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Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients

2024-12-09T14:31:58Z

DDeel:

{{Reference
|Reference=Publication: A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients
}}
{{Study Note
|Study Note=Studies that look at other outcomes in the same sample are [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]] and [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]].
}}
=Brief summary=
In this study by Bairati and colleagues, 540 patients with head and neck cancer in the first or second cancer stage were examined. The patients were in five different hospitals in Canada, but were all treated with radiotherapy. They were randomly divided into groups and given either vitamin E and beta-carotene or corresponding placebos. Due to concerns about the side effects of beta-carotene during the course of the study, the treatment arm was only given vitamin E from 1996 onwards and, in addition to the analyses of all 540 patients, separate calculations were made for patients who had received the vitamin combination and patients who had received vitamin E alone.
The sample collected was analyzed in three different studies (see also [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]] and [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]]). This study investigated the occurrence of secondary primary tumors and the disease-free interval. The results showed that taking the vitamin combination increased the incidence of second primary tumors in the first 3.5 years and reduced it in the following 3.5 years. The same was found for the disease-free interval. In the arm that received only vitamin E, significantly more second primary tumors were detected both in the first three and a half years after randomization and in the period thereafter in comparison to the placebo arm. While significantly more recurrences and second primary tumors were detected in the arm that received only vitamin E than in the placebo arm within the first three and a half years after randomization, there were fewer cases in this arm in the years thereafter.
Overall, the results should not be generalized. Due to the fact that beta-carotene was discontinued after a relatively short time, the sample examined up to that point was not sufficient to be able to carry out precise analyses and draw reliable conclusions. It is therefore difficult to draw conclusions about the effect of a combination of beta-carotene and vitamin E. A positive aspect of this study was the double blinding and the fact that most patients took the medication as prescribed in the study. On the negative side, however, due to the lack of some characteristics of the vitamin E arm and placebo patients, it cannot be assumed that the arms were fully comparable. In addition, further distortions cannot be ruled out due to the poor report quality.

In dieser Untersuchung von Bairati und Kollegen wurden 540 Patienten mit Kopf-Hals Karzinomen im ersten oder zweiten Krebsstadium untersucht. Die Patienten befanden sich in fünf verschiedenen Krankenhäusern in Kanada, wurden aber alle mit Radiotherapie behandelt. Man gab ihnen in zufällig aufgeteilten Gruppen entweder Vitamin E und Betacarotin oder entsprechende Placebos. Dadurch, dass es im Verlauf der Studie Bedenken bzgl. der Nebenwirkungen von Betacarotin gab, wurde der Behandlungsgruppe ab 1996 nur noch Vitamin E verabreicht und es fanden zusätzlich zu den Analysen aller 540 Patienten separate Berechnungen statt für Patienten, die die Vitaminkombination, und Patienten, die nur Vitamin E erhalten hatten.
Die erhobene Stichprobe wurde in drei verschiedenen Studien ausgewertet (siehe auch [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]] und [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]]). In dieser Studie wurde das Auftreten von sekundären Primärtumoren und das krankheitsfreie Intervall untersucht. Die Ergebnisse zeigten, dass die Einnahme der Vitaminkombination das Auftreten zweiter Primärtumore in den ersten 3.5 Jahren erhöhte und in den darauffolgenden 3.5 verringerte. Das Gleiche fand man das krankheitsfreie Intervall betreffend. In der Gruppe, die nur Vitamin E erhielt, wurden sowohl in den ersten dreieinhalb Jahren nach der Randomisierung, als auch im Zeitraum danach bedeutsam mehr zweite Primärtumore festgestellt als in der Placebogruppe. Während innerhalb der ersten dreieinhalb Jahre nach der Randomisierung in der Gruppe, die nur Vitamin E erhielt, bedeutsam mehr Rezidive und zweite Primärtumore als in der Placebogruppe festgestellt wurden, waren es in den Jahren danach weniger Fälle im dieser Gruppe.
Insgesamt sollte man die Ergebnisse allerdings alle nicht verallgemeinern. Aufgrund der Tatsache, dass Betacarotin nach relativ kurzer Zeit abgesetzt wurde, reicht die bis dahin untersuchte Stichprobe nicht, um genaue Analysen durchführen zu können und gesicherte Aussagen zu treffen. Rückschlüsse auf die Wirkung einer Kombination aus Betacarotin und Vitamin E sind somit nur schwer möglich. Positiv an dieser Studie war die doppelte Verblindung und dass die meisten Patienten die Medikation so eingenommen haben, wie in der Studie vorgegeben. Negativ war jedoch, dass aufgrund des Fehlens einiger Charakteristika der Gruppe Vitamin E und Placebo-Patienten nicht von einer vollständigen Vergleichbarkeit der Gruppen ausgegangen werden kann. Außerdem können wegen der schlechten Berichtqualität weitere Verzerrungen nicht ausgeschlossen werden

=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=- First diagnosis of stage I or II, histologically documented, squamous cell carcinoma of the tongue, gum, mouth, oropharynx, hypopharynx, pharynx, or larynx
- scheduled to be treated by radiation therapy between October 1, 1994, and June 6, 2000, in one of five radiation therapy centers in the province of Quebec, Canada
|Exclusion criteria=- Karnofsky performance score of less than 60
- multiple primary head and neck cancers or a history of cancer
- severe cardiovascular disease
- inadequate renal, hepatic, or hematologic function
- anticoagulant therapy
- pregnancy
- average daily supplement intake of β-carotene or vitamin E in the preceding year greater than 6.0 mg and 50 IU, respectively
|N randomized=540
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Main analyses conducted in two ways:
1) among all participants (any supplementation)
2) separately for the first 156 participants (combined intake of beta-carotene and Vitamin E) and for the 384 patients subsequently enrolled (only Vitamin E)

Analyses were performed by partitioning the time (after visual check of proportionality assumption of the models):
1) from entry until 3.5 years after randomization
2) beyond 3.5 years after randomization

