundschleimhäute erhoben. Während der Einnahme der Tabletten wurde wöchentlich die Mundhöhle untersucht und der Grad der Schleimhautentzündung eingeschätzt. Es konnte kein bedeutsamer Unterschied zwischen den beiden Gruppen festgestellt werden, was das Auftreten von Mundschleimhautentzündungen betrifft. Auch konnten am Ende der Studie keine Unterschiede zwischen den Selenspiegeln der beiden Gruppen festgestellt werden. Die Studie hat insgesamt eine geringe Teilnehmeranzahl und die Anzahl der Patienten, die am Ende in die Analyse eingeschlossen wurden ist nicht nachvollziehbar dargestellt.

=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 with head and neck cancer, who were due to receive radiation on at least two-thirds of the oral cavity; aged 18-85 years with a normal renal function (creatinine clearence > 60ml/min) and an acceptable performance status (Karnofsky performance status > 70%) without any history of radiotherapy were eligible for this study
|Exclusion criteria=NI
|N randomized=84
|Analysis=PP Analysis
|Specifications on analyses=Occurrence, duration and severity of oral mucositis (WHO: grade 0-4, weekly check of oral status during radiotherapy, then monthly by doctor and an author);
log rank analysis
|Countries of data collection=Iran
|LoE=Level 2 Oxford 2011
|Outcome timeline=Oral mucositis
T0: Baseline

Follow up: weekly for 7 weeks

Selenium level

T0: Baseline

T1: End of radiation
}}
=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=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=* Radiation therapy: 5 fractions per week at 60-70 Gy cumulative doses over 6 weeks to 7 weeks
* Chemotherapy: 18 (48.6%) patients from the selenium and 16 (47.1%) from the placebo arm with cisplatin (30-50mg/m2 weekly, during radiation)
* Grade of neutropenia and renal failure was evaluated based on the NCI CTCAE
* Creatinine level increase of > 0.3 mg/dL or 1.5–2.0 mg/dL above baselinewas considered as renal failure and a neutrophil count decrease to 1000–500 mm3 was considered as grade 3 of this toxicity
* After 7 weeks no differencences in the incidence of other adverse effects related to chemoradiation such as neutropenia and renal failure in the selenium arm and the placebo arm
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Male n(%) per arm:
Selenium arm: 25 (67.9), placebo arm: 25 (73.5)

Female n(%) per arm:
Selenium arm: 12 (32.1), placebo arm: 9 (26.5)
|Age groups=Adults (18+)
|Age groups specification=Age in years, mean (min-max) per arm:
Selenium arm: 52.14 (22-81), placebo arm: 54.74 (18-81)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=42
|Drop-out=9
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=1
Lost to follow-up: discontinued tablets (n=1); discontinued radiation due to individual preferences: n=4

Inconsistencies in the number of drop-outs in the selenium arm: flowchart reports analyzed n=33 from n=42, but only reports drop-out reasons for n=6 (reasons missing n=3); table of baseline characteristics reports data of n=37
|Intervention=Selenium
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
|Dosage and regime=2x 200 mcg tablets of selenium (Webber Naturals, Coquitlam, BC, Canada) daily from the first day until the end of radiation (including days without radiation exposure)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=42
|Drop-out=8
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=4
Lost to follow-up: discontinued radiation due to individual preferences: n=4
|Intervention=Placebo
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
|Dosage and regime=2x placebo tablets daily from the first day until the end of radiation (including days without radiation exposure)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Mucositis
|Outcome specification=Inflammation of the oral mucosa (mucositis) due to radiotherapy

Grade of oral mucositis (WHO Toxicity Scale):

grade 0 = normal, no oral mucosits;

grade 1 = soreness and erythema;

grade 2 = erythema, ulcers, can eat solids;

grade 3 = ulcers, requires liquid diet only;

grade 4 = alimentation not possible

The assessments were performed by an assigned oral medicine specialist and one author, who were both blind to arms
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Significant difference for incidence of severe mucositis at week 3: selenium arm 9.8% vs. placebo arm 42.0% (p=0.017)
|Results after intervention=After 7 weeks no significant differences between the selenium arm and the placebo arm for:
* mean duration of oral mucositis (grade 1–4) (p=0.27)
* onset of oral mucosits (p =0.31)
* recovery (day after radiation completion (p=0.80)
* cumulative incidence of oral mucusitis (grade 1–4) (p=0.79)

Severe oral mucositis (grade 3 or 4) was seen in 25 patients in the selenium arm and in 20 patients in the placebo arm.

Addition: Development of oral mucositis in patients with selenium levels >65 mcg/l significantly delayed from baseline (p=0.04, no further explanation given)
|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=some concerns
|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=high risk
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=NA
|Results after intervention=At the end of radiation (after 7 weeks) there was no difference in the mean serum selenium level between the selenium arm and placebo arm (p=0.24)

Based on the selenium level before radiation, developing severe oral mucositis was statistically significant postponed in patients who had selenium levels ≥ 65 mcg/L (p=0.04)
|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=No funding
|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=* Selenium levels in intervention arm were not significantly higher than in placebo arm after supplementation and selenium levels in placebo arm also increased over the course of the study
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=NI
|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=NA
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Power analysis conducted.
* Selenium levels measured at the beginning and end of radiotherapy.
* Adherence checked via self-report.

CONTRA:
* No intent-to-treat analysis conducted.
* Authors state baseline characteristics are comparable but do not provide statistical analysis.
* No explanation of how double-blinding was ensured.
* Unclear whose baseline values are reported—apparent discrepancy in patient numbers between intervention (34 patients evaluated) and placebo arm (37 patients' characteristics reported but only 33 evaluated according to flow diagram).
* Inconsistencies in patient numbers and dropout not clearly presented for the intervention arm.
* Small sample size.
* Selenium levels in the intervention arm were not significantly higher after supplementation compared to placebo, and selenium levels in the placebo arm increased during the study.
* Analyses in the results section are unclear and most are not reported in the methodology (post-hoc analyses).
* Results are presented without supporting tables or explanation of the analysis, making them difficult to interpret.
* Timeline of the study is unclear as it's uncertain when the values for "end of study" were taken—intervention was only 7 weeks but Kaplan-Meier curve is presented up to week 12.
}}

Laali et al. (2020): Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer

2024-11-07T07:47:12Z

JDoerfler:

{{Reference
|Reference=Publication: Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer
}}
{{Study Note}}
=Brief summary=
In this study, 84 patients with pre-existing head and neck tumours were included. These patients were randomly divided into two arms. One arm (37 patients) received 400 micrograms of selenium daily while the other arm (34 patients) received placebo tablets. Both arms received the regular combined radiochemotherapy in addition to the tablets. The occurrence of inflammation of the oral mucosa, which is a common side effect of radiochemotherapy, was investigated. For this purpose, both the blood selenium level and the current condition of the oral mucosa were recorded at the beginning of the study. While taking the tablets, the oral cavity was examined weekly and the degree of inflammation of the mucous membranes was assessed. No significant difference was found between the two arms with regard to the occurrence of oral mucosal inflammation. No differences between the selenium levels of the two arms were found at the end of the study either. Overall, the study had a small number of participants and the number of patients included in the final analysis is not clearly presented.

In dieser Studie wurden 84 Patienten mit bereits bestehenden Kopf-Hals-Tumoren eingeschlossen. Diese Patienten wurden zufällig in zwei Gruppen eingeteilt. Die eine Gruppe (37 Patienten) erhielt täglich 400 Mikrogramm Selen während die andere Gruppe (34 Patienten) Placebotabletten bekam. Beide Gruppen erhielten neben den Tabletten die reguläre kombinierte Radiochemotherapie. Untersucht wurde das Auftreten von Entzündungen der Mundschleimhaut, welche eine häufige Nebenwirkung der Radiochemotherapie darstellt. Dazu wurden am Anfang der Studie sowohl der Blutselenspiegel als auch der aktuelle Zustand der Mundschleimhäute erhoben. Während der Einnahme der Tabletten wurde wöchentlich die Mundhöhle untersucht und der Grad der Schleimhautentzündung eingeschätzt. Es konnte kein bedeutsamer Unterschied zwischen den beiden Gruppen festgestellt werden, was das Auftreten von Mundschleimhautentzündungen betrifft. Auch konnten am Ende der Studie keine Unterschiede zwischen den Selenspiegeln der beiden Gruppen festgestellt werden. Die Studie hat insgesamt eine geringe Teilnehmeranzahl und die Anzahl der Patienten, die am Ende in die Analyse eingeschlossen wurden ist nicht nachvollziehbar dargestellt.

=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 with head and neck cancer, who were due to receive radiation on at least two-thirds of the oral cavity; aged 18-85 years with a normal renal function (creatinine clearence > 60ml/min) and an acceptable performance status (Karnofsky performance status > 70%) without any history of radiotherapy were eligible for this study
|Exclusion criteria=NI
|N randomized=84
|Analysis=PP Analysis
|Specifications on analyses=Occurrence, duration and severity of oral mucositis (WHO: grade 0-4, weekly check of oral status during radiotherapy, then monthly by doctor and an author);
log rank analysis
|Countries of data collection=Iran
|LoE=Level 2 Oxford 2011
|Outcome timeline=Oral mucositis
T0: Baseline

Follow up: weekly for 7 weeks

Selenium level

T0: Baseline

T1: End of radiation
}}
=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=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=* Radiation therapy: 5 fractions per week at 60-70 Gy cumulative doses over 6 weeks to 7 weeks
* Chemotherapy: 18 (48.6%) patients from the selenium and 16 (47.1%) from the placebo arm with cisplatin (30-50mg/m2 weekly, during radiation)
* Grade of neutropenia and renal failure was evaluated based on the NCI CTCAE
* Creatinine level increase of > 0.3 mg/dL or 1.5–2.0 mg/dL above baselinewas considered as renal failure and a neutrophil count decrease to 1000–500 mm3 was considered as grade 3 of this toxicity
* After 7 weeks no differencences in the incidence of other adverse effects related to chemoradiation such as neutropenia and renal failure in the selenium arm and the placebo arm
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Male n(%) per arm:
Selenium arm: 25 (67.9), placebo arm: 25 (73.5)

Female n(%) per arm:
Selenium arm: 12 (32.1), placebo arm: 9 (26.5)
|Age groups=Adults (18+)
|Age groups specification=Age in years, mean (min-max) per arm:
Selenium arm: 52.14 (22-81), placebo arm: 54.74 (18-81)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=42
|Drop-out=9
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=1
Lost to follow-up: discontinued tablets (n=1); discontinued radiation due to individual preferences: n=4

Inconsistencies in the number of drop-outs in the selenium arm: flowchart reports analyzed n=33 from n=42, but only reports drop-out reasons for n=6 (reasons missing n=3); table of baseline characteristics reports data of n=37
|Intervention=Selenium
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
|Dosage and regime=2x 200 mcg tablets of selenium (Webber Naturals, Coquitlam, BC, Canada) daily from the first day until the end of radiation (including days without radiation exposure)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=42
|Drop-out=8
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=4
Lost to follow-up: discontinued radiation due to individual preferences: n=4
|Intervention=Placebo
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
|Dosage and regime=2x placebo tablets daily from the first day until the end of radiation (including days without radiation exposure)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Mucositis
|Outcome specification=Inflammation of the oral mucosa (mucositis) due to radiotherapy

Grade of oral mucositis (WHO Toxicity Scale):

grade 0 = normal, no oral mucosits;

grade 1 = soreness and erythema;

grade 2 = erythema, ulcers, can eat solids;

grade 3 = ulcers, requires liquid diet only;

grade 4 = alimentation not possible

The assessments were performed by an assigned oral medicine specialist and one author, who were both blind to arms
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Significant difference for incidence of severe mucositis at week 3: selenium arm 9.8% vs. placebo arm 42.0% (p=0.017)
|Results after intervention=After 7 weeks no significant differences between the selenium arm and the placebo arm for:
* mean duration of oral mucositis (grade 1–4) (p=0.27)
* onset of oral mucosits (p =0.31)
* recovery (day after radiation completion (p=0.80)
* cumulative incidence of oral mucusitis (grade 1–4) (p=0.79)

Severe oral mucositis (grade 3 or 4) was seen in 25 patients in the selenium arm and in 20 patients in the placebo arm.

Addition: Development of oral mucositis in patients with selenium levels >65 mcg/l significantly delayed from baseline (p=0.04, no further explanation given)
|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=some concerns
|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=high risk
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=NA
|Results after intervention=At the end of radiation (after 7 weeks) there was no difference in the mean serum selenium level between the selenium arm and placebo arm (p=0.24)

Based on the selenium level before radiation, developing severe oral mucositis was statistically significant postponed in patients who had selenium levels ≥ 65 mcg/L (p=0.04)
|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=No funding
|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=* Selenium levels in intervention arm were not significantly higher than in placebo arm after supplementation and selenium levels in placebo arm also increased over the course of the study
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=NI
|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=NA
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Power analysis conducted.
* Selenium levels measured at the beginning and end of radiotherapy.
* Adherence checked via self-report.

CONTRA:
* No intent-to-treat analysis conducted.
* Authors state baseline characteristics are comparable but do not provide statistical analysis.
* No explanation of how double-blinding was ensured.
* Unclear whose baseline values are reported—apparent discrepancy in patient numbers between intervention (34 patients evaluated) and placebo arm (37 patients' characteristics reported but only 33 evaluated according to flow diagram).
* Inconsistencies in patient numbers and dropout not clearly presented for the intervention arm.
* Small sample size.
* Selenium levels in the intervention arm were not significantly higher after supplementation compared to placebo, and selenium levels in the placebo arm increased during the study.
* Analyses in the results section are unclear and most are not reported in the methodology (post-hoc analyses).
* Results are presented without supporting tables or explanation of the analysis, making them difficult to interpret.
* Timeline of the study is unclear as it's uncertain when the values for "end of study" were taken—intervention was only 7 weeks but Kaplan-Meier curve is presented up to week 12.
}}

Laali et al. (2020): Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer

2024-11-07T07:46:37Z

JDoerfler:

{{Reference
|Reference=Publication: Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer
}}
{{Study Note}}
=Brief summary=
In this study, 84 patients with pre-existing head and neck tumours were included. These patients were randomly divided into two arms. One arm (37 patients) received 400 micrograms of selenium daily while the other arm (34 patients) received placebo tablets. Both arms received the regular combined radiochemotherapy in addition to the tablets. The occurrence of inflammation of the oral mucosa, which is a common side effect of radiochemotherapy, was investigated. For this purpose, both the blood selenium level and the current condition of the oral mucosa were recorded at the beginning of the study. While taking the tablets, the oral cavity was examined weekly and the degree of inflammation of the mucous membranes was assessed. No significant difference was found between the two arms with regard to the occurrence of oral mucosal inflammation. No differences between the selenium levels of the two arms were found at the end of the study either. Overall, the study had a small number of participants and the number of patients included in the final analysis is not clearly presented.

In dieser Studie wurden 84 Patienten mit bereits bestehenden Kopf-Hals-Tumoren eingeschlossen. Diese Patienten wurden zufällig in zwei Gruppen eingeteilt. Die eine Gruppe (37 Patienten) erhielt täglich 400 Mikrogramm Selen während die andere Gruppe (34 Patienten) Placebotabletten bekam. Beide Gruppen erhielten neben den Tabletten die reguläre kombinierte Radiochemotherapie. Untersucht wurde das Auftreten von Entzündungen der Mundschleimhaut, welche eine häufige Nebenwirkung der Radiochemotherapie darstellt. Dazu wurden am Anfang der Studie sowohl der Blutselenspiegel als auch der aktuelle Zustand der Mundschleimhäute erhoben. Während der Einnahme der Tabletten wurde wöchentlich die Mundhöhle untersucht und der Grad der Schleimhautentzündung eingeschätzt. Es konnte kein bedeutsamer Unterschied zwischen den beiden Gruppen festgestellt werden, was das Auftreten von Mundschleimhautentzündungen betrifft. Auch konnten am Ende der Studie keine Unterschiede zwischen den Selenspiegeln der beiden Gruppen festgestellt werden. Die Studie hat insgesamt eine geringe Teilnehmeranzahl und die Anzahl der Patienten, die am Ende in die Analyse eingeschlossen wurden ist nicht nachvollziehbar dargestellt.

=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 with head and neck cancer, who were due to receive radiation on at least two-thirds of the oral cavity; aged 18-85 years with a normal renal function (creatinine clearence > 60ml/min) and an acceptable performance status (Karnofsky performance status > 70%) without any history of radiotherapy were eligible for this study
|Exclusion criteria=NI
|N randomized=84
|Analysis=PP Analysis
|Specifications on analyses=Occurrence, duration and severity of oral mucositis (WHO: grade 0-4, weekly check of oral status during radiotherapy, then monthly by doctor and an author);
log rank analysis
|Countries of data collection=Iran
|LoE=Level 2 Oxford 2011
|Outcome timeline=Oral mucositis
T0: Baseline

Follow up: weekly for 7 weeks

Selenium level

T0: Baseline

T1: End of radiation
}}
=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=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=* Radiation therapy: 5 fractions per week at 60-70 Gy cumulative doses over 6 weeks to 7 weeks
* Chemotherapy: 18 (48.6%) patients from the selenium group and 16 (47.1%) from the placebo arm with cisplatin (30-50mg/m2 weekly, during radiation)
* Grade of neutropenia and renal failure was evaluated based on the NCI CTCAE
* Creatinine level increase of > 0.3 mg/dL or 1.5–2.0 mg/dL above baselinewas considered as renal failure and a neutrophil count decrease to 1000–500 mm3 was considered as grade 3 of this toxicity
* After 7 weeks no differencences in the incidence of other adverse effects related to chemoradiation such as neutropenia and renal failure in the selenium arm and the placebo arm
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Male n(%) per arm:
Selenium arm: 25 (67.9), placebo arm: 25 (73.5)

Female n(%) per arm:
Selenium arm: 12 (32.1), placebo arm: 9 (26.5)
|Age groups=Adults (18+)
|Age groups specification=Age in years, mean (min-max) per arm:
Selenium arm: 52.14 (22-81), placebo arm: 54.74 (18-81)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=42
|Drop-out=9
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=1
Lost to follow-up: discontinued tablets (n=1); discontinued radiation due to individual preferences: n=4

Inconsistencies in the number of drop-outs in the selenium arm: flowchart reports analyzed n=33 from n=42, but only reports drop-out reasons for n=6 (reasons missing n=3); table of baseline characteristics reports data of n=37
|Intervention=Selenium
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
|Dosage and regime=2x 200 mcg tablets of selenium (Webber Naturals, Coquitlam, BC, Canada) daily from the first day until the end of radiation (including days without radiation exposure)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=42
|Drop-out=8
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=4
Lost to follow-up: discontinued radiation due to individual preferences: n=4
|Intervention=Placebo
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
|Dosage and regime=2x placebo tablets daily from the first day until the end of radiation (including days without radiation exposure)
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Mucositis
|Outcome specification=Inflammation of the oral mucosa (mucositis) due to radiotherapy

Grade of oral mucositis (WHO Toxicity Scale):

grade 0 = normal, no oral mucosits;

grade 1 = soreness and erythema;

grade 2 = erythema, ulcers, can eat solids;

grade 3 = ulcers, requires liquid diet only;

grade 4 = alimentation not possible

The assessments were performed by an assigned oral medicine specialist and one author, who were both blind to arms
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Significant difference for incidence of severe mucositis at week 3: selenium arm 9.8% vs. placebo arm 42.0% (p=0.017)
|Results after intervention=After 7 weeks no significant differences between the selenium arm and the placebo arm for:
* mean duration of oral mucositis (grade 1–4) (p=0.27)
* onset of oral mucosits (p =0.31)
* recovery (day after radiation completion (p=0.80)
* cumulative incidence of oral mucusitis (grade 1–4) (p=0.79)

Severe oral mucositis (grade 3 or 4) was seen in 25 patients in the selenium arm and in 20 patients in the placebo arm.

Addition: Development of oral mucositis in patients with selenium levels >65 mcg/l significantly delayed from baseline (p=0.04, no further explanation given)
|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=some concerns
|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=high risk
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=NA
|Results after intervention=At the end of radiation (after 7 weeks) there was no difference in the mean serum selenium level between the selenium arm and placebo arm (p=0.24)

Based on the selenium level before radiation, developing severe oral mucositis was statistically significant postponed in patients who had selenium levels ≥ 65 mcg/L (p=0.04)
|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=No funding
|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=* Selenium levels in intervention arm were not significantly higher than in placebo arm after supplementation and selenium levels in placebo arm also increased over the course of the study
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=NI
|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=NA
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Power analysis conducted.
* Selenium levels measured at the beginning and end of radiotherapy.
* Adherence checked via self-report.

CONTRA:
* No intent-to-treat analysis conducted.
* Authors state baseline characteristics are comparable but do not provide statistical analysis.
* No explanation of how double-blinding was ensured.
* Unclear whose baseline values are reported—apparent discrepancy in patient numbers between intervention (34 patients evaluated) and placebo arm (37 patients' characteristics reported but only 33 evaluated according to flow diagram).
* Inconsistencies in patient numbers and dropout not clearly presented for the intervention arm.
* Small sample size.
* Selenium levels in the intervention arm were not significantly higher after supplementation compared to placebo, and selenium levels in the placebo arm increased during the study.
* Analyses in the results section are unclear and most are not reported in the methodology (post-hoc analyses).
* Results are presented without supporting tables or explanation of the analysis, making them difficult to interpret.
* Timeline of the study is unclear as it's uncertain when the values for "end of study" were taken—intervention was only 7 weeks but Kaplan-Meier curve is presented up to week 12.
}}

Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients

2024-11-07T07:44:37Z

JDoerfler:

{{Reference
|Reference=Publication: Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients
}}

=Brief summary=
In this study, 39 patients with advanced head and neck tumors and selenium deficiency were randomly divided into two arms. One arm (22 participants) received selenium during radiotherapy and another arm (17 participants) received nothing in addition to radiotherapy. It was investigated whether selenium administration can influence the side effects of radiotherapy. At the end of radiotherapy, no differences were found between the arms for the maximum severity of the radiotherapy-induced symptoms “dry mouth”, “inflammation of the oral mucosa”, “loss of sense of taste” and “nutritional deficiency”. No differences were found in terms of frequency either. Only at week seven, the last week of radiotherapy, were the symptoms of “nutritional deficiency” more pronounced in the control arm than in the selenium arm. Overall, the study provides a very clear description of the procedure and the results. However, important demographic data such as concomitant diseases and tumor stage of the patients are not given and therefore cannot be considered in the analysis. Furthermore, as no placebo was used, it was not possible to blind the subjects or the investigators.

In dieser Studie wurden 39 Probanden mit fortgeschrittenen Kopf-Hals Tumoren und Selendefizit zufällig in zwei Gruppen eingeteilt. Eine Gruppe (22 Probanden) bekamen Selen während der Radiotherapie und eine andere Gruppe (17 Probanden) erhielt nichts Zusätzliches zur Radiotherapie. Untersucht wurde ob Selengabe die Nebenwirkungen der Radiotherapie beeinflussen kann. Am Ende der Radiotherapie konnten bezügliche den Radiotherapie verursachten Symptomen „Trockener Mund“, „Entzündung der Mundschleimhaut“, „Verlust des Geschmackssinnes“ und „Ernährungsdefizit“ keine Unterschiede zwischen den Gruppen für die maximale Ausprägung gefunden werden. Es konnten auch keine Unterschiede bezüglich der Häufigkeit gefunden werden. Nur zu Woche sieben und der damit letzten Woche der Radiotherapie waren die Symptome des „Ernährungsdefizits“ in der Kontrollgruppe stärker ausgeprägt als in der Selen-Gruppe. Insgesamt gibt die Studie eine sehr übersichtliche Beschreibung des Ablaufs und auch der Ergebnisse. Allerdings werden wichtige demographische Angaben wie Begleiterkrankungen und Tumorstadium der Patienten nicht angegeben und können deshalb auch nicht in der Analyse berücksichtigt werden. Da kein Placebo eingesetzt wurde, konnte zudem keine Verblindung der Probanden oder der Prüfungsleiter durchgeführt werden.

=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=Patients with squamous cell carcinoma of the head and neck region; atom absorption spectrometry showed a deficiency in selenium and the radiation field included 75% of the major salivary glands
|Exclusion criteria=NI
|N randomized=39
|Analysis=ITT Analysis
|Specifications on analyses=ITT-analysis not specified, but no drop-out occured
|Countries of data collection=Germany
|LoE=2b Oxford 2009
|Outcome timeline=Selenium concentration measured at baseline, after 4 weeks, after the end of Radiotherapy and 6 weeks after the end of Radiotherapy

Outcome assessed at baseline and then once a week and 6 weeks after Radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Head and Neck Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Selenium deficit
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=Male n=31, female n=8
|Age groups=Adults (18+)
|Age groups specification=Mean(SD) = 63.5(9.31) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=22
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Sodium selenite
|Dosage and regime=500µg sodium selenite 2 days before the start of radiotherapy and on days with radiotherapy; and 300 µg sodium selenite on days without radiotherapy (weekends and vacations), orally as a liquid 1 hour before radiotherapy
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=17
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Usual care
|Dosage and regime=NA
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=Grade of radiotherapy-associated side effects: Xerostomia, stomatitis, ageusia, and dysphagia
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=Maximum toxicity intervention vs. control arm: dysphagia 22.7% vs. 35.3%, ageusia 22.7% vs. 47.1%, xerostomia 22.7% vs. 23.5%, and stomatitis 36.4% vs. 23.5%; no significant differences;

Significant mean difference between arms only for dysphagia at week 7: mean intervention arm 1.533 vs. control 2.167 (p=0.05)
|Results after intervention=No significant differences;

overall number of serious adverse events, not significantly different: intervention arm 23x and control arm 22x (p=0.476)
|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 Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Sponsored by biosyn Arzneimittel GmbH, Fellbach, Germany
|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=NA
|Possibility of placebo effects=Yes
|Other reasons=* No information about the comparability at baseline in the results section, nor information on how this was achieved – especially considering the unequal group sizes
* No detailed description of the data collection in the individual clinics and whether they were comparable
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=No
|Measurement of compliance=NI
|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=Yes
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Clear presentation of results.
* Detailed description of the research question and selenium level testing.

CONTRA:
* Unequal arm sizes despite randomization.
* No power analysis.
* No placebo and thus no blinding possible.
* Unclear randomization process.
* No information on the comparability of arms at baseline in the results section or how this was achieved—especially considering the unequal arm sizes.
* Lack of additional demographic variables such as comorbidities, tumor stage, etc.
* No detailed description of the assessments in the individual clinics and whether they were comparable.
}}

Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients

2024-11-07T07:44:21Z

JDoerfler:

{{Reference
|Reference=Publication: Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients
}}
{{Study Note}}
=Brief summary=
In this study, 39 patients with advanced head and neck tumors and selenium deficiency were randomly divided into two arms. One arm (22 participants) received selenium during radiotherapy and another arm (17 participants) received nothing in addition to radiotherapy. It was investigated whether selenium administration can influence the side effects of radiotherapy. At the end of radiotherapy, no differences were found between the arms for the maximum severity of the radiotherapy-induced symptoms “dry mouth”, “inflammation of the oral mucosa”, “loss of sense of taste” and “nutritional deficiency”. No differences were found in terms of frequency either. Only at week seven, the last week of radiotherapy, were the symptoms of “nutritional deficiency” more pronounced in the control arm than in the selenium arm. Overall, the study provides a very clear description of the procedure and the results. However, important demographic data such as concomitant diseases and tumor stage of the patients are not given and therefore cannot be considered in the analysis. Furthermore, as no placebo was used, it was not possible to blind the subjects or the investigators.