4 patients (1 in intervention arm, 3 in placebo arm) did not complete their radiation therapy as planned but were included in the analyses
|Countries of data collection=Canada
|LoE=2b Oxford 2009
|Outcome timeline=T0: before radiotherapy
T1: during radiotherapy

T2: immediately post-radiotherapy

T3: 1 month post-radiotherapy

from T4: every 6 months for 3 years, then once a year until 30.06.2003
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I or stage II cancer, n (%) of stage II disease per arm:
- intervention: 101 (37)
- placebo: 107 (40)
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=N (%) of men per arm:
- intervention: 223 (82)
- placebo: 203 (76)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) in years per arm:
- intervention: 62.9 (10.0)
- placebo: 62.3 (9.5)
}}
=Arms=

{{Arm
|Number of participants (arm)=273
|Drop-out=40 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=4)
Discontinued intervention (n=36)
- Capsule side-effects (n=6)
- Difficulty swallowing capsules (n=3)
- Other medical problems (n=9)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=2)
- Physician requested to stop (n=3)
|Intervention=Beta-carotene + Vitamin E
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=79)
- 30mg Betacarotin + 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=194)
- 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=62)
- Cardiovascular: 1
- Endocrine: 1
- Flu-like symptoms: 3
- Gastrointestinal: 31
- Genitourinary: 1
- Neurologic: 3
- Skin: 3
- Yellowing of the skin: 19
|Order number=1
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm
|Number of participants (arm)=267
|Drop-out=41 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=7)
Discontinued intervention (n=34)
- Capsule side-effects (n=6)
- Other medical problems (n=8)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=5)
- Physician requested to stop (n=2)
|Intervention=Placebos
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=77)
- 1 placebo daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=190)
- 2 placebos daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=32)
- Gastrointestinal: 23
- Genitourinary: 1
- Neurologic: 2
- Skin: 6
|Order number=2
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Tumor progression
|Outcome specification=Incidence of second primary tumors (SPT) from the day of randomization until the occurrence of the SPT/death/date of the last visit;
median follow-up: 52 months
|Type of measurement=Observation
|Results during intervention=SPT for '''any supplementation''' up to 3.5 years after randomization:
HR = 2.42 (95% CI: 1.45, 4.04), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)

SPT for '''beta-carotene + Vit. E''' up to 3.5 years after randomization:
HR = 1.51 (95% CI: 0.58, 3.98), i.e. no significant difference between intervention and placebo arm

SPT for '''only Vit. E''' up to 3.5 years after randomization:
HR = 2.88 (95% CI: 1.56, 5.31), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)

No influence of smoking status
|Results after intervention=SPT for '''any supplementation''' beyond 3.5 years after randomization:
HR = 0.57 (95% CI: 0.31, 1.07), i.e. no significant difference between intervention and placebo arm

SPT for '''beta-carotene + Vit. E''' beyond 3.5 years after randomization:
HR = 1.11 (95% CI: 0.47, 2.61), i.e. no significant difference between intervention and placebo arm

SPT for '''only Vit. E''' beyond 3.5 years after randomization:
HR = 0.41 (95% CI: 0.16, 1.03), i.e. no significant difference between intervention and placebo arm

No influence of smoking status
|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=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=Number of events (recurrence, second primary tumor), median follow-up: 52 months
|Type of measurement=Observation
|Results during intervention=DFS for '''any supplementation''' up to 3.5 years after randomization:
HR = 1.65 (95% CI: 1.21, 2.25), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)

DFS for '''beta-carotene + Vit. E''' up to 3.5 years after randomization:
HR = 1.27 (95% CI: 0.73, 2.21), i.e. no significant difference between intervention and placebo arm

DFS for '''only Vit. E''' up to 3.5 years after randomization:
HR = 1.86 (95% CI: 1.27, 2.72), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)
|Results after intervention=DFS for '''any supplementation''' beyond 3.5 years after randomization:
HR = 0.85 (95% CI: 0.48, 1.50), i.e. no significant difference between intervention and placebo arm

DFS for '''beta-carotene + Vit. E''' beyond 3.5 years after randomization:
HR = 1.11 (95% CI: 0.47, 2.61), i.e. no significant difference between intervention and placebo arm

DFS for '''only Vit. E''' beyond 3.5 years after randomization:
HR = 0.71 (95% CI: 0.33, 1.53), i.e. no significant difference between intervention and 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=2
|Outcome topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=* Financially supported by National Cancer Institute (with funds from the Canadian Cancer Society)
* Bairati: Recipient of a Senior Scientist Award from the Fonds de Recherche en Santé du Québec
* All capsules were supplied by Roche Vitamins Inc. (Parsippany, NJ)
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|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 vote
* Comparably high compliance in both arms
* Information on the development of beta-carotene/vitamin E levels
* Low dropout (T3: 3%)
* Performance of power analyses
* Double blinding
* Intention-to-treat analysis
* Consideration of possible confounding variables (e.g. clinical or smoking status)

CONTRA:
* Possible group differences from baseline in the subgroups (beta-carotene + vitamin E/ vitamin E only, were not analyzed separately)
* Differently sized groups despite the indication of a 1:1 randomization
* Changes to the study protocol during the course of the study
* Poor report quality, sometimes contradictory information in the individual publications (see Study Note) for results
}}

Beer et al. (2007): Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators

2024-12-05T13:26:26Z

DDeel:

{{Reference
|Reference=Publication: Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators
}}
{{Study Note}}
=Brief summary=
This study investigated the effectiveness of vitamin D in combination with docetaxel (a chemotherapeutic agent) in prostate cancer patients. One arm received docetaxel and vitamin D and the other arm docetaxel and placebo. There were no differences between the arms in terms of treatment response rate and time to disease progression, but patients in the vitamin D arm lived longer on average. In addition, although there were no fewer side effects overall in the vitamin D arm, there were fewer serious side effects than in the other arm. Positive aspects of this study are the large sample size and the double blinding (observers/patients do not know which arm they belong to). However, a major criticism of this study is that the vitamin D level was not recorded and taken into account. Thus, there is no verification of whether there was a vitamin D deficiency at the beginning of the study and whether the vitamin D treatment worked (i.e. that patients in the vitamin D arm had higher levels due to vitamin D supplementation).