In dieser Studie wurden 39 Probanden mit fortgeschrittenen Kopf-Hals Tumoren und Selendefizit zufällig in zwei Gruppen eingeteilt. Eine Gruppe (22 Probanden) bekamen Selen während der Radiotherapie und eine andere Gruppe (17 Probanden) erhielt nichts Zusätzliches zur Radiotherapie. Untersucht wurde ob Selengabe die Nebenwirkungen der Radiotherapie beeinflussen kann. Am Ende der Radiotherapie konnten bezügliche den Radiotherapie verursachten Symptomen „Trockener Mund“, „Entzündung der Mundschleimhaut“, „Verlust des Geschmackssinnes“ und „Ernährungsdefizit“ keine Unterschiede zwischen den Gruppen für die maximale Ausprägung gefunden werden. Es konnten auch keine Unterschiede bezüglich der Häufigkeit gefunden werden. Nur zu Woche sieben und der damit letzten Woche der Radiotherapie waren die Symptome des „Ernährungsdefizits“ in der Kontrollgruppe stärker ausgeprägt als in der Selen-Gruppe. Insgesamt gibt die Studie eine sehr übersichtliche Beschreibung des Ablaufs und auch der Ergebnisse. Allerdings werden wichtige demographische Angaben wie Begleiterkrankungen und Tumorstadium der Patienten nicht angegeben und können deshalb auch nicht in der Analyse berücksichtigt werden. Da kein Placebo eingesetzt wurde, konnte zudem keine Verblindung der Probanden oder der Prüfungsleiter durchgeführt werden.

=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=Patients with squamous cell carcinoma of the head and neck region; atom absorption spectrometry showed a deficiency in selenium and the radiation field included 75% of the major salivary glands
|Exclusion criteria=NI
|N randomized=39
|Analysis=ITT Analysis
|Specifications on analyses=ITT-analysis not specified, but no drop-out occured
|Countries of data collection=Germany
|LoE=2b Oxford 2009
|Outcome timeline=Selenium concentration measured at baseline, after 4 weeks, after the end of Radiotherapy and 6 weeks after the end of Radiotherapy

Outcome assessed at baseline and then once a week and 6 weeks after Radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Head and Neck Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Selenium deficit
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=Male n=31, female n=8
|Age groups=Adults (18+)
|Age groups specification=Mean(SD) = 63.5(9.31) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=22
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Sodium selenite
|Dosage and regime=500µg sodium selenite 2 days before the start of radiotherapy and on days with radiotherapy; and 300 µg sodium selenite on days without radiotherapy (weekends and vacations), orally as a liquid 1 hour before radiotherapy
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=17
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Usual care
|Dosage and regime=NA
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=Grade of radiotherapy-associated side effects: Xerostomia, stomatitis, ageusia, and dysphagia
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=Maximum toxicity intervention vs. control arm: dysphagia 22.7% vs. 35.3%, ageusia 22.7% vs. 47.1%, xerostomia 22.7% vs. 23.5%, and stomatitis 36.4% vs. 23.5%; no significant differences;

Significant mean difference between arms only for dysphagia at week 7: mean intervention arm 1.533 vs. control 2.167 (p=0.05)
|Results after intervention=No significant differences;

overall number of serious adverse events, not significantly different: intervention arm 23x and control arm 22x (p=0.476)
|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 Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Sponsored by biosyn Arzneimittel GmbH, Fellbach, Germany
|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=NA
|Possibility of placebo effects=Yes
|Other reasons=* No information about the comparability at baseline in the results section, nor information on how this was achieved – especially considering the unequal group sizes
* No detailed description of the data collection in the individual clinics and whether they were comparable
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=No
|Measurement of compliance=NI
|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=Yes
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Clear presentation of results.
* Detailed description of the research question and selenium level testing.

CONTRA:
* Unequal arm sizes despite randomization.
* No power analysis.
* No placebo and thus no blinding possible.
* Unclear randomization process.
* No information on the comparability of arms at baseline in the results section or how this was achieved—especially considering the unequal arm sizes.
* Lack of additional demographic variables such as comorbidities, tumor stage, etc.
* No detailed description of the assessments in the individual clinics and whether they were comparable.
}}

Main Page

2024-11-07T07:27:31Z

JDoerfler:

<html>
== Welcome to CAMIH, the Complementary and Alternative Medicine Insights Hub! ==

CAMIH is a database offering up-to-date evidence from randomized controlled trials on complementary approaches and methods for treating oncology patients. Each study has been meticulously reviewed and critically evaluated for methodological rigor using the Cochrane Risk of Bias Tool 2.0. This approach ensures that the database not only provides a comprehensive collection of evidence but also contextualizes these findings within a framework of methodological quality.
 
Study searches can be conducted directly via the search bar, but we also offer a thematically organized overview of all studies. Additionally, CAMIH provides an option for specific, customized search queries (via the Query Helper) to generate a targeted summary on the topic of interest.
 
Via FAQ you can get information on the Level of Evidence, the RoB Tool 2.0. and types of analyses.

== Important Links ==
 
<gallery mode=nolines>
File:studies_by_type.png |'''Studies by study type'''|link=Category:Study
File:studies_by_topic.png |'''Studies by topic'''|link=Study_Overview
File:all_publications.png |'''All available publications'''|link=Category:Publication
File:faq.png |'''FAQ'''|link=FAQ
File:helper.png |'''Query helper'''|link=https://camih.med.uni-jena.de/helper
</gallery>

== Creator Tools ==
* [[Form:Author|Create a new Author]] (optional)
* [[Form:Publication|Create a new Publication]]
* [[Form:RCT_Study|Create a new RCT Study]]
* [[Form:SR_Study|Create a new SR Study]]

Main Page

2024-11-07T07:27:01Z

JDoerfler:

<html>
== Welcome to CAMIH, the Complementary and Alternative Medicine Insights Hub! ==

CAMIH is a database offering up-to-date evidence from randomized controlled trials on complementary approaches and methods for treating oncology patients. Each study has been meticulously reviewed and critically evaluated for methodological rigor using the Cochrane Risk of Bias Tool 2.0. This approach ensures that the database not only provides a comprehensive collection of evidence but also contextualizes these findings within a framework of methodological quality.
 
Study searches can be conducted directly via the search bar, but we also offer a thematically organized overview of all studies. Additionally, CAMIH provides an option for specific, customized search queries (via the CAMIH Helper) to generate a targeted summary on the topic of interest.
 
Via FAQ you can get information on the Level of Evidence, the RoB Tool 2.0. and types of analyses.

== Important Links ==
 
<gallery mode=nolines>
File:studies_by_type.png |'''Studies by study type'''|link=Category:Study
File:studies_by_topic.png |'''Studies by topic'''|link=Study_Overview
File:all_publications.png |'''All available publications'''|link=Category:Publication
File:faq.png |'''FAQ'''|link=FAQ
File:helper.png |'''Query helper'''|link=https://camih.med.uni-jena.de/helper
</gallery>

== Creator Tools ==
* [[Form:Author|Create a new Author]] (optional)
* [[Form:Publication|Create a new Publication]]
* [[Form:RCT_Study|Create a new RCT Study]]
* [[Form:SR_Study|Create a new SR Study]]

Main Page

2024-11-07T07:26:49Z

JDoerfler:

<html>
== Welcome to CAMIH, the Complementary and Alternative Medicine Insights Hub! ==

CAMIH is a database offering up-to-date evidence from randomized controlled trials on complementary approaches and methods for treating oncology patients. Each study has been meticulously reviewed and critically evaluated for methodological rigor using the Cochrane Risk of Bias Tool 2.0. This approach ensures that the database not only provides a comprehensive collection of evidence but also contextualizes these findings within a framework of methodological quality.
 
Study searches can be conducted directly via the search bar, but we also offer a thematically organized overview of all studies. Additionally, CAMIH provides an option for specific, customized search queries (via the CAMIH Helper) to generate a targeted summary on the topic of interest.

Via FAQ you can get information on the Level of Evidence, the RoB Tool 2.0. and types of analyses.

== Important Links ==
 
<gallery mode=nolines>
File:studies_by_type.png |'''Studies by study type'''|link=Category:Study
File:studies_by_topic.png |'''Studies by topic'''|link=Study_Overview
File:all_publications.png |'''All available publications'''|link=Category:Publication
File:faq.png |'''FAQ'''|link=FAQ
File:helper.png |'''Query helper'''|link=https://camih.med.uni-jena.de/helper
</gallery>

== Creator Tools ==
* [[Form:Author|Create a new Author]] (optional)
* [[Form:Publication|Create a new Publication]]
* [[Form:RCT_Study|Create a new RCT Study]]
* [[Form:SR_Study|Create a new SR Study]]

Büntzel et al. (2010): Selenium Substitution During Radiotherapy of Solid Tumours - Laboratory Data from Two Observation Studies in Gynaecological and Head and Neck Cancer Patients

2024-11-05T14:55:57Z

JDoerfler:

{{Reference
|Reference=Publication: Selenium Substitution During Radiotherapy of Solid Tumours Laboratory Data from Two Observation Studies in Gynaecological and Head and Neck Cancer Patients
}}
{{Study Note
|Study Note=This study includes the samples of 2 studies ([[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]], [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]]), reporting the outcome of change in selenium concentration in the blood as a result of selenium administration.
}}
=Brief summary=
This study includes the samples of two studies, each with a sample of head and neck patients [[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]] or gynecological cancer patients [[Muecke et al. (2010): Multicenter, phase three trial comparing selenium supplementation with observation in gynecologic radiation oncology]] who were randomly divided into two arms and received or did not receive additional selenium during the period of radiotherapy. All subjects had a proven selenium deficiency. This study served only to demonstrate the change in selenium concentration in the blood as a result of selenium administration. Both arms had comparable selenium levels at the beginning of the study. There was a significantly higher selenium concentration in the blood of the arm that received selenium halfway through radiotherapy (around week four) and at the end of radiotherapy. This difference was no longer significant six weeks after radiotherapy. This study can be seen more as an addition to the two studies by Büntzel et al. (2008) and Mücke et al. (2008) than as an independent study. Very little marginal information is given here about the patients or the course of treatment and no details are given about the drop-outs that obviously took place.

Diese Studie umfasst die Stichproben von zwei Studien mit jeweils einer Stichprobe von Hals-Nasen-Kopf Tumorpatienten [[Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients]] oder gynäkologischen Krebspatienten [[Muecke et al. (2010): Multicenter, phase three trial comparing selenium supplementation with observation in gynecologic radiation oncology]], welche zufällig in zwei Gruppen eingeteilt wurden und während der Zeit der Radiotherapie zusätzlich Selen erhielten oder nicht. Alle Probanden hatten ein nachgewiesenes Selendefizit. Diese Studie diente nur zur Darstellung der Veränderung der Selenkonzentration im Blut durch die Selengabe. Beide Gruppen hatten zu Beginn der Studie einen vergleichbaren Selenspiegel. Es zeigte sich jeweils zur Hälfte der Radiotherapie (etwa vierte Woche) und zu dessen Ende eine bedeutsam höhere Selenkonzentration im Blut der Gruppe welche Selen erhalten hatten. Dieser Unterschied war sechs Wochen nach der Radiotherapie nicht mehr bedeutsam. Diese Studie kann eher als Zusatz zu den beiden Studien von Büntzel et al. (2008) und Mücke et al. (2008) gesehen werden, als eine eigenständige Studie. Es wird hier sehr wenig Randinformation zu den Patienten oder den Ablauf der Behandlung gegeben und es werden keine Angaben zu den offensichtlich stattgefundenen Drop-Outs gemacht.

=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=Patients suffering from gynaecological or head and neck cancer who were irradiated because of their disease
|Exclusion criteria=NI
|N randomized=128
|Analysis=PP Analysis
|Specifications on analyses=NA
|Countries of data collection=Germany
|LoE=2b Oxford 2009
|Outcome timeline=Selenium concentration measured at baseline, after 4 weeks, after the end of radiotherapy and 6 weeks after the end of radiotherapy

Overall duration: 7 weeks of radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Gynecologic Cancers, Head and Neck Cancers
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Head and Neck cancer - Advanced Stage
Gynecologic cancer - FIGO Stadium I-IV
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=NI
|Age groups=Adults (18+)
|Age groups specification=Mean(SD)

Intervention arm: 63.83(9.2) years

Control arm: 63.03(10.5) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=63
|Drop-out=Not seperated by arm n=7
|Drop-out reasons=NI
|Intervention=Sodium selenite
|Dosage and regime=500µg sodium selenite 2 days before the start of radiotherapy and on days with radiotherapy; and 300 µg sodium selenite on days without radiotherapy (weekends and vacations), orally as a liquid 1 hour before radiotherapy
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=-999
|Drop-out=Not seperated by arm n=7
|Drop-out reasons=NI
|Intervention=Usual Care
|Dosage and regime=NA
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Selenium level
|Outcome specification=Serum concentration and whole blood concentration
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=At baseline no significant differences;

Significant differences in selenium concentrations (serum and blood) at half of radiotherapy (p<0.0001)
|Results after intervention=At 6 weeks after irradiation no significant differences;

Significant differences in selenium concentrations (serum and blood) at the end of radiotherapy (p<0.0001)
|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
}}

{{Additional Notes
|Additional Notes=PRO:
* Ethics approval obtained.

CONTRA:
* Arm comparability tested only for age.
* No demographic information provided.
* No information on the dropout of 7 participants.
* Few conditions given.
}}

Publication: L-Carnitine Improves Postoperative Liver Function in Hepatectomized Patients

2024-11-05T14:42:21Z

JDoerfler:

{{Publication
|Title=L-Carnitine Improves Postoperative Liver Function in Hepatectomized Patients
|Topic=Carnitine
|Author=Okabayashi T; Sui K; Mastumoto T; Iwata J; Morita S; Iiyama T; Shimada Y
|Year=2020
|Journal=Journal of parenteral and enteral nutrition
|DOI=https://doi.org/10.1002/jpen.1720
|Authors Abstract=Background and aims: The effect of perioperative treatment with L-carnitine in hepatectomized patients is unclear. The objectiveof the current study is to evaluate the short-term outcomes after liver cancer surgery in patients treated with L-carnitine comparedwith nontreated patients.

Methods: Patients with primary liver malignancies scheduled to undergo a hepatectomy were randomlyassigned to receive either perioperative treatment with L-carnitine (carnitine group) or usual intake (control group). The primaryendpoint of this study was the short-term outcome after liver surgery.

Results: The study participants were randomly assigned into2 groups: 106 patients in the control group and 102 patients in the perioperative L-carnitine supplementation group. The restorationof serum ammonia levels, prothrombin time, and peripheral neutrophil count at 3 days after the operation was significantly fasterin the carnitine group than in the control group. Fewer patients in the carnitine group developed grade B posthepatic liver failure,according to the grading system of the International Study Group of Liver Surgery, than patients in the control group (20% vs76%). The length of hospitalization was significantly shorter in patients in the carnitine group than in those in the control group.

Conclusions: We found that perioperative treatment with L-carnitine was significantly better than ordinary treatment in reducingpostoperative serum ammonia levels, suggesting that L-carnitine may serve as a pivotal regulator of liver injury and repair andresult in shorter postoperative hospitalization
}}

Muecke et al. (2014): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization

2024-11-05T13:45:23Z

JDoerfler:

{{Reference
|Reference=Publication: Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization
}}
{{Study Note
|Study Note=This study is a follow-up analysis of [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]]. There is a study with a subgroup-analysis of the 2010 study: [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]].
}}
=Brief summary=
This study included 81 patients with uterine or cervical cancer. They were randomly divided into two arms and received either 500µg selenium in addition to radiotherapy or no additional preparations. All participants had a selenium deficiency at the beginning of the study. This is a further analysis of the [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] - the follow-up study shows that after ten years there is no difference between the arms in terms of overall survival or disease-free survival.

Diese Studie schloss 81 Patientinnen mit Gebärmutter- oder Gebärmutterhalskrebs ein. Sie wurden zufällig in zwei Gruppen eingeteilt und erhielten entweder zusätzlich zur Radiotherapie 500µg Selen oder keine zusätzlichen Präparate. Alle Probanden hatten zu Beginn der Studie ein Selendefizit. Die Follow-Up Studie zeigt, dass nach zehn Jahren kein Unterschied zwischen den Gruppen bezüglich des Gesamtüberlebens oder dem Krankheitsfreien-Überleben besteht. Es ist eine weitere Analyse der Studie [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] - die Follow-Up Studie zeigt, dass nach zehn Jahren kein Unterschied zwischen den Gruppen bezüglich des Gesamtüberlebens oder dem Krankheitsfreien-Überleben besteht.

=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=NA
|Exclusion criteria=NA
|N randomized=81
|Analysis=NI
|Specifications on analyses=No information about possible drop-out
|Countries of data collection=Germany
|LoE=1b Oxford 2009
|Outcome timeline=NA
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=NI
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=Selenium concentration lower than 84µg/L at start of the original study (Muecke et al., 2010)
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery, Radiation therapy
|Gender=Female
|Gender specifications=NA
|Age groups=Adults (18+)
|Age groups specification=Start of the original study (Muecke et al., 2010): mean (SD); range: 64.3 (10.1); 31–80 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=39
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Sodium Selenite
|Dosage and regime=500 µg selenium in the form of sodium selenite [selenase®), orally on radiotherapy days and 300 µg on days without radiotherapy
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=42
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Usual care
|Dosage and regime=NA
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=10-year disease-free survival
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=10-year disease-free survival intervention arm 80.1% vs. control arm 83.2%; not significant; p = 0.65
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=1
}}
{{Outcome
|Outcome type=NI
|Outcome name=OS (Overall Survival)
|Outcome specification=10-year overall survival
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=10-year overall survival intervention arm 55.3% vs. control arm 42.7%; not significant; p = 0.09
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=2
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by a grant from the pharmaceutical company biosyn-Arzneimittel GmbH Fellbach, Germany.
|Conflicts of Interest=The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ralph Muecke has had conference and travel expenses reimbursed and has received lecture fees from the pharmaceutical company biosyn-Arzneimittel GmbH to help run the study.
}}
=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=NA
|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=NI
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Testing for selenium deficiency.
* Power analysis conducted.
* Comparability of arms established.
* Very detailed and clear presentation of results.

CONTRA:
* No placebo control.
* No information on possible blinding.
* No information on potential dropouts.
* "Total dose of external radiotherapy (Gy)" at p=0.06 — close to significance between arms.
* No testing whether selenium significantly decreases in the control arm.
* No verification of supplementation outside the study.
* Few demographic variables provided.
}}

Muecke et al. (2013): Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology-a subgroup analysis of a multicenter, phase III trial

2024-11-05T13:44:02Z

JDoerfler:

{{Reference
|Reference=Publication: Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology--a subgroup analysis of a multicenter, phase III trial
}}
{{Study Note
|Study Note=This study is a subgroup-analysis of [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]]. There is a follow-up study to the 2010 study: [[Muecke et al. (2014): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization]]
}}
=Brief summary=
This study included 81 patients with uterine or cervical cancer. They were randomly divided into two arms and received either 500µg selenium in addition to radiotherapy or no additional preparations. All participants had a selenium deficiency at the beginning of the study. This is a further analysis of [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] - in this study the arm was divided into those with a large target volume and those with a small one. This showed that the reduction in diarrhea due to selenium was only significant in the arm with a large target volume, i.e. the irradiated part of the pelvis. This indicates that the effect originally found is significantly influenced by the size of the target volume.

Diese Studie schloss 81 Patientinnen mit Gebärmutter- oder Gebärmutterhalskrebs ein. Sie wurden zufällig in zwei Gruppen eingeteilt und erhielten entweder zusätzlich zur Radiotherapie 500µg Selen oder keine zusätzlichen Präparate. Alle Probanden hatten zu Beginn der Studie ein Selendefizit. Es ist eine weitere Analyse der Studie [[Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology]] - in dieser Studie wurde die Gruppe geteilt, in jeden mit einem großen Zielvolumen und jeden mit einem kleinen. Hierbei zeigte sich, dass die Reduzierung des Durchfalls durch Selen nur noch bedeutsam in der Gruppe mit einem großen Zielvolumen, also dem bestrahlten Anteil des Beckens ist. Was darauf hinweist, dass der ursprünglich gefundene Effekt von der Größe des Zielvolumens maßgeblich beeinflusst wird.

=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=NA
|Exclusion criteria=NA
|N randomized=81
|Analysis=NI
|Specifications on analyses=No information about possible drop-out
|Countries of data collection=Germany
|LoE=1b Oxford 2009
|Outcome timeline=NA
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Gynecologic Cancers - Cervical Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=FIGO Stadium I-IV
|Comorbidity=Selenium concentration lower than 84µg/L
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=External radiotherapy was delivered with a 6- to 18-MV linear accelerator. Five fractions per week were planned. Treatment was given with a three- to four-field box technique. Radiotherapy was given as three-dimensional conformal radiotherapy. Computed tomography–based treatment planning was performed in all cases. The clinical target volume encompassed the primary tumor region and the pelvic regional lymph nodes. High-dose rate brachytherapy of the vagina was considered optional in accordance with German evidence-based guidelines. Brachytherapy was delivered by iridium 192 afterloading.
|Previous cancer therapies=Surgery
|Gender=Female
|Gender specifications=NA
|Age groups=Adults (18+)
|Age groups specification=Mean (SD), range): 64.3 (10.1); 31–80 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=39
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Sodium Selenite
|Dosage and regime=500 µg selenium in the form of sodium selenite [selenase®), orally on radiotherapy days and 300 µg on days without radiotherapy
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=42
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Usual Care
|Dosage and regime=NA
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=Diarrhea
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=Overall Analysis:
Median PTV in both arms: 1302 ml (916-4608); mean PTV in the intervention arm: 1604 ml vs. 1447 ml in the control arm; p=0.55

If PTV ≤ 1302 ml (n=41), then occurrence of at least grade 2 diarrhea in the intervention arm was 22.3% (4/18 patients) vs. 34.8% (8/23 patients) in the control arm; p=0.50

With PTV > 1302 ml (n=40), the intervention arm had 19.1% (4/21 patients) vs. the control arm with 52.6% (10/19 patients); p=0.046
|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=some concerns
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=“Supported by a grant by the pharmaceutical company biosyn, Fellbach, Germany.“
|Conflicts of Interest=„RM has had conference and travel expenses reimbursed and has received lecture fees from the pharmaceutical company biosyn-Arzneimittel GmbH, biosyn-Arzneimittel GmbH is not financing this manuscript. The other authors declare that they have no competing interests.“
}}
=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=NI
|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=NI
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Testing for selenium deficiency.
* Power analysis conducted.
* Comparability of arms established.
* Very detailed and clear presentation of results.

CONTRA:
* No placebo control.
* No information on possible blinding.
* No information on potential dropouts.
* "Total dose of external radiotherapy (Gy)" at p=0.06 — close to significance between arms.
* No testing whether selenium significantly decreases in the control arm.
* No verification of supplementation outside the study.
* Few demographic variables provided.
}}

Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology

2024-11-05T13:42:27Z

JDoerfler:

{{Reference
|Reference=Publication: Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology
}}
{{Study Note
|Study Note=One study with a subgroup-analysis of the sample was published: [[Muecke et al. (2013): Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology--a subgroup analysis of a multicenter, phase III trial]] and one follow-up study: [[Muecke et al. (2014): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization]]
}}
=Brief summary=
This study included 81 patients with uterine or cervical cancer. They were randomly divided into two arms and received either 500µg selenium in addition to radiotherapy or no additional preparations. All participants had a selenium deficiency at the beginning of the study. After about seven weeks and thus the end of radiotherapy, a significantly increased selenium concentration was found in the selenium arm compared to the control arm. There was also a lower incidence of radiotherapy-induced diarrhea in the selenium arm compared to the control arm. However, no differences were found with regard to performance status, quality of life, overall survival or disease-free survival after five years. The study impresses with a clear presentation of the results and an examination of the selenium concentration of the participants. However, little information is given about the patients beyond their disease and selenium status and accordingly none can be included in the interpretation of the results. Overall, however, the study can be regarded as methodologically sound.

Diese Studie schloss 81 Patientinnen mit Gebärmutter- oder Gebärmutterhalskrebs ein. Sie wurden zufällig in zwei Gruppen eingeteilt und erhielten entweder zusätzlich zur Radiotherapie 500µg Selen oder keine zusätzlichen Präparate. Alle Probanden hatten zu Beginn der Studie ein Selendefizit. Nach etwa sieben Wochen und damit dem Ende der Radiotherapie zeigte sich eine bedeutsam erhöhte Selenkonzentration in der Selen-Gruppe im Vergleich zur Kontrollgruppe. Es zeigte sich zudem eine geringere Häufigkeit von durch die Radiotherapie verursachtem Durchfall in der Selengruppe im Vergleich zur Kontrollgruppe. Es konnten allerdings keine Unterschiede bezüglich dem Performanz-status, der Lebensqualität oder dem Gesamtüberleben oder dem Krankheitsfreien-Überleben nach fünf Jahren festgestellt werden. Die Studie überzeugt durch eine übersichtliche Darstellung der Ergebnisse und einer Prüfung der Selenkonzentration der Probanden. Allerdings werden über Krankheit- und Selenstatus hinaus wenig Informationen zu den Patientinnen gegeben und dementsprechend können auch keine in die Interpretation der Ergebnisse einbezogen werden. Im Ganzen kann die Studie aber als methodisch solide betrachtet werden.

=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=Patients with histopathologically confirmed carcinomas of the cervix or corpus uteri with a significant whole-blood selenium deficiency (i.e., concentration <85 µg/L) after curative surgical treatment
|Exclusion criteria=Patients with metastatic disease, diarrhea before radiotherapy, radiochemotherapy, or supplementation of selenium before radiotherapy, as well as patients who had undergone previous pelvic radiotherapy
|N randomized=81
|Analysis=NI
|Specifications on analyses=No information about possible drop-out
|Countries of data collection=Germany
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline

T1: Half of the radiotherapy (about 4 weeks)

T2: End of radiotherapy

T3: 6 weeks after radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Gynecologic Cancers - Cervical Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=FIGO Stadium I-IV
|Comorbidity=Selenium concentration (whole-blood) lower than 84µg/L
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=External radiotherapy was delivered with a 6- to 18-MV linear accelerator.
Five fractions per week were planned. Treatment was given with a three- to four-field box technique. Radiotherapy was given as three-dimensional conformal radiotherapy. Computed tomography–based treatment planning was performed in all cases. The clinical target volume encompassed the primary tumor region and the pelvic regional lymph nodes. High-dose rate brachytherapy of the vagina was considered optional in accordance with German evidence-based guidelines. Brachytherapy was delivered by iridium 192 afterloading.
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=NA
|Age groups=Adults (18+)
|Age groups specification=Mean (SD), range: 64.3 (10.1), 31–80 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=39
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Sodium Selenite
|Dosage and regime=500 µg selenium in the form of sodium selenite (selenase®), orally on radiotherapy days and 300 µg on days without radiotherapy
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=42
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Usual Care
|Dosage and regime=NA
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Selenium level
|Outcome specification=Efficiancy of supplementation
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=No difference between arms at baseline, but significantly higher in the intervention arm than the control arm at mid-study (intervention arm: 93.2 µg/L vs. control arm: 67.3 µg/L) and end of study (intervention arm: 90.9±19.9 µg/L vs. control arm: 61.4±15.5 µg/L; p < 0.001)
|Results after intervention=After 6 weeks post radiotherapy, levels between arms were comparable
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Diarrhea
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=Lower incidence of grade 1-3 diarrhea at mid-study in the intervention arm compared to the control arm; p = 0.01
|Results after intervention=Overall incidence of grade 2 diarrhea: intervention arm 20.5% vs. control arm 44.5% (p = 0.04)
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Performance Status
|Outcome specification=NA
|Type of measurement=ECOG Performance Status Scale (Eastern Cooperative Oncology Group)
|Results during intervention=No difference between arms
|Results after intervention=No difference between arms
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NA
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=No difference between arms
|Results after intervention=No difference between arms
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Median follow-up of 49 months (range, 0-75): 5-year disease free survival in the intervention arm was 80.1% vs. 83.2% in the control arm, no significant difference; p = 0.74
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=5
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Median follow-up of 51 months (range 6-75): 5-year overall survival in the intervention arm was 91.9% vs. 83.1% in the control arm, no significant difference; p = 0.34
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding="Supported by a grant from biosyn Arzneimittel GmbH, Fellbach, Germany"
|Conflicts of Interest=The authors declare 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=Yes
|Other reasons=* Open study design (knowledge of group assigment)
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=NI
|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=NI
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Testing for selenium deficiency.
* Power analysis conducted.
* Comparability of arms established.
* Very detailed and clear presentation of results.