In dieser Studie wurde die Wirksamkeit von Vitamin D in Kombination mit Docetaxel (ein Chemotherapeutikum) bei Prostatakrebspatienten untersucht. Ein Arm bekam Docetaxel und Vitamin D und der andere Arm Docetaxel und Placebo. Es zeigten sich keine Unterschiede zwischen den Armen hinsichtlich der Ansprechrate der Behandlung und der Zeit bis zum Krankheitsfortschreiten, aber der Vitamin-D Arm lebten die Patienten im Durchschnitt länger. Zudem traten im Vitamin-D-Arm zwar insgesamt nicht weniger Nebenwirkungen auf, aber es gab weniger schwerwiegende Nebenwirkungen als im anderen Arm. Positiv an dieser Studie sind die große Stichprobe und die doppelte Verblindung (Beobachter/Patienten wissen nicht, welchem Arm sie angehören). Ein großer Kritikpunkt dieser Studie ist jedoch, dass der Vitamin D Spiegel nicht erhoben und berücksichtigt wurde. Somit gibt es keine Überprüfung, ob zu Beginn der Studie ein Vitamin D Mangel bestand und ob die Vitamin D Behandlung funktioniert hat (d.h. dass Patienten im Vitamin-D-Arm durch Vitamin D Präparat einen höheren Spiegel hatten).

=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=Men with histopathologically or cytologically proven metastatic adenocarcinoma of the prostate with evidence of progression (the development of new metastatic lesions or rising PSA) despite standard hormonal management (orchiectomy, gonadotropin-releasing hormone agonist or antagonist including withdrawal of antiandrogens, if applicable; 6 weeks for bicalutamide, 4 weeks for flutamide or nilutamide) were eligible;
serum PSA ≥ 5.0 ng/mL, serum testosterone level ≤ 50 ng/dL, Eastern Cooperative Oncology Group performance status ≤ 2, life expectancy ≥ 3 months, age ≥ 18 years, patient agreement to use adequate contraception, and patient ability to give informed consent.
|Exclusion criteria=Active malignancy within 5 years (except nonmelanoma skin cancer), significant active medical illness that would preclude protocol treatment, a history of hypercalcemia or vitamin D toxicity, or hospitalization for treatment of angina, myocardial infarction, or congestive heart failure in the previous 12 months;
kidney stones (calcium salt) within 5 years, hypersensitivity to calcitriol or drugs formulated with polysorbate-80, grade 2 or higher peripheral neuropathy, neutrophil count less than 1,500/mm3 , platelet count lower than 100,000/ mm3 , serum creatinine more than upper limit of normal (ULN), serum calcium more than ULN, conjugated bilirubin more than ULN, alkaline phosphatase more than 4 x ULN (patients with known bone involvement and a normal conjugated bilirubin, ALT, and AST were not excluded), ALT or AST more than 2.0 x ULN when alkaline phosphatase is less than 2.5 x ULN, ALT or AST more than 1.5 x ULN when alkaline phosphatase is more than 2.5 x ULN,
prior investigational therapy or use of calcitriol within 30 days, prior chemotherapy for prostate cancer except for adjuvant therapy more than 12 months before enrollment, prior chemotherapy with docetaxel, treatment with radiotherapy within 4 weeks or treatment with other radiopharmaceuticals within 8 weeks
|N randomized=250
|Analysis=ITT Analysis
|Specifications on analyses=Primary analysis for efficacy was on the intention to treat population and toxicity was evaluated in the as-treated population. These two populations were identical.
|Countries of data collection=NI
|LoE=1b Oxford 2009
|Outcome timeline=Every 4 weeks
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=Metastatic adenocarcinoma of the prostate with evidence of progression
|Comorbidity=No
|Current cancer therapy=Chemotherapy, Hormone therapy
|Specifications on cancer therapies=Weekly docetaxel 36 mg/m2 intravenously and dexamethasone (4 mg orally 12 hours before, 1 hour before, and 12 hours after docetaxel administration)
|Previous cancer therapies=No therapy
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median (range): 68 (45-87)
Placebo arm: median (range): 70 (47-92)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=125
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcitriol
|Dosage and regime=DN-101 (45 μg) orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No increase in toxicity was seen with the addition of DN-101 to docetaxel
|Order number=1
|Arm topic=Vitamin D
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=125
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Placebo orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=?
|Order number=1
|Arm topic=Vitamin D
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=PSA level (Prostate-Specific Antigen)
|Outcome specification=PSA response (≥ 50% PSA reduction, confirmed at least 4 weeks later)
|Type of measurement=Blood Test
|Results during intervention=Within 6 months of enrollment: no significant differences in PSA decline;
at any time while on study: PSA decline achieved in 52% of placebo- treated patients and 63% of DN-101-treated patients (p = .07);
median time to PSA response was 5.3 months in placebo-treated patients and 2.9 months in DN-101-treated patients (p = .06)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Tumor response
|Outcome specification=Tumor response rate
|Type of measurement=RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=low risk
|Order number=2
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=PSA (defined by consensus criteria), tumor, and clinical progression-free survival (defined as either tumor progression, occurrence of a skeletal-related event, or death from any cause)
|Type of measurement=Observation
|Results during intervention=No significant differences in median duration of PSA progression-free survival;
median duration of tumor progression-free survival and median duration of clinical progression-free survival could not be reliably assessed due to the lack of regularly scheduled tumor imaging
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=Defined as the time from random assignment to a skeletal-related event or death from any cause, skeletal-related events were defined as pathologic bone fracture, spinal cord compression, surgery to the bone, or radiation to the bone
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After adjustment for baseline characteristics of hemoglobin and Eastern Cooperative Oncology Group performance status, overall survival showed a promising improvement in intervention arm over the placebo arm with a HR of 0.67 (95% CI, 0.45 to 0.97; p = .04)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=All adverse events are reported regardless of perceived relationship to treatment
|Type of measurement=Observation
|Results during intervention=The incidence of any grade 3 or 4 adverse events was not significantly different;
serious adverse events, generally those requiring hospitalization, were observed in 41% of placebo-treated patients and 27% of DN-101-treated patients (p = .023);