CONTRA:
* No placebo control.
* No information on possible blinding.
* No information on potential dropouts.
* "Total dose of external radiotherapy (Gy)" at p=0.06 — close to significance between arms.
* No testing whether selenium significantly decreases in the control arm.
* No verification of supplementation outside the study.
* Few demographic variables provided.
}}

Muecke et al. (2010): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology

2024-11-05T13:39:59Z

JDoerfler:

{{Reference
|Reference=Publication: Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology
}}
{{Study Note
|Study Note=Connected to this study one with a subgroup-analysis of the sample: [[Muecke et al. (2013): Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology--a subgroup analysis of a multicenter, phase III trial]] and one follow-up study exists: [[Muecke et al. (2014): Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization]]
}}
=Brief summary=
This study included 81 patients with uterine or cervical cancer. They were randomly divided into two arms and received either 500µg selenium in addition to radiotherapy or no additional preparations. All participants had a selenium deficiency at the beginning of the study. After about seven weeks and thus the end of radiotherapy, a significantly increased selenium concentration was found in the selenium arm compared to the control arm. There was also a lower incidence of radiotherapy-induced diarrhea in the selenium arm compared to the control arm. However, no differences were found with regard to performance status, quality of life, overall survival or disease-free survival after five years. The study impresses with a clear presentation of the results and an examination of the selenium concentration of the participants. However, little information is given about the patients beyond their disease and selenium status and accordingly none can be included in the interpretation of the results. Overall, however, the study can be regarded as methodologically sound.

Diese Studie schloss 81 Patientinnen mit Gebärmutter- oder Gebärmutterhalskrebs ein. Sie wurden zufällig in zwei Gruppen eingeteilt und erhielten entweder zusätzlich zur Radiotherapie 500µg Selen oder keine zusätzlichen Präparate. Alle Probanden hatten zu Beginn der Studie ein Selendefizit. Nach etwa sieben Wochen und damit dem Ende der Radiotherapie zeigte sich eine bedeutsam erhöhte Selenkonzentration in der Selen-Gruppe im Vergleich zur Kontrollgruppe. Es zeigte sich zudem eine geringere Häufigkeit von durch die Radiotherapie verursachtem Durchfall in der Selengruppe im Vergleich zur Kontrollgruppe. Es konnten allerdings keine Unterschiede bezüglich dem Performanz-status, der Lebensqualität oder dem Gesamtüberleben oder dem Krankheitsfreien-Überleben nach fünf Jahren festgestellt werden. Die Studie überzeugt durch eine übersichtliche Darstellung der Ergebnisse und einer Prüfung der Selenkonzentration der Probanden. Allerdings werden über Krankheit- und Selenstatus hinaus wenig Informationen zu den Patientinnen gegeben und dementsprechend können auch keine in die Interpretation der Ergebnisse einbezogen werden. Im Ganzen kann die Studie aber als methodisch solide betrachtet werden.

=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=Patients with histopathologically confirmed carcinomas of the cervix or corpus uteri with a significant whole-blood selenium deficiency (i.e., concentration <85 µg/L) after curative surgical treatment
|Exclusion criteria=Patients with metastatic disease, diarrhea before radiotherapy, radiochemotherapy, or supplementation of selenium before radiotherapy, as well as patients who had undergone previous pelvic radiotherapy
|N randomized=81
|Analysis=NI
|Specifications on analyses=No information about possible drop-out
|Countries of data collection=Germany
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline

T1: Half of the radiotherapy (about 4 weeks)

T2: End of radiotherapy

T3: 6 weeks after radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Gynecologic Cancers - Cervical Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=FIGO Stadium I-IV
|Comorbidity=Selenium concentration (whole-blood) lower than 84µg/L
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=External radiotherapy was delivered with a 6- to 18-MV linear accelerator.
Five fractions per week were planned. Treatment was given with a three- to four-field box technique. Radiotherapy was given as three-dimensional conformal radiotherapy. Computed tomography–based treatment planning was performed in all cases. The clinical target volume encompassed the primary tumor region and the pelvic regional lymph nodes. High-dose rate brachytherapy of the vagina was considered optional in accordance with German evidence-based guidelines. Brachytherapy was delivered by iridium 192 afterloading.
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=NA
|Age groups=Adults (18+)
|Age groups specification=Mean (SD), range: 64.3 (10.1), 31–80 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=39
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Sodium Selenite
|Dosage and regime=500 µg selenium in the form of sodium selenite (selenase®), orally on radiotherapy days and 300 µg on days without radiotherapy
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=1
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=42
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Usual Care
|Dosage and regime=NA
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=NA
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Selenium level
|Outcome specification=Efficiancy of supplementation
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=No difference between arms at baseline, but significantly higher in the intervention arm than the control arm at mid-study (intervention arm: 93.2 µg/L vs. control arm: 67.3 µg/L) and end of study (intervention arm: 90.9±19.9 µg/L vs. control arm: 61.4±15.5 µg/L; p < 0.001)
|Results after intervention=After 6 weeks post radiotherapy, levels between arms were comparable
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Diarrhea
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=Lower incidence of grade 1-3 diarrhea at mid-study in the intervention arm compared to the control arm; p = 0.01
|Results after intervention=Overall incidence of grade 2 diarrhea: intervention arm 20.5% vs. control arm 44.5% (p = 0.04)
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Performance Status
|Outcome specification=NA
|Type of measurement=ECOG Performance Status Scale (Eastern Cooperative Oncology Group)
|Results during intervention=No difference between arms
|Results after intervention=No difference between arms
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NA
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=No difference between arms
|Results after intervention=No difference between arms
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Median follow-up of 49 months (range, 0-75): 5-year disease free survival in the intervention arm was 80.1% vs. 83.2% in the control arm, no significant difference; p = 0.74
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=5
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Median follow-up of 51 months (range 6-75): 5-year overall survival in the intervention arm was 91.9% vs. 83.1% in the control arm, no significant difference; p = 0.34
|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=some concerns
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding="Supported by a grant from biosyn Arzneimittel GmbH, Fellbach, Germany"
|Conflicts of Interest=The authors declare 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=Yes
|Other reasons=* Open study design (knowledge of group assigment)
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=NI
|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=NI
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Testing for selenium deficiency.
* Power analysis conducted.
* Comparability of arms established.
* Very detailed and clear presentation of results.

CONTRA:
* No placebo control.
* No information on possible blinding.
* No information on potential dropouts.
* "Total dose of external radiotherapy (Gy)" at p=0.06 — close to significance between arms.
* No testing whether selenium significantly decreases in the control arm.
* No verification of supplementation outside the study.
* Few demographic variables provided.
}}

Mix et al. (2015): Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck

2024-11-05T13:36:20Z

JDoerfler:

{{Reference
|Reference=Publication: Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck
}}

=Brief summary=
In this study, 18 patients with squamous cell carcinoma of the head and neck who were undergoing chemotherapy and radiotherapy were randomly assigned to two arms in which they either received selenium seven days before, during and three weeks after treatment or a placebo. The results after seven weeks showed no differences between the arms in the development of oral mucosal inflammation or tumor response to treatment. There were also no differences in overall survival, progression-free survival or quality of life at twelve months. There were a number of side effects of chemotherapy and radiotherapy in both arms. However, no direct comparison was carried out here. Overall, the sample is very small, which may well mean that differences were not significant, but as described, comparisons were not always made. Overall, the reporting is very superficial in view of the general study descriptions/framework conditions and in particular the description of the results.

In dieser Studie wurden 18 Patienten mit Plattenepithelkarzinom des Kopf-Hals-Bereiches, welche sich einer Chemo- und Radiotherapie unterzogen zufällig zwei Gruppen zugeordnet, in der sie entweder Selen sieben Tage vor, während der Behandlung und drei Wochen danach bekamen oder ein Placebo. Die Ergebnisse nach sieben Wochen zeigen keine Unterschiede zwischen den Gruppen bezüglich der Entwicklung von Mundschleimhautentzündung, oder der Tumorantwort auf die Behandlung. Es zeigen sich auch keine Unterschiede im Gesamtüberleben oder dem Progressionsfreien-Überleben, sowie der Lebensqualität nach zwölf Monaten. Es zeigten sich eine Reihe von Nebenwirkungen der Chemo- und Radiotherapie in beiden Gruppen. Hier wurde allerdings kein Gruppenvergleich durchgeführt. Insgesamt ist die Stichprobe sehr klein, dies kann durchaus dazu führen, dass Unterschiede nicht signifikant geworden sind, allerdings wurden wie beschrieben auch nicht immer Vergleiche durchgeführt. Insgesamt ist die Berichterstattung sehr oberflächlich in Anbetracht der allgemeinen Studienbeschreibungen/ Rahmenbedingungen und insbesondere der Ergebnisbeschreibung.

=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=Patients with stage III or IV Head and Neck Squamous Cell Carcinoma scheduled for 7 weeks of concurrent cisplatin and radiation, biopsy-proven locally advanced Head and Neck Squamous Cell Carcinoma, in oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, or paranasal sinuses, Eastern Cooperative Oncology Group performance status of 0-2
|Exclusion criteria=Patients who underwent definitive surgery (anything beyond excisional biopsy), those with Stage IVc disease (nonregional metastatic disease), those with malignancy within the previous five years, prior radiotherapy, HIV or hepatitis C positivity, platinum hypersensitivity, inability to tolerate oral medications (in absence of feeding tube), symptomatic peripheral neuropathy, planned use of amifostine, and significant comorbidity
|N randomized=18
|Analysis=ITT Analysis
|Specifications on analyses=Three interim analyses were planned: the first after 20 patients have completed Chemo-Radiotherapy to ensure toxicity in the selenium arm was not unacceptably high and the second and third after one third and two thirds of the patients had been followed for at least 18 months
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline

T1: Week 4

T2: Week 7 during treatment

T3: Week 6-8 post-treatment

T4: Follow-up 3 months after completion of the study

and then at further 3-month intervals over 2 years, then every 6 months until 5 years thereafter
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Skin Cancer - Squamous Cell Carcinoma
|Stage cancer=Advanced Stage
|Cancer stage specification=Head and Neck region; stage III or IV
|Comorbidity=No selenium deficit at baseline
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Radiotherapy: 70 Gy at 2 Gy per fraction in 35 daily treatments, 5 days a week for 7 weeks, chemotherapy: Cisplatin dosed at 100 mg/m² intravenously over 3h in 1000mL saline on days 1, 22, and 43 of radiotherapy
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=17/18 male
|Age groups=Adults (18+)
|Age groups specification=Median: 57 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=10
|Drop-out=1
|Drop-out reasons=Patient complained of "bad taste" and withdrew from the trial
|Intervention=Selenomethionine
|Dosage and regime=Selenomethionine 3600 µg/m²(in 800 µg tablets) 2x daily 7 days before chemotherapy, during chemotherapy 1x daily, and daily for 3 weeks after chemotherapy
|One-time application=No
|Duration in days=49
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=8
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=2x daily 7 days before chemotherapy, during chemotherapy 1x daily, and daily for 3 weeks after chemotherapy
|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=Grade 3 or 4
|Type of measurement=NI
|Results during intervention=NA
|Results after intervention=Overall: No significant differences between arms (grade 3 intervention arm 2x, placebo arm 3x, no grade 4)
|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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Tumor response
|Outcome specification=Complete response rate (CR)
|Type of measurement=RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
|Results during intervention=NA
|Results after intervention=Only one patient from the intervention arm did not reach CR and died
|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=some concerns
|Overall RoB judgment=low risk
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=After 12 months: No significant differences between arms
|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=some concerns
|Overall RoB judgment=low risk
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=After 12 months: No significant differences between arms
|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=some concerns
|Overall RoB judgment=low risk
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=Measured with EORTC C-30 Version 3 and EORTC QLQ - H&N35
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=No significant difference for the 7 weeks of intervention
|Results after intervention=No significant difference for week 6-8 post-treatment and Follow-up within a year
|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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=5
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Other treatment-associated side effects such as xerostomia, renal impairment, hearing dysfunction, and myelosuppression
|Type of measurement=NI
|Results during intervention=NA
|Results after intervention=Overall:
* Hearing dysfunction n=1 each in the intervention arm and placebo arm;

* elevated creatinine n=1 in the placebo arm;

* myelosuppression: anemia in the placebo arm n=1;

* leukopenia in the intervention arm n=3 and placebo arm n=2;

* dermatitis in the intervention arm n=2;

* dry mouth in the placebo arm n=2;

* dysgeusia in the intervention arm n=2, placebo arm n=1;

* odyno-/dysphagia in the intervention arm n=1, placebo arm n=2;

* oral/throat pain in the placebo arm n=2;

* mucus/sputum intervention arm n=3, placebo arm n=1
|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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=6
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=“Supported by A grant from the Health Research Council of
New Zealand (in part).“
|Conflicts of Interest=Authors declare 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="The trial was planned to recruit 80 patients but, due to funding constraints, recruitment was suspended after 18 patients and an interim analysis was performed to see if a sufficiently promising effect could be discerned to warrant further funding."
|Samples sufficiently large=No
|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=* Small sample size, possibility of beta error
|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=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=No
|Side effects taken into account in the interpretation of the results=NA
|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
|Additional Notes=Note: Chemotherapy compliance: 8x every 3 cycles of cisplatin, 6x 2 cycles, 2x 1 cycle, 1x, 1x no chemotherapy

PRO:
* Ethics approval obtained.
* Participants were instructed to keep a diary of tablet intake.
* Intent-to-treat analysis conducted.
* Sample size calculation performed.
* Measurement of selenium concentration at baseline (no group difference).
* Comparability of groups at baseline established.

CONTRA:
* Very small sample size.
* No indication of selenium deficiencies present.
* Very superficial reporting, particularly in the results section, with little information on blinding.
* No group comparison for number of chemotherapy/radiotherapy side effects or selenium concentration.
}}

Karp et al. (2012): Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597

2024-11-05T13:34:43Z

JDoerfler:

{{Reference
|Reference=Publication: Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597
}}

=Brief summary=
In this study, 1561 participants with resected non-small cell lung cancer were included. They were randomly divided into two arms and were each to take 200 µg of yeast selenium (1040 participants) or a placebo (521 participants) every day. However, the study was terminated early, as an interim analysis after a study period of around nine years showed that no benefit could be achieved for the selenium arm; instead, there was a positive trend for the placebo arm. In a final analysis another two years later, there were no significant differences in the incidence of secondary tumors, lung cancer or other cancer recurrence, time to recurrence or overall survival of the patients. However, it was shown that participants who had never smoked had a higher survival time after three and five years than those who were current smokers or had only quit in the last year. The study leaves out basic framework descriptions. A promising subgroup analysis between different selenium concentrations and their effects on the cancer-free time interval remains without statistical value and thus cannot be clearly interpreted.