Among the grade 3 or 4 nonhematologic toxicities, the most common were fatigue (16% placebo; 8% DN-101), infection (13% placebo; 8% DN- 101), and hyperglycemia (12% placebo; 6% DN-101)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=low risk
|Order number=6
|Outcome topic=Vitamin D
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Some authors receive honoraria/research funding from various pharmaceutical companies or they advise them
|Conflicts of Interest=According to information financial conflicts of interest may exist
}}
=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
|Possibility of placebo effects=No
|Other reasons=We do not know whether the arms had baseline values without significant differences in vitamin D levels.
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=NI
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Double blinding
* Large sample according to power analysis
* Low dropout (8%) and intention-to-treat analysis

CONTRA:
* Vitamin D levels not assessed
* Group differences not excluded
* Fewer endpoints calculated for PFS than specified in the protocol

Tsay et al. (2008): Effects of Reflexotherapy on Acute Postoperative Pain and Anxiety Among Patients With Digestive Cancer.

2024-12-05T13:25:19Z

DDeel:

{{Reference
|Reference=Publication: Effects of Reflexotherapy on Acute Postoperative Pain and Anxiety Among Patients With Digestive Cancer.
}}
{{Study Note}}
=Brief summary=
62 cancer patients were randomly assigned to one of two arms. One arm received one session of reflexotherapy in addition to conventional treatment immediately after the operation for four days, the other group did not. The patients were interviewed with regard to pain and anxiety using established questionnaires/instruments. The arms were comparable in all respects beforehand. Over the study period, there was a difference between the arms in terms of pain and anxiety, with the patients who had received reflex therapy making more positive statements. This difference was not only statistically demonstrable on an instrument, but also significant for the patients. In addition, the request for anesthetics was lower in the reflex therapy arm on the fifth and sixth day of the study (39.59 mg Demerol). It was not evaluated whether the patients also received different amounts of analgesics via patient-controlled analgesia beforehand. As the control group did not receive a comparable placebo, the positive effects cannot be explicitly attributed to the reflexology massage. The results could just as well have been due to the additional attention, touch or the effect of a simple foot massage.

62 Krebspatienten wurden zufällig in eine von zwei Gruppen eingeteilt. Die eine Gruppe hat zusätzlich zur konventionellen Behandlung direkt nach der OP vier Tage lang jeweils eine Sitzung Reflextherapie erhalten, die andere Gruppe nicht. Die Patienten wurden hinsichtlich Schmerzen und Angst mit etablierten Fragebögen/ Instrumenten befragt. Die Gruppen waren in allen Belangen vorab vergleichbar. Über die Studienzeit hinweg zeigte sich ein Gruppenunterschied hinsichtlich der Angaben von Schmerzen und Angst, wobei die Patienten, die Reflextherapie erhalten hatten, positivere Angaben machten. Auf einem Instrument war dieser Unterschied nicht nur statistisch nachweisbar, sondern für die Patienten auch bedeutsam. Zudem war in der Reflextherapiegruppe die Anfrage nach Betäubungsmitteln am fünften und sechsten Tag der Studie geringer (39,59 mg Demerol). Es wurde nicht ausgewertet, ob die Patienten davor auch unterschiedliche Mengen an Schmerzmitteln über die patientengesteuerte Analgesie erhielten. Da die Kontrollgruppe kein vergleichbares Placebo erhalten hat, lassen sich die positiven Effekte nicht explizit der Reflexzonen-Massage zuschreiben. Die Ergebnisse können genauso gut durch die zusätzliche Aufmerksamkeit, Berührung oder den Effekt einer einfachen Fußmassage zustande gekommen sein.

=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=18 years or older, had major abdominal surgery for mainly hepatocellular cancer and gastric cancer in the 24 hours prior, alert, awake, in a stable medical condition, able to verbally communicate, received general anesthetics, and used PCAs for pain
|Exclusion criteria=History of chronic pain, disseminated cancer, narcotic or ethanol addiction, peripheral neuropathy, foot amputation, diagnosed deep vein thrombosis, open wound on foot, dementia, or psychiatric diagnoses.
|N randomized=62
|Analysis=NI
|Specifications on analyses=Generalized estimation equations (GEE)
|Countries of data collection=Taiwan
|LoE=1b Oxford 2009
|Outcome timeline=T0: Day 2 surgery
T1-T3: Day 2-4 post surgery;

Follow up: Day 5, Day 6 surgery
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Gastrointestinal Cancers - Gastric (Stomach) Cancer, Gastrointestinal Cancers - Liver Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Surgery
|Specifications on cancer therapies=Major abdominal surgery for mainly hepatocellular cancer and gastric cancer in the 24 hours
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=52.46 % female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) = 59.8 (14.7)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=31
|Drop-out=N=0
|Drop-out reasons=NA
|Intervention=Reflexotherapy
|Dosage and regime=The foot reflexology was initiated during the evening on postoperative day 2 while patients are on PCA and between 1 and 3 hours after a dose of pain medication, day 3 after surgery and day 4 after surgery, duration: 20 min each)
|One-time application=No
|Duration in days=3
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Reflexology
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=31
|Drop-out=N=1
|Drop-out reasons=Postoperative complications
|Intervention=Surgery
|Dosage and regime=NA
|One-time application=No
|Duration in days=1
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Reflexology
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Baseline; T1-T3 (Day 2 post surgery - Day 4 post surgery, follow-up)
Value; coefficient of the time x group interaction effect βI (standard error),p-value
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=On average (across all time points), there are sig. lower (better) values in intervention than in passive control arm (βG=-21.22 (4.93); p<0.001). In addition, there is a sig. different development in the two arms, in the sense that the values in intervention tend to remain the same, whereas they tend to increase in passive control arm (βI= -2.41 (1.38); p=0.0107).
|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=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Baseline, Follow-up
|Type of measurement=SF-MPQ (Short-Form McGill Pain Questionnaire)
|Results during intervention=On average (across all time points) there are no sig. differences between the two arms (βG=-0.63 (1.23); p=0.61). However, there is a decrease in symptoms in both arms, which is sig. stronger in intervention arm over time (βI= -3.17 (1.41); p=0.02).
|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=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Anxiety
|Outcome specification=Baseline, Follow-up
|Type of measurement=HADS (Hospital Anxiety and Depression Scale)
|Results during intervention=On average (across all time points) there are no sig. differences between the two arms (βG=0.31 (0.98); p=0.753). But in both arms there is a decrease in symptoms, which is sig. stronger in intervention arm over time (βI= -1.12 (0.49); p=0.231).
|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=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Additional medication
|Outcome specification=Postoperative opiate consumption: Meperidin, Follow-up
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Sig. lower consumption in intervention than arm passive control (mean diff.= 39.59 mg Demerol; p= 0.015)
|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=Reflexology
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=No information were reported by the authors.
|Conflicts of Interest=No Information were reported by the authors.
}}
=Further points for assessing the study=

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

Koyama et al. (2017): Intravenous Carnitine Administration in Addition to Parenteral Nutrition With Lipid Emulsion May Decrease the Inflammatory Reaction in Postoperative Surgical Patients

2024-12-05T13:24:34Z

DDeel:

{{Reference
|Reference=Publication: Intravenous Carnitine Administration in Addition to Parenteral Nutrition With Lipid Emulsion May Decrease the Inflammatory Reaction in Postoperative Surgical Patients
}}
{{Study Note}}
=Brief summary=
The study investigated the influence of carnitine on the inflammatory and insulin response in patients following surgery for gastric or colorectal cancer. Eight patients were randomly assigned to the control group, who received the usual parenteral nutrition after colorectal cancer surgery. In the intervention group, the 8 patients were also given carnitine. The administration took place in both groups over 4 days after surgery and showed no differences in laboratory values, insulin response or other characteristics between the two groups. The additional administration of carnitine does not appear to have any health benefits for the target group, but the results should be interpreted with caution due to the small sample size.

Die Studie untersuchte den Einfluss von Carnitin auf die Entzündungs- und Insulinreaktion bei Patienten nach einer Operation aufgrund eines Magen – oder Kolorektalen Karzinoms. Es wurden 8 Patienten zufällig in die Kontrollgruppe eingeteilt, diese erhielten die übliche Gabe an parentaler Ernährung nach der Operation des Darmkrebses. In der Interventionsgruppe wurde den 8 Patienten zusätzlich Carnitin verabreicht. Die Gabe erfolgte in beiden Gruppen über 4 Tage nach der Operation und zeigte keine Unterschiede in den Laborwerten, der Insulin Reaktion oder anderen Merkmalen zwischen den beiden Gruppen. Die zusätzliche Gabe von Carnitin scheint der Zielgruppe keine gesundheitlichen Vorteile zu bringen, aufgrund der kleinen Stichprobe sind die Ergebnisse aber mit Vorsicht zu interpretieren.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Preoperative gastric or colorectal cancer patients without distant metastasis
|Exclusion criteria=Liver dysfunction, respiratory dysfunction, cardiac dysfunction, renal failure, ongoing infection, history of recent immunosuppressive or immunologic disease (including preoperative chemo-therapy and/or radiation therapy), or diabetes mellitus
|N randomized=16
|Analysis=ITT Analysis
|Specifications on analyses=ITT not specified, but no drop-out reported.
|Countries of data collection=Japan
|LoE=2b Oxford 2009
|Outcome timeline=T0: preoperative phase
T1: 1 day after surgery
T2-T7: Day 2-7 after surgery

Blood samples at T0, T1, T3 and T4; carnitine concentration at T0, T1, T3, T7; C-reactive protein (CRP) at T3 and T7, urine samples at T3 and T7
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Colorectal Cancer, Gastrointestinal Cancers - Gastric (Stomach) Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Stage I-III
|Comorbidity=NI
|Current cancer therapy=Surgery
|Specifications on cancer therapies=Open or Laparoscopic surgery for gastric or colorectal cancer

+ Peripheral postoperative parenteral nutrition (PPN): glucose, amino acid, lipid emulsion
|Previous cancer therapies=No therapy
|Gender=Mixed
|Gender specifications=43.8% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 68 (9.6) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=8
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Carnitin + PPN

+ Additional administration of solutions to supply water and electrolytes possible. No oral nutrition until day 4 and oral water intake from day 2.
|Dosage and regime=Peripheral PN (PPN) 100ml (20% lipid emulsion) + carnitine, IV, -1st postoperative day OP to day 4, average administration: 72.6mg/kg daily (SD = 37.3)
Duration: 4 days
|One-time application=No
|Duration in days=4
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Carnitine
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=-999
|Drop-out=0
|Drop-out reasons=NA
|Intervention=PPN