In dieser Studie wurden 1561 Probanden mit reseziertem nicht-kleinzelligem Lungenkarzinom eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt und sollten jeweils jeden Tag 200 µg Hefeselen (1040 Probanden) oder ein Placebo (521 Probanden) zu sich nehmen. Die Studie wurde allerdings frühzeitig abgebrochen, da sich in einer Zwischenanalyse nach etwa neun Jahren Studienlaufzeit abzeichnete, dass kein Vorteil für die Selengruppe erzielt werden könne, stattdessen gab es einen positiven Trend für die Placebogruppe. In einer abschließenden Analyse weitere zwei Jahre später zeigten sich keine bedeutsamen Unterschiede bezüglich des Auftretens von sekundären Tumoren, Lungenkrebs oder sonstiger Rückkehr von Krebs, sowie der Zeit bis zur Rückkehr oder dem Gesamtüberleben der Patienten. Allerdings wurde gezeigt, dass Personen, die nie geraucht haben, eine höhere Überlebenszeit nach drei und fünf Jahren zeigten, als Probanden die aktuell rauchten, oder erst im letzten Jahr aufgehört hatten. Die Studie vernachlässigt grundlegende Rahmenbeschreibungen. Eine vielversprechende Subgruppenanalyse zwischen verschieden hohen Selenkonzentration und deren Auswirkungen auf das Krebsfreie-Zeitintervall bleibt ohne statistische Wertangabe und kann damit nicht eindeutig interpretiert werden.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=36 months from complete resection of histologically proven stage IA (pT1N0) or stage IB (pT2N0) NSCLC (carcinoid tumors were excluded); pathologic stage N0 confirmed by sampling at least one mediastinal lymph node at resection; chest x-ray or computed tomography scan ≤ 8 weeks before registration without sign of new or recurrent lung cancer; no concurrent cancers or any other prior cancer history within the past 5 years, except localized nonmelanoma skin cancer; no synchronous lesions (lung + nonlung) or metastasis, even if resectable; no history of greater than one lung cancer primary tumor at any time; normal hepatic function (total bilirubin and Aspartat-Aminotransferase or Alanin-Aminotransferase ≤ institutional upper limit of normal); laboratory values (including Complete Blood Count) obtained within 8 weeks before registration; and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients with stage IA Non-Small Cell Lung Cancer should not have received any therapy other than surgery. Patients with stage IB Non-Small Cell Lung Cancer were allowed to have received other primary therapy (chemotherapy, radiotherapy, or biologic therapy) provided this was completed at least 6 months before study registration and all treatment-related symptoms had subsided before study registration.

Supplements were defined as any nonfood compound taken by mouth or injection to provide dietary factors. Supplements containing ≥ 70 µg of selenium taken regularly (≥ three times per week for ≥ 4 consecutive weeks during the prior year) were required to be discontinued ≥ 1 month before registration. Supplements containing ≤ 70 µg of selenium were continued throughout study participation. Supplements not containing selenium were either discontinued ≥ 2 weeks before study entry or continued throughout study participation.
|Exclusion criteria=NI
|N randomized=1561
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=Study period: October 6, 2000 - November 5, 2009
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage
|Cancer stage specification=IA (pT1N0) or IB (pT2N0)
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Mixed
|Gender specifications=Female: intervention arm 51%, placebo arm 52%
|Age groups=Adults (18+)
|Age groups specification=Age (median): 66 years; range: intervention arm 24-94 years; placebo arm 38-86 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=1040
|Drop-out=N=817
|Drop-out reasons=Ineligible (n = 10);
No therapy (n = 12)

Discontinued treatment:
Completed (n = 238);
Progression (n = 117);
Toxicity (n = 20);
Death (n = 18);
Withdrawal (n = 157);
Nonprotocol treatment (n = 1);
Complicating disease (n = 30);
Maximum dose (n = 2);
Other (n = 212)
|Intervention=Selenium
|Dosage and regime=200 µg daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=26 in intervention arm had a diabetes diagnosis
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=521
|Drop-out=N=406
|Drop-out reasons=Ineligible (n = 6);
No therapy (n = 2)

Discontinued treatment:
Completed (n = 134);
Progression (n = 52);
Toxicity (n = 8);
Death (n = 12);
Withdrawal (n = 67);
Nonprotocol treatment (n = 3);
Complicating disease (n = 17);
Other (n = 105)
|Intervention=Placebo
|Dosage and regime=Daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=12 in placebo arm had a diabetes diagnosis
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=DFS Randomization until secondary tumors or recurrence and 5-year DFS
|Type of measurement=Observation
|Results during intervention=During study: n=44 non-melanoma skin cancers, (n=14 and n=13 basal cell carcinoma and n=11 and n=6 squamous cell carcinoma in intervention and placebo arm), no significant values given
|Results after intervention=Interim analysis October 2009:
N=83 secondary lung tumors; Rate intervention arm: 1.91 per 100 persons per year vs. 1.36 in placebo arm; p=ns

June 2011:
N=252 secondary tumors in 224 patients, of which 98 (out of 97 patients) were lung cancer (38.9%); Lung cancer and other cancers (SPT) in intervention arm: 1.62 and 3.54 per 100 persons per year vs. placebo arm: 1.30 and 3.39 per 100 persons per year; p=0.294

5-year DFS:
October 2009:
Intervention arm: 72% vs. placebo arm: 78%, no significance values given

June 2011:
Intervention arm: 74.4% vs. placebo arm: 79.6%; p=0.69

Note: 5-year DFS rates with subdivision into low, average and high selenium concentration intervention vs. placebo: 75.5% (SE, 10.3%) vs. 72.9% (SE, 12.7%), 75.6% (SE, 2.27%) vs. 78.2% (SE, 3.3%), and 72.9% (SE, 4.5%) vs. 80.9% (SE, 5.2%)
|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=some concerns
|Overall RoB judgment=low risk
|Order number=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=5-year OS
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Intervention arm: 76.8% (SE, 1.6%) vs. placebo arm: 79.9% (SE, 2.1%); p=0.154

Note: Distribution significantly different for smoking status (p=0.027): active smokers or those who had quit within one year showed a 3-year OS of 85.5% (SE, 1.7%) and 5-year OS of 74.9% (SE, 2.4%), whereas participants who had never smoked showed a 3-year OS of 90% (SE, 2.8%) and a 5-year OS of 83.6% (SE, 3.6%); no difference for DFS; p=0.245
|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=some concerns
|Overall RoB judgment=low risk
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Collected in 865 patients in intervention arm and 477 in placebo arm:
* Grade 1-2 toxicity in intervention arm: 31% and placebo arm: 26% of subjects
* Grade ≥ 3 toxicity occurred in less than 2% of subjects in intervention arm and 3% in placebo arm
* n=1 patient in placebo arm had constitutional lethal toxicity
* no arm comparison performed
|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=some concerns
|Overall RoB judgment=low risk
|Order number=3
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Selenium level at baseline (n=1,022), year 2 (n=375), and year 4 (n=194): at baseline selenium level mostly in normal range, after 2 and 4 years significantly increased selenium concentration in the intervention arm
|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=some concerns
|Overall RoB judgment=low risk
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=According to authors none.
|Conflicts of Interest=“Employment or Leadership Position: None; Consultant or Advisory Role: David H. Johnson, Peloton Therapeutics (C), Mirna Therapeutics (C) Stock Ownership: None; Honoraria: None; research; Expert Testimony: None; Patents: None Other Remuneration: None“
}}
=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=No
|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=* Subjects could continue to take supplements that contained ≤70 µg selenium and also others that did not contain selenium
|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=NA
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=Note: Interim analysis in October 2009 (46% of endpoints reached with 1561 patients randomized), study was stopped by DMC on November 5, 2009 as a trend for a placebo arm benefit was found; June 2011 update with 54% of the endpoints

PRO:
* Prior testing of compliance in a 4-week phase and then testing every 3 months.
* Stratification by demographic variables.
* Power analysis conducted.
* Intent-to-treat analysis performed.
* Measurement of selenium concentration.
* Very detailed presentation of data.

CONTRA:
* Participants could continue taking supplements containing ≤70 µg of selenium and others containing no selenium.
* Subgroup analysis based on selenium concentration level but without significance values.
* No mention of ethics approval.
* Confusing description of DFS (disease-free survival).
* Figure 2b describes OS (overall survival) in days (typographical error).
* OS curves diverge significantly after approximately 7.5 years, but no explanation of these data is provided.
}}

Karp et al. (2012): Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597

2024-11-05T13:32:20Z

JDoerfler:

{{Reference
|Reference=Publication: Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597
}}
{{Study Note}}
=Brief summary=
In this study, 1561 participants with resected non-small cell lung cancer were included. They were randomly divided into two arms and were each to take 200 µg of yeast selenium (1040 participants) or a placebo (521 participants) every day. However, the study was terminated early, as an interim analysis after a study period of around nine years showed that no benefit could be achieved for the selenium arm; instead, there was a positive trend for the placebo arm. In a final analysis another two years later, there were no significant differences in the incidence of secondary tumors, lung cancer or other cancer recurrence, time to recurrence or overall survival of the patients. However, it was shown that participants who had never smoked had a higher survival time after three and five years than those who were current smokers or had only quit in the last year. The study leaves out basic framework descriptions. A promising subgroup analysis between different selenium concentrations and their effects on the cancer-free time interval remains without statistical value and thus cannot be clearly interpreted.

In dieser Studie wurden 1561 Probanden mit reseziertem nicht-kleinzelligem Lungenkarzinom eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt und sollten jeweils jeden Tag 200 µg Hefeselen (1040 Probanden) oder ein Placebo (521 Probanden) zu sich nehmen. Die Studie wurde allerdings frühzeitig abgebrochen, da sich in einer Zwischenanalyse nach etwa neun Jahren Studienlaufzeit abzeichnete, dass kein Vorteil für die Selengruppe erzielt werden könne, stattdessen gab es einen positiven Trend für die Placebogruppe. In einer abschließenden Analyse weitere zwei Jahre später zeigten sich keine bedeutsamen Unterschiede bezüglich des Auftretens von sekundären Tumoren, Lungenkrebs oder sonstiger Rückkehr von Krebs, sowie der Zeit bis zur Rückkehr oder dem Gesamtüberleben der Patienten. Allerdings wurde gezeigt, dass Personen, die nie geraucht haben, eine höhere Überlebenszeit nach drei und fünf Jahren zeigten, als Probanden die aktuell rauchten, oder erst im letzten Jahr aufgehört hatten. Die Studie vernachlässigt grundlegende Rahmenbeschreibungen. Eine vielversprechende Subgruppenanalyse zwischen verschieden hohen Selenkonzentration und deren Auswirkungen auf das Krebsfreie-Zeitintervall bleibt ohne statistische Wertangabe und kann damit nicht eindeutig interpretiert werden.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=36 months from complete resection of histologically proven stage IA (pT1N0) or stage IB (pT2N0) NSCLC (carcinoid tumors were excluded); pathologic stage N0 confirmed by sampling at least one mediastinal lymph node at resection; chest x-ray or computed tomography scan ≤ 8 weeks before registration without sign of new or recurrent lung cancer; no concurrent cancers or any other prior cancer history within the past 5 years, except localized nonmelanoma skin cancer; no synchronous lesions (lung + nonlung) or metastasis, even if resectable; no history of greater than one lung cancer primary tumor at any time; normal hepatic function (total bilirubin and Aspartat-Aminotransferase or Alanin-Aminotransferase ≤ institutional upper limit of normal); laboratory values (including Complete Blood Count) obtained within 8 weeks before registration; and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients with stage IA Non-Small Cell Lung Cancer should not have received any therapy other than surgery. Patients with stage IB Non-Small Cell Lung Cancer were allowed to have received other primary therapy (chemotherapy, radiotherapy, or biologic therapy) provided this was completed at least 6 months before study registration and all treatment-related symptoms had subsided before study registration.

Supplements were defined as any nonfood compound taken by mouth or injection to provide dietary factors. Supplements containing ≥ 70 µg of selenium taken regularly (≥ three times per week for ≥ 4 consecutive weeks during the prior year) were required to be discontinued ≥ 1 month before registration. Supplements containing ≤ 70 µg of selenium were continued throughout study participation. Supplements not containing selenium were either discontinued ≥ 2 weeks before study entry or continued throughout study participation.
|Exclusion criteria=NI
|N randomized=1561
|Analysis=ITT Analysis
|Specifications on analyses=NA
|Countries of data collection=United States
|LoE=2b Oxford 2009
|Outcome timeline=Study period: October 6, 2000 - November 5, 2009
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage
|Cancer stage specification=IA (pT1N0) or IB (pT2N0)
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Mixed
|Gender specifications=Female: intervention arm 51%, placebo arm 52%
|Age groups=Adults (18+)
|Age groups specification=Age (median): 66 years; range: intervention arm 24-94 years; placebo arm 38-86 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=1040
|Drop-out=N=817
|Drop-out reasons=Ineligible (n = 10);
No therapy (n = 12)

Discontinued treatment:
Completed (n = 238);
Progression (n = 117);
Toxicity (n = 20);
Death (n = 18);
Withdrawal (n = 157);
Nonprotocol treatment (n = 1);
Complicating disease (n = 30);
Maximum dose (n = 2);
Other (n = 212)
|Intervention=Selenium
|Dosage and regime=200 µg daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=26 in intervention arm had a diabetes diagnosis
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=521
|Drop-out=N=406
|Drop-out reasons=Ineligible (n = 6);
No therapy (n = 2)

Discontinued treatment:
Completed (n = 134);
Progression (n = 52);
Toxicity (n = 8);
Death (n = 12);
Withdrawal (n = 67);
Nonprotocol treatment (n = 3);
Complicating disease (n = 17);
Other (n = 105)
|Intervention=Placebo
|Dosage and regime=Daily
|One-time application=No
|Duration in days=1460
|Side Effects / Interactions=Unclear association, but in long-term follow-up: n=12 in placebo arm had a diabetes diagnosis
|Order number=1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=DFS Randomization until secondary tumors or recurrence and 5-year DFS
|Type of measurement=Observation
|Results during intervention=During study: n=44 non-melanoma skin cancers, (n=14 and n=13 basal cell carcinoma and n=11 and n=6 squamous cell carcinoma in intervention and placebo arm), no significant values given
|Results after intervention=Interim analysis October 2009:
N=83 secondary lung tumors; Rate intervention arm: 1.91 per 100 persons per year vs. 1.36 in placebo arm; p=ns