+ Additional administration of solutions to supply water and electrolytes possible. No oral nutrition until day 4 and oral water intake from day 2.
|Dosage and regime=Peripheral PN (PPN) 100ml (20% lipid emulsion)
|One-time application=No
|Duration in days=4
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Carnitine
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Postoperative morbidity/ complications
|Outcome specification=Reduction of complication rates: infectious, mechanical, overall after surgery
|Type of measurement=NI
|Results during intervention=No differences between the arms for complications (in both arms n=2 each; p=0.715) or type of complication (p>0.05)
|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=Carnitine
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This work was supported financially by Grants-in-Aid for Science Research from the Ministry of Education, Science, Sports and Culture, Japan (Project no. 15K10047).
|Conflicts of Interest=According to authors no conflict of interest.
}}
=Further points for assessing the study=

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

CONTRA:
* At baseline: BMI, TLC, and ChE significantly higher in intervention arm (p < 0.05).
* Measurements of individual variables taken on different days.
* Unclear temporal definition of preoperative phase.
* 14 out of 16 participants had colorectal cancer, mostly stage I.
* Very brief data presentation.
* Very small sample size.
* Short intervention phase.
* BMI: significant preoperative difference between groups, with the difference on postoperative day 7 even larger but no longer significant.
* No reporting of significance values when no difference was found.
}}

Rostock et al. (2013): Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Four-Arm Randomized Trial on the Effectiveness of Electroacupuncture

2024-12-05T13:14:41Z

DDeel:

{{Reference
|Reference=Publication: Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Four-Arm Randomized Trial on the Effectiveness of Electroacupuncture
}}
{{Study Note}}
=Brief summary=
In the study by Rostock and colleagues, 59 patients who were currently undergoing a rehabilitation program after chemotherapy were examined. They were randomly divided into four arms and examined over three weeks. The arms received either electroacupuncture, hydroelectric baths, a vitamin combination of vitamin B1 and B6 or placebo capsules. The symptoms of peripheral neuropathy, a disorder of one or more nerves, were assessed by the patients themselves. The neuropathy scores, the intensity of the symptoms (assessed by a neurologist) and the quality of life were also recorded. The results showed that the arms did not differ with regard to the factors examined. They all improved in their symptoms, the neuropathy value decreased, the intensity of the symptoms decreased and the quality of life tended to increase. However, the different treatment measures did not appear to have any significant reinforcing or inhibiting influence on this. The main criticism of this study is the small sample size and the fact that the patients' complaints were already low at the beginning. It is possible that this made it difficult to achieve an improvement in general and that differences could not be detected for this reason. In addition, the patients were treated in parallel with medication and therapies such as psychotherapy or sports therapy, so it remains unclear what effect these had on the results and the well-being of the patients. For this reason, the results should only be viewed critically and the effect of the combination of vitamin B1 and B6 should not be generalized.

In der Studie von Rostock und Kollegen wurden 59 Patienten untersucht, die sich gerade in einem Rehabilitationsprogramm nach einer Chemotherapie befanden. Sie wurden zufällig in vier Gruppen aufgeteilt und über drei Wochen untersucht. Die Gruppen bekamen entweder Elektroakupunktur, Hydroelektrische Bäder, eine Vitaminkombination aus Vitamin B1 und B6 oder Placebo-Kapseln. Untersucht wurden die Symptome peripherer Neuropathie, einer Störung einer oder mehrerer Nerven, die durch die Patienten selbst beurteilt wurden. Außerdem wurden die Werte der Neuropathie, die Intensität der Beschwerden (eingeschätzt durch einen Neurologen) und die Lebensqualität erhoben. Die Ergebnisse zeigten, dass sich die Gruppen hinsichtlich der untersuchten Faktoren nicht unterschieden. Sie verbesserten sich alle in ihren Symptomen, der Neuropathie-Wert sank, die Intensität der Beschwerden ließen nach und die Lebensqualität stieg tendenziell an. Die unterschiedlichen Behandlungsmaßnahmen hatten darauf aber scheinbar keinen bedeutsamen verstärkenden oder hemmenden Einfluss. Hauptkritikpunkt dieser Studie ist die geringe Stichprobengröße und die schon von zu Beginn geringen Beschwerden der Patienten. Dies kann dafür gesorgt haben, dass eine Verbesserung generell nur noch schwer möglich war und Unterschiede aus diesem Grund nicht entdeckt werden konnten. Außerdem wurden die Patienten parallel medikamentös und durch Therapien, wie bspw. Psycho- oder Sporttherapie betreut, sodass hier unklar bleibt, welchen Effekt diese auf die Ergebnisse und das Wohlbefinden der Patienten hatten. Man sollte die Ergebnisse aus diesem Grund nur kritisch betrachten und die Wirkung der Kombination von Vitamin B1 und B6 nicht verallgemeinern.

=Study Design=
Blinding: double-blind for vitamin B and placebo, open for electroacupuncture and hydroelectric baths

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

{{RCT study general properties
|Inclusion criteria=Patients in remission after chemotherapy with taxanes, platinumderivatives, or vinca alkaloids and who presented with symptoms of CIPN
|Exclusion criteria=?
|N randomized=60
|Analysis=mITT Analysis
|Specifications on analyses=n (Analysis) = 59, 1 drop-out in hydroelectric bath arm (no treatment received); "all randomized patients who received at least one study treatment were included in all (effectiveness or safety) analyses"
|Countries of data collection=Germany
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline, Day 0 of therapy
T1: Day 21, i.e. directly after treatment
T2: Follow-up, day 84 after treatment
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Breast Cancer, Gynecologic Cancers - Ovarian Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Other Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=Four patients (3 in hydroelectric bath arm, 1 in placebo arm) presented with additional neurological problems other than CIPN:
- 2 patients: facial paresis
- 1 patient: double vision
- 1 patient: one had diminished strength in the right hand
|Current cancer therapy=No therapy
|Specifications on cancer therapies=Mean times from the last chemotherapy, last surgery, or last radiotherapy were comparable between groups (all 𝑃 values >0.25)
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Female
|Gender specifications=Overall 78% female; male/female per arm:
- electroacupuncture arm: 4/10
- hydroelectric bath arm: 1/12
- vit. B arm: 5/10
- placebo arm: 3/14
|Age groups=Adults (18+)
|Age groups specification=Overall mean (SD): 52.7 (10.0) years; per arm:
- electroacupuncture arm: 49.9 (9.6)
- hydroelectric bath arm: 52.3 (11.3)
- vit. B arm: 56.3 (11.1)
- placebo arm: 52.0 (8.1)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=14
|Drop-out=3
|Drop-out reasons=- Anxious of being needled (day 1): n=1
- Lost to follow-up (day 21): n=1
- Lost to follow-up (day 84): n=1
|Intervention=Electroacupuncture
|Dosage and regime=8x ± 1 sessions for 15min