June 2011:
N=252 secondary tumors in 224 patients, of which 98 (out of 97 patients) were lung cancer (38.9%); Lung cancer and other cancers (SPT) in intervention arm: 1.62 and 3.54 per 100 persons per year vs. placebo arm: 1.30 and 3.39 per 100 persons per year; p=0.294

5-year DFS:
October 2009:
Intervention arm: 72% vs. placebo arm: 78%, no significance values given

June 2011:
Intervention arm: 74.4% vs. placebo arm: 79.6%; p=0.69

Note: 5-year DFS rates with subdivision into low, average and high selenium concentration intervention vs. placebo: 75.5% (SE, 10.3%) vs. 72.9% (SE, 12.7%), 75.6% (SE, 2.27%) vs. 78.2% (SE, 3.3%), and 72.9% (SE, 4.5%) vs. 80.9% (SE, 5.2%)
|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=some concerns
|Overall RoB judgment=low risk
|Order number=1
}}
{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=5-year OS
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Intervention arm: 76.8% (SE, 1.6%) vs. placebo arm: 79.9% (SE, 2.1%); p=0.154

Note: Distribution significantly different for smoking status (p=0.027): active smokers or those who had quit within one year showed a 3-year OS of 85.5% (SE, 1.7%) and 5-year OS of 74.9% (SE, 2.4%), whereas participants who had never smoked showed a 3-year OS of 90% (SE, 2.8%) and a 5-year OS of 83.6% (SE, 3.6%); no difference for DFS; p=0.245
|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=some concerns
|Overall RoB judgment=low risk
|Order number=2
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Collected in 865 patients in intervention arm and 477 in placebo arm:
* Grade 1-2 toxicity in intervention arm: 31% and placebo arm: 26% of subjects
* Grade ≥ 3 toxicity occurred in less than 2% of subjects in intervention arm and 3% in placebo arm
* n=1 patient in placebo arm had constitutional lethal toxicity
* no arm comparison performed
|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=some concerns
|Overall RoB judgment=low risk
|Order number=3
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Selenium level at baseline (n=1,022), year 2 (n=375), and year 4 (n=194): at baseline selenium level mostly in normal range, after 2 and 4 years significantly increased selenium concentration in the intervention arm
|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=some concerns
|Overall RoB judgment=low risk
|Order number=4
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=According to authors none.
|Conflicts of Interest=“Employment or Leadership Position: None; Consultant or Advisory Role: David H. Johnson, Peloton Therapeutics (C), Mirna Therapeutics (C) Stock Ownership: None; Honoraria: None; research; Expert Testimony: None; Patents: None Other Remuneration: None“
}}
=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=No
|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=* Subjects could continue to take supplements that contained ≤70 µg selenium and also others that did not contain selenium
|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=NA
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=Yes
|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
|Additional Notes=Note: Interim analysis in October 2009 (46% of endpoints reached with 1561 patients randomized), study was stopped by DMC on November 5, 2009 as a trend for a placebo arm benefit was found; June 2011 update with 54% of the endpoints

PRO:
* Prior testing of compliance in a 4-week phase and then testing every 3 months.
* Stratification by demographic variables.
* Power analysis conducted.
* Intent-to-treat analysis performed.
* Measurement of selenium concentration.
* Very detailed presentation of data.

CONTRA:
* Participants could continue taking supplements containing ≤70 µg of selenium and others containing no selenium.
* Subgroup analysis based on selenium concentration level but without significance values.
* No mention of ethics approval.
* Confusing description of DFS (disease-free survival).
* Figure 2b describes OS (overall survival) in days (typographical error).
* OS curves diverge significantly after approximately 7.5 years, but no explanation of these data is provided.
}}

Jahangard-Rafsanjani et al. (2013): The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial

2024-11-05T12:55:39Z

JDoerfler:

{{Reference
|Reference=Publication: The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial
}}

=Brief summary=
This study included 77 patients with acute lymphoblastic or myeloid leukemia who were undergoing high-dose chemotherapy and subsequent stem cell transplantation. The aim of the study was to find out whether the intake of selenium can influence the occurrence of mucositis. Other laboratory parameters and symptoms of the patients were also recorded. For the study, the patients were randomly divided into two arms, so that one arm (38 participants) received 200 mcg of selenium twice a day during chemotherapy and up to 14 days after the transplant, while the other arm received a placebo. Overall, there were no differences in the onset, frequency, or duration of mucositis between the two arms. However, there were significantly fewer severe cases of mucositis in the selenium arm, and the duration of the more severe cases in the selenium arm was also shorter compared to the placebo arm. There were no differences in length of hospital stay, duration of fever, frequency of immunologic response to the transplant, mortality, or other laboratory parameters related to liver or kidney function. The study is methodologically well conducted, but provides little information about the sample included (few demographic details). An existing selenium deficiency can be deduced from the available values despite the absence of a direct mention of it. The use of medication for the general prevention of mucositis could also have affected the direct influence of selenium on mucositis.

In dieser Studie wurden 77 Patienten mit akuter lymphatischer oder myeloischer Leukämie eingeschlossen, welche sich einer hochdosierten Chemotherapie und anschließend einer Stammzelltransplantation unterzogen. Ziel der Studie war es herauszufinden, ob die Einnahme von Selen das Auftreten von Mukositis beeinflussen kann. Es wurden zudem weitere Laborparameter und Symptome der Patienten erhoben. Für die Studie wurden die Patienten zufällig in zwei Gruppen eingeteilt, so dass eine Gruppe (38 Probanden) während der Chemotherapie und bis 14 Tage nach der Transplantation jeden Tag 2x täglich 200mcg Selen erhielten und die andere Gruppe ein Placebo. Insgesamt gab es keine Unterschiede über den Beginn, die Häufigkeit oder die Dauer der Mukositis zwischen den beiden Gruppen. Es gab allerdings bedeutsam weniger schwere Fälle von Mukositis in der Selen-Gruppe, und auch die Dauer der schwereren Fälle in der Selengruppe war kürzer im Vergleich zur Placebogruppe. Es gab keine Unterschiede bezüglich Länge des Krankenhausaufenthaltes, Dauer des aufgetretenen Fiebers, der Häufigkeit der immunologischen Abwehrreaktion auf das Transplantat oder der Sterblichkeit, sowie weitere Laborparameter bezüglich der Leber- oder Nierenfunktion. Die Studie ist methodisch gut durchgeführt, gibt aber wenig Informationen über die einbezogene Stichprobe (wenig demographische Angaben). Ein vorliegender Selenmangel kann trotz Fehlens eines direkten Erwähnens dessen aus den vorliegenden Werten abgeleitet werden. Auch der Einsatz von Medikamenten zur generellen Mukositisprävention könnte den direkten Einfluss von Selen auf die Mukositis beeinträchtigt 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=Patients with Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia, undergoing allogenic Hematopoietic Stem Cell Transplantation, all patients had adequate cardiac, pulmonary, renal, and hepatic function as determined by the institutional protocol

+ baseline indicates a mild selenium deficiency
|Exclusion criteria=Patients were excluded if they had a Karnofsky performance status under 70%
|N randomized=77
|Analysis=PP Analysis
|Specifications on analyses=analyzed n=74
|Countries of data collection=Iran
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline (start of chemotherapy)

T1: End of chemotherapy (6 days)

T2: +1 day: transplantation

T3: 21 days after transplantation

T4: Follow-up after 3 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid)
|Stage cancer=NA
|Cancer stage specification=Patients in different stages of complete remission: CR1, CR2, CR3
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Stem cell or bone marrow transplant
|Specifications on cancer therapies=The high-dose chemotherapy included busulfan 4 mg/kg p.o. in divided doses daily for 4 days (total dose 16 mg/kg) followed by cyclophsophamide 60 mg/kg once daily i.v. for 2 days (total dose 120 mg/kg) + peripheral blood hematopoietic stem cells 1 day after completion of chemotherapy
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=43.2% female
|Age groups=Adults (18+)
|Age groups specification=Mean; median; range in years:
Intervention arm 33.3; 32; 18-55 and placebo arm 34; 32; 18-55
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=38
|Drop-out=1
|Drop-out reasons=Patient was non-adherent
|Intervention=Selenium tablet

+ every arm similar regime for prevention oc mucositis: 20 drops of nystatin every 3h, a chewable tablet of sucralfate 500mg every 8h and mouth washes containing 10 cc chlorhexidine 0.02% plus 10 cc diluted povidone iodine every 3h
|Dosage and regime=Selenium tablet (Webber Naturals, Coquitlam, BC, Canada, 200 mcg) twice daily, from the starting day of HDC to 14 days after transplantation
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=39
|Drop-out=2
|Drop-out reasons=N=1 patient died, n=1 patient was non-adherent
|Intervention=Placebo

+ every arm similar regime for prevention oc mucositis: 20 drops of nystatin every 3 h, a chewable tablet of sucralfate 500mg every 8 h and mouth washes containing 10 cc chlorhexidine 0.02% plus 10 cc diluted povidone iodine every 3h
|Dosage and regime=Placebo twice daily, from the starting day of HDC to 14 days after transplantation
|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=Oral Mucositis
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Onset of mucositis after transplantation comparable in both selenium arm (6.16±1.57) and placebo arm (6.27±1.8); p=0.81
|Results after intervention=Overall: Cumulative incidence (grade 1-4) comparable in both selenium arm (83.8%) and placebo arm (81.1%); p=0.76; grade 3-4 mucositis significantly lower in selenium arm (10.8%) compared to placebo arm (35.1%); p=0.013 (grade 4: 2x in placebo arm, 0x in selenium arm)

Mean duration comparable (p=0.048), only duration of objective mucositis from grade 2 to 4 and back was significantly shorter in the selenium arm (3.6±1.84 days) than in the placebo arm (5.3±2.2 days); p=0.014
|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=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Haematological indices
|Outcome specification=Neutrophil and platelet engraftment time (the time point after transplantation at which a patient can maintain a sustained ANC of 4500 cells/mm3 and a sustained platelet count of at least 20 000/mm3 lasting 3 consecutive days without transfusions during hospital stay)
|Type of measurement=Blood Test
|Results during intervention=No difference between arms (p=0.32, p=0.87)
|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=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fever
|Outcome specification=Duration of fever
|Type of measurement=Observation
|Results during intervention=Fever above 38.3°C in 72 patients (97.3%) during neutropenia; duration of fever comparable in both selenium arm (3.81±1.96 days) and placebo arm (3.83±2.93 days); p=0.98
|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=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Length of hospital stay
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No difference between selenium arm (26.92±6.26 days) and placebo arm (25.81±4.33 days); p=0.38
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Incidence of acute GVHD (Graft-Versus-Host Disease)
|Outcome specification=Graft-versus-host disease is a condition where the donated stem cells (graft) attack the recipient's body (host)
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Overall: No difference between the arms; p= 0.35
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=5
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Mortality rate
|Outcome specification=At 3 months
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No difference between the arms; p= 0.69
|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)=low risk
|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=6
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Non-haematological indices
|Outcome specification=Serum creatinine level and blood urea nitrogen test for renal function assessment and aspartate aminotransferase and alanine transaminase for liver function assessment, recorded daily
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Overall: No difference between arms for increase in serum creatinine; p=0.31 or increase in aspartate aminotransferase and alanine transaminase: p=0.62
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=7
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Significant difference in mean serum selenium level between two arms at 14 days after transplantation (8.34 mcg/dL in the selenium arm vs 7.36 mcg/dL in the placebo arm), p=0.018
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=8
}}
{{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=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=NI
|Correction for multiple testing=No
|Measurement of compliance=No
|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=No
|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.
* Placebo-controlled and double-blind.
* Power analysis and adherence to sample size.
* Detailed protocol description.
* Measurement of selenium levels.

CONTRA:
* No compliance verification.
* No information on side effects or potential interactions with medications for mucositis prevention.
* Focus on small effects rather than clinically relevant ones and those corresponding to the predefined research question.
* Despite stating that previous studies show most stem cell transplant patients suffer from selenium deficiency, this was not tested or described here.
* Very few demographic variables provided.
* No verification of successful blinding.
* No information on whether participants could or did take other supplements.
}}

Jahangard-Rafsanjani et al. (2013): The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial

2024-11-05T12:55:31Z

JDoerfler:

{{Reference
|Reference=Publication: The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial
}}
{{Study Note}}
=Brief summary=
This study included 77 patients with acute lymphoblastic or myeloid leukemia who were undergoing high-dose chemotherapy and subsequent stem cell transplantation. The aim of the study was to find out whether the intake of selenium can influence the occurrence of mucositis. Other laboratory parameters and symptoms of the patients were also recorded. For the study, the patients were randomly divided into two arms, so that one arm (38 participants) received 200 mcg of selenium twice a day during chemotherapy and up to 14 days after the transplant, while the other arm received a placebo. Overall, there were no differences in the onset, frequency, or duration of mucositis between the two arms. However, there were significantly fewer severe cases of mucositis in the selenium arm, and the duration of the more severe cases in the selenium arm was also shorter compared to the placebo arm. There were no differences in length of hospital stay, duration of fever, frequency of immunologic response to the transplant, mortality, or other laboratory parameters related to liver or kidney function. The study is methodologically well conducted, but provides little information about the sample included (few demographic details). An existing selenium deficiency can be deduced from the available values despite the absence of a direct mention of it. The use of medication for the general prevention of mucositis could also have affected the direct influence of selenium on mucositis.

In dieser Studie wurden 77 Patienten mit akuter lymphatischer oder myeloischer Leukämie eingeschlossen, welche sich einer hochdosierten Chemotherapie und anschließend einer Stammzelltransplantation unterzogen. Ziel der Studie war es herauszufinden, ob die Einnahme von Selen das Auftreten von Mukositis beeinflussen kann. Es wurden zudem weitere Laborparameter und Symptome der Patienten erhoben. Für die Studie wurden die Patienten zufällig in zwei Gruppen eingeteilt, so dass eine Gruppe (38 Probanden) während der Chemotherapie und bis 14 Tage nach der Transplantation jeden Tag 2x täglich 200mcg Selen erhielten und die andere Gruppe ein Placebo. Insgesamt gab es keine Unterschiede über den Beginn, die Häufigkeit oder die Dauer der Mukositis zwischen den beiden Gruppen. Es gab allerdings bedeutsam weniger schwere Fälle von Mukositis in der Selen-Gruppe, und auch die Dauer der schwereren Fälle in der Selengruppe war kürzer im Vergleich zur Placebogruppe. Es gab keine Unterschiede bezüglich Länge des Krankenhausaufenthaltes, Dauer des aufgetretenen Fiebers, der Häufigkeit der immunologischen Abwehrreaktion auf das Transplantat oder der Sterblichkeit, sowie weitere Laborparameter bezüglich der Leber- oder Nierenfunktion. Die Studie ist methodisch gut durchgeführt, gibt aber wenig Informationen über die einbezogene Stichprobe (wenig demographische Angaben). Ein vorliegender Selenmangel kann trotz Fehlens eines direkten Erwähnens dessen aus den vorliegenden Werten abgeleitet werden. Auch der Einsatz von Medikamenten zur generellen Mukositisprävention könnte den direkten Einfluss von Selen auf die Mukositis beeinträchtigt 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=Patients with Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia, undergoing allogenic Hematopoietic Stem Cell Transplantation, all patients had adequate cardiac, pulmonary, renal, and hepatic function as determined by the institutional protocol

+ baseline indicates a mild selenium deficiency
|Exclusion criteria=Patients were excluded if they had a Karnofsky performance status under 70%
|N randomized=77
|Analysis=PP Analysis
|Specifications on analyses=analyzed n=74
|Countries of data collection=Iran
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline (start of chemotherapy)

T1: End of chemotherapy (6 days)

T2: +1 day: transplantation

T3: 21 days after transplantation

T4: Follow-up after 3 months
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid)
|Stage cancer=NA
|Cancer stage specification=Patients in different stages of complete remission: CR1, CR2, CR3
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Stem cell or bone marrow transplant
|Specifications on cancer therapies=The high-dose chemotherapy included busulfan 4 mg/kg p.o. in divided doses daily for 4 days (total dose 16 mg/kg) followed by cyclophsophamide 60 mg/kg once daily i.v. for 2 days (total dose 120 mg/kg) + peripheral blood hematopoietic stem cells 1 day after completion of chemotherapy
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=43.2% female
|Age groups=Adults (18+)
|Age groups specification=Mean; median; range in years:
Intervention arm 33.3; 32; 18-55 and placebo arm 34; 32; 18-55
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=38
|Drop-out=1
|Drop-out reasons=Patient was non-adherent
|Intervention=Selenium tablet

+ every arm similar regime for prevention oc mucositis: 20 drops of nystatin every 3h, a chewable tablet of sucralfate 500mg every 8h and mouth washes containing 10 cc chlorhexidine 0.02% plus 10 cc diluted povidone iodine every 3h
|Dosage and regime=Selenium tablet (Webber Naturals, Coquitlam, BC, Canada, 200 mcg) twice daily, from the starting day of HDC to 14 days after transplantation
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=39
|Drop-out=2
|Drop-out reasons=N=1 patient died, n=1 patient was non-adherent
|Intervention=Placebo

+ every arm similar regime for prevention oc mucositis: 20 drops of nystatin every 3 h, a chewable tablet of sucralfate 500mg every 8 h and mouth washes containing 10 cc chlorhexidine 0.02% plus 10 cc diluted povidone iodine every 3h
|Dosage and regime=Placebo twice daily, from the starting day of HDC to 14 days after transplantation
|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=Oral Mucositis
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Onset of mucositis after transplantation comparable in both selenium arm (6.16±1.57) and placebo arm (6.27±1.8); p=0.81
|Results after intervention=Overall: Cumulative incidence (grade 1-4) comparable in both selenium arm (83.8%) and placebo arm (81.1%); p=0.76; grade 3-4 mucositis significantly lower in selenium arm (10.8%) compared to placebo arm (35.1%); p=0.013 (grade 4: 2x in placebo arm, 0x in selenium arm)

Mean duration comparable (p=0.048), only duration of objective mucositis from grade 2 to 4 and back was significantly shorter in the selenium arm (3.6±1.84 days) than in the placebo arm (5.3±2.2 days); p=0.014
|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=high risk
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Haematological indices
|Outcome specification=Neutrophil and platelet engraftment time (the time point after transplantation at which a patient can maintain a sustained ANC of 4500 cells/mm3 and a sustained platelet count of at least 20 000/mm3 lasting 3 consecutive days without transfusions during hospital stay)
|Type of measurement=Blood Test
|Results during intervention=No difference between arms (p=0.32, p=0.87)
|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=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fever
|Outcome specification=Duration of fever
|Type of measurement=Observation
|Results during intervention=Fever above 38.3°C in 72 patients (97.3%) during neutropenia; duration of fever comparable in both selenium arm (3.81±1.96 days) and placebo arm (3.83±2.93 days); p=0.98
|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=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Length of hospital stay
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No difference between selenium arm (26.92±6.26 days) and placebo arm (25.81±4.33 days); p=0.38
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Incidence of acute GVHD (Graft-Versus-Host Disease)
|Outcome specification=Graft-versus-host disease is a condition where the donated stem cells (graft) attack the recipient's body (host)
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Overall: No difference between the arms; p= 0.35
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=5
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Mortality rate
|Outcome specification=At 3 months
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No difference between the arms; p= 0.69
|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)=low risk
|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=6
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Non-haematological indices
|Outcome specification=Serum creatinine level and blood urea nitrogen test for renal function assessment and aspartate aminotransferase and alanine transaminase for liver function assessment, recorded daily
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Overall: No difference between arms for increase in serum creatinine; p=0.31 or increase in aspartate aminotransferase and alanine transaminase: p=0.62
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=7
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=NA
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Significant difference in mean serum selenium level between two arms at 14 days after transplantation (8.34 mcg/dL in the selenium arm vs 7.36 mcg/dL in the placebo arm), p=0.018
|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=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=8
}}
{{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=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=NI
|Correction for multiple testing=No
|Measurement of compliance=No
|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=No
|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.
* Placebo-controlled and double-blind.
* Power analysis and adherence to sample size.
* Detailed protocol description.
* Measurement of selenium levels.

CONTRA:
* No compliance verification.
* No information on side effects or potential interactions with medications for mucositis prevention.
* Focus on small effects rather than clinically relevant ones and those corresponding to the predefined research question.
* Despite stating that previous studies show most stem cell transplant patients suffer from selenium deficiency, this was not tested or described here.
* Very few demographic variables provided.
* No verification of successful blinding.
* No information on whether participants could or did take other supplements.
}}

Goossens et al. (2016): Phase III randomised chemoprevention study with selenium on the recurrence of non-invasive urothelial carcinoma. The SELEnium and BLAdder cancer Trial

2024-11-05T12:39:51Z

JDoerfler:

{{Reference
|Reference=Publication: Phase III randomised chemoprevention study with selenium on the recurrence of non-invasive urothelial carcinoma. The SELEnium and BLAdder cancer Trial
}}

=Brief summary=
In this study, 292 subjects with non-invasive bladder cancer were divided into two arms and given either daily selenium or a placebo for around three years. The effects on the return of the cancer or its progression were relevant. The results show no significant differences between the two arms with regard to these points. Also, controlling the analysis performed for key demographic variables or excluding patients who had left the study made no difference. Overall, the percentage for recurrence and progression was very low and thus remained below the expected figures, which, together with the statistically insufficiently large sample, may well have contributed to the fact that a possible effect could not be found. Overall, the study is convincing with its high methodological quality, a very detailed description of the procedure, a very careful execution of the study and the testing of the subjects' selenium concentration at the beginning and end of the study.

In dieser Studie wurden 292 Probanden mit einem nichtinvasivem Harnblasenkarzinom in zwei Gruppen eingeteilt und es wurde ihnen über etwa drei Jahre entweder täglich Selen gegeben oder sie bekamen ein Placebo. Relevant waren die Auswirkungen auf die Rückkehr der Krebserkrankung oder dessen Fortschreiten. Die Ergebnisse zeigen bezüglich dieser Punkte keine bedeutsamen Unterschiede zwischen den beiden Gruppen. Auch eine Kontrolle der durchgeführten Analyse für wichtige demographische Variablen oder den Ausschluss von Patienten, die die Studie verlassen hatten, machte keinen Unterschied. Insgesamt war der Prozentsatz für das Wiederauftreten und die Progression sehr gering und blieb damit unter den erwarteten Zahlen, was zusammen mit der statistisch nicht ausreichend großen Stichprobe durchaus dazu beigetragen haben könnte, dass ein möglicherweise vorhandener Effekt nicht gefunden werden konnte. Insgesamt überzeugt die Studie mit hoher methodischer Qualität, einer sehr detaillierten Beschreibung des Ablaufs, einer sehr sorgfältigen Durchführung dieser, sowie durch die durchgeführte Testung der Selenkonzentration der Probanden zu Beginn und Ende der Studie.

=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=Underwent a transurethral resection (TUR) for a histologically confirmed low-grade or high-grade non-invasive urothelial carcinoma (transitional cell carcinoma of the bladder), stage Ta, T1, or carcinoma in situ (Tis)
|Exclusion criteria=History of any type of malignancy within the past 5 years and other serious medical or psychiatric illness that would preclude giving informed consent
|N randomized=292
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Evaluated ITT n=292, PP n=259;
Sensitivity analysis n=216
|Countries of data collection=Belgium
|LoE=2b Oxford 2009
|Outcome timeline=Described unclear
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Genitourinary Cancers - Bladder Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Transurethral resected urinary bladder carcinoma (non-invasive urinary bladder carcinoma, Ta, T1, Tis)
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=Female intervention arm: 13.2%, placebo arm: 21.3%
|Age groups=Adults (18+)
|Age groups specification=Median; range: 68; 46-90 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=151
|Drop-out=41
|Drop-out reasons=3 months follow-up: randomized in error, not meeting inclusion criteria n=6, death n=1, withdrew consent n=8;
Follow-up over 3 years: adverse events n=2, withdrew consent n=24
|Intervention=Selenium yeast (selenium-enriched yeast)
|Dosage and regime=200 µg 1x per day, orally
|One-time application=No
|Duration in days=1.095
|Side Effects / Interactions=Not separated between arms:
Unclear cause: n=13 cystectomy (intervention arm: n=6, placebo arm: n=7), n=23 deceased (intervention arm: n=13, placebo arm: n=10);

Report of side effects: intervention arm: n=7 and placebo arm: n=10, all grade 1 except n=1, grade 2 pain in the intervention arm; side effects were change in nails, back and neck pain, constipation, sleep disturbances, dizziness, and arthralgia, with one n=1 patient reporting nausea, pain, and stomach problems and another patient dizziness and diarrhea
|Order number=1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=141
|Drop-out=35
|Drop-out reasons=3 months follow-up: randomized in error, not meeting inclusion criteria n=10, cystectomy n= 3, withdrew consent n=5;
Follow-up over 3 years: reccurence n=1, adverse events n=2, withdrew consent n=14
|Intervention=Placebo
|Dosage and regime=1x per day
|One-time application=No
|Duration in days=1.095
|Side Effects / Interactions=Not separated between arms:
Unclear cause: n=13 cystectomy (intervention arm: n=6, placebo arm: n=7), n=23 deceased (intervention arm: n=13, placebo arm: n=10);

Report of side effects: intervention arm: n=7 and placebo arm: n=10, all grade 1 except n=1, grade 2 pain in the intervention arm; side effects were change in nails, back and neck pain, constipation, sleep disturbances, dizziness, and arthralgia, with one n=1 patient reporting nausea, pain, and stomach problems and another patient dizziness and diarrhea
|Order number=2
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=RFS (Recurrence-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=ITT: intervention arm n=43 (28%; 95% CI: 0.21, 0.35) and placebo arm n=45 (32%; 95% CI: 0.24, 0.40); HR: 0.85 (95% CI: 0.56, 1.29); p=0.44, not significant

PP: (all participants remaining in the study after 3 months): intervention arm n=42 and placebo arm n=39 (28%; 95% CI: 0.20, 0.35); HR: 0.96 (95% CI: 0.62, 1.48)); p=0.85, not significant

No influence of age, gender, nicotine consumption, stage, selenium concentration at baseline and hospital
|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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Remark:
After 3 months: progression in 24 patients, median progression time 22 months in both arms; Patients in intervention arm had 48% more chance of progression than those in the placebo arm, but not statistically significant (HR = 1.48 (95% CI: 0.65, 3.38); p=0.35);

Progression in the intervention arm 15x, placebo arm 14x ITT: HR: 0.97 (95% CI: 0.47, 2.00); p=0.93, not significant
|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=some concerns
|Bias in selection of the reported result=low risk
|Other sources of bias=low risk
|Overall RoB judgment=some concerns
|Order number=2
}}
{{Outcome
|Outcome type=Others
|Outcome name=Selenium level
|Outcome specification=Measured at baseline and after 3 years
|Type of measurement=Blood Test
|Results during intervention=NA
|Results after intervention=Significant difference in selenium concentration after 3 years (n=67 (55%)): 187.6 mg/dl ± 57.7 mg/dl intervention arm vs. 88.9 mg/dl ± 22.2 mg/dl placebo arm; p=0.00
|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=some concerns
|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=“The SELEBLAT study was funded by an unconditional grant of the Agency for Innovation by Science and Technology Belgium (IWT) (project IWT 70699). (…) Drugs were supplied by PharmaNord, Vojens, Denmark and prepared according to the principles of good manufacturing practice (GMP).”
|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=No
|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=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=NA
|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
|Additional Notes=PRO:
* Ethics approval obtained.
* Intention-to-treat analysis and per-protocol analysis conducted.
* Placebo-controlled and double-blind study.
* Blinding tested with a final survey.
* Compliance checked by counting tablets.
* Baseline selenium level measurement.
* Power analysis performed.
* Very detailed description of criteria for endpoints and cancer stage.
* Inclusion of key demographic variables in the analysis.
* Use of an external review committee.
* Testing of selenium concentration difference at the end of the study.

CONTRA:
* Sample size not adequate according to the power analysis.
* Timeline in the study unclear: T0 is study entry and T3 is after 3 months—uncertain if there is a T2.
* Follow-up time averaged 1½ years, which is not explained; it should have been 3 years.
* No information on the current treatment of patients.
}}