Point combinations for ...
- patients with CIPN symptoms in the lower extremities: LV3 (Taichong), SP9 (Xiongxiang), GB41 (Zulingqi),GB34 (Yanglingquan)
- patients with CIPN symptoms in the upper extremities: LI4 (Hegu), LI11 (Quchi), SI3 (Houxi), and HT3 (Shaohai)
- patients with CIPN symptoms in the upper and lower extremities: treated with complete point combination

Acupuncture needles were deeply inserted bilaterally until the deqi phenomenon was triggered; each session included 15 minutes of electrostimulation (50Hz) consisting of a combination of rectangular currents and high amplitude waves
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=13
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Hydroelectric baths
|Dosage and regime=8x ± 1 sessions for 15min

- patients dipped their arms up to a hand’s width above the elbow and their feet up to a hand’s width above the ankle into a special
water basin with water at a temperature of about 35∘
- cross-galvanisation of each individual extremity by low-frequency (50Hz) faradic current (direct current impulses) up to the individual’s sensitive
threshold (i.e., the point where the tingling feeling is considered to be just acceptable)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=15
|Drop-out=8
|Drop-out reasons=- Study was too strenuous (day 1): n=1
- Tumor progession (day 13): n=1
- Lost to follow-up (day 21): n=2
- Lost to follow-up (day 84): n=4
|Intervention=Vitamin B Complex (vitamin B1/B6)
|Dosage and regime=100mg thiamine nitrate + 100mg pyridoxine hydrochloride, oral, 3 capsules daily
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=3
|Arm topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=17
|Drop-out=5
|Drop-out reasons=- Withdrawal of consent (day 1): n=1
- Lost to follow-up (day 21): n=1
- Lost to follow-up (day 84): n=3
|Intervention=Placebo
|Dosage and regime=Same form and frequency as in Vit. B arm (oral, 3 lactose capsules daily)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=4
|Arm topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Peripheral neuropathy
|Outcome specification=- Extension and intensity (non, mild, moderate,or severe) of CIPN complaints (numbness, swelling, tingling, pain, and subjective impairment in everyday life and at work)
- Heaviness of suffering due to CIPN complaints
- Severity of neuropathic symptoms
-> Outcome change from day 0 of treatment until day 21 (after treatment)
|Type of measurement=NRS (Numeric Rating Scale), Interview
|Results during intervention=Improvement of symptoms in all arms, no significant group difference at day 21 (directly after treatment): d = -0.3; CI: -1.4, 0.8; p = 0.705)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=1
|Outcome topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Peripheral neuropathy
|Outcome specification=Neuropathy score (assessed by an independent neurologist)
|Type of measurement=Neurologic examination
|Results during intervention=Neuropathy score decreased in all arms during treatment (from day 0 until day 21);
no significant differences between any two arms (no p-values reported)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=2
|Outcome topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Peripheral neuropathy
|Outcome specification=Electroneurographical tests/sensible nerve conduction studies of the median (upper extremities) and the sural nerve (lower extremities)
|Type of measurement=Neurologic examination
|Results during intervention=No significant differences between the treatment arms (from day 0 until day 21); no p-value reported
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=3
|Outcome topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Peripheral neuropathy
|Outcome specification=Intensity of the CIPN complaints
|Type of measurement=NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria), Neurologic examination
|Results during intervention=Similar improvement in all four arms during treatment (from day 0 until day 21);
no significant differences in the four arms (no p-value reported)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=4
|Outcome topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=Moderate increase in all four arms during treatment (from day 0 until day 21);
no significant differences in the four arms (no p-value reported)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=5
|Outcome topic=Vitamin B1, Vitamin B6, Electroacupuncture
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Study was supported by the Fördergesellschaft Forschung Tumorbiologie, Freiburg, Germany, and the Karl and Veronica Carstens Foundation, Essen, Germany.
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
|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 vote available
* Calculation of power analyses
* Intention-to-treat analyses
* Double-blinded if possible
CONTRA:
* Small sample size
* Low intensity of complaints, which left little room for improvement (floor effect)
* Possibility of confounding variables exists (medication and other concurrent therapies, inequality of cancer treatment medication use between arms caused by unequal distribution of cancer types (n.s.), also descriptive inequality of symptoms (n.s))
* Little detailed description of the follow-up results (overall concise results section)
}}

Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients

2024-12-05T13:13:09Z

DDeel:

{{Reference
|Reference=Publication: Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients
}}
{{Study Note
|Study Note=Studies that look at other outcomes in the same sample are [[Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients]] and [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]].
}}
=Brief summary=
In this study by Bairati and colleagues, 540 patients with head and neck cancer in the first or second cancer stage were examined. The patients were in five different hospitals in Canada, but were all treated with radiotherapy. They were randomly divided into groups and given either vitamin E and beta-carotene or corresponding placebos. Due to concerns about the side effects of beta-carotene during the course of the study, the treatment arm was only given vitamin E from 1996 onwards and, in addition to the analyses of all 540 patients, separate calculations were made for patients who had received the vitamin combination and patients who had received vitamin E alone.
The sample collected was analyzed in three different studies (see also [[Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients]] and [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]]). In this study, the effects on the tolerability of the radiotherapy treatment and the quality of life were investigated. The side effects caused by radiotherapy were less severe in patients in the treatment arm receiving beta-carotene and vitamin E, which was particularly evident in the larynx. Quality of life was generally not improved by the vitamins, although patients in the treatment arm had less sleep disturbances. On the other hand, the patients mentioned had more frequent diarrhea and, due to the more frequent occurrence of local recurrences, it is questionable to what extent the vitamin combination may have reduced the effect of radiotherapy. In patients who only received vitamin E, there were no significant differences in the side effects compared to the placebo arm.
Overall, the results should not be generalized. Due to the fact that beta-carotene was discontinued after a relatively short time, the sample examined up to that point was not sufficient to be able to carry out precise analyses and draw reliable conclusions. It is therefore difficult to draw conclusions about the effect of a combination of beta-carotene and vitamin E. A positive aspect of this study was the double blinding and the fact that most patients took the medication as prescribed in the study. On the negative side, however, due to the lack of some characteristics of the vitamin E arm and placebo patients, it cannot be assumed that the groups were fully comparable. In addition, further distortions cannot be ruled out due to the poor report quality.

In dieser Untersuchung von Bairati und Kollegen wurden 540 Patienten mit Kopf-Hals Karzinomen im ersten oder zweiten Krebsstadium untersucht. Die Patienten befanden sich in fünf verschiedenen Krankenhäusern in Kanada, wurden aber alle mit Radiotherapie behandelt. Man gab ihnen in zufällig aufgeteilten Gruppen entweder Vitamin E und Betacarotin oder entsprechende Placebos. Dadurch, dass es im Verlauf der Studie Bedenken bzgl. der Nebenwirkungen von Betacarotin gab, wurde der Behandlungsgruppe ab 1996 nur noch Vitamin E verabreicht und es fanden zusätzlich zu den Analysen aller 540 Patienten separate Berechnungen statt für Patienten, die die Vitaminkombination, und Patienten, die nur Vitamin E erhalten hatten.
Die erhobene Stichprobe wurde in drei verschiedenen Studien ausgewertet (siehe auch [[Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients]] and [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]]). In dieser Studie wurden die Auswirkungen auf die Verträglichkeit der Radiotherapiehandlung sowie die Lebensqualität untersucht. Die Nebenwirkungen, die durch die Radiotherapie ausgelöst wurden, waren bei Patienten der Behandlungsgruppe, welche Betacarotin und Vitamin E erhielt, weniger schwer, was insbesondere am Kehlkopf zu sehen war. Die Lebensqualität verbesserte sich durch die Vitamine im Allgemeinen nicht, allerdings hatten Patienten in der Behandlungsgruppe seltener Schlafstörungen. Auf der anderen Seite hatten die genannten Patienten häufiger Durchfall und durch das häufigere Auftreten von Lokalrezidiven ist es fraglich, inwiefern, die Vitaminkombination die Wirkung der Radiotherapie evtl. verringerte. Bei Patienten, welche nur Vitamin E erhielten, zeigten sich bei den Nebenwirkungen keine bedeutsamen Unterschiede im Vergleich zur Placebogruppe.
Insgesamt sollte man die Ergebnisse allerdings alle nicht verallgemeinern. Aufgrund der Tatsache, dass Betacarotin nach relativ kurzer Zeit abgesetzt wurde, reicht die bis dahin untersuchte Stichprobe nicht, um genaue Analysen durchführen zu können und gesicherte Aussagen zu treffen. Rückschlüsse auf die Wirkung einer Kombination aus Betacarotin und Vitamin E sind somit nur schwer möglich. Positiv an dieser Studie war die doppelte Verblindung und dass die meisten Patienten die Medikation so eingenommen haben, wie in der Studie vorgegeben. Negativ war jedoch, dass aufgrund des Fehlens einiger Charakteristika der Gruppe Vitamin E und Placebo-Patienten nicht von einer vollständigen Vergleichbarkeit der Gruppen ausgegangen werden kann. Außerdem können wegen der schlechten Berichtqualität weitere Verzerrungen nicht ausgeschlossen werden.

=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=- First diagnosis of stage I or II, histologically documented, squamous cell carcinoma of the tongue, gum, mouth, oropharynx, hypopharynx, pharynx, or larynx
- scheduled to be treated by radiation therapy between October 1, 1994, and June 6, 2000, in one of five radiation therapy centers in the province of Quebec, Canada
|Exclusion criteria=- Karnofsky performance score of less than 60
- multiple primary head and neck cancers or a history of cancer
- severe cardiovascular disease
- inadequate renal, hepatic, or hematologic function
- anticoagulant therapy
- pregnancy
- average daily supplement intake of β-carotene or vitamin E in the preceding year greater than 6.0 mg and 50 IU, respectively
|N randomized=540
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Main analyses conducted in two ways:
1) among all participants (any supplementation)
2) separately for the first 156 participants (combined intake of beta-carotene and Vitamin E) and for the 384 patients subsequently enrolled (only Vitamin E)

4 patients (1 in intervention arm, 3 in placebo arm) did not complete their radiation therapy as planned but were included in the analyses
|Countries of data collection=Canada
|LoE=2b Oxford 2009
|Outcome timeline=T0: before radiotherapy
T1: during radiotherapy

T2: immediately post-radiotherapy

T3: 1 month post-radiotherapy

from T4: every 6 months for 3 years, then once a year until 30.06.2003
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I or stage II cancer, n (%) of stage II disease per arm:
- intervention: 101 (37)
- placebo: 107 (40)
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=?
|Gender specifications=N (%) of men per arm:
- intervention: 223 (82)
- placebo: 203 (76)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) in years per arm:
- intervention: 62.9 (10.0)
- placebo: 62.3 (9.5)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=273
|Drop-out=40 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=4)
Discontinued intervention (n=36)
- Capsule side-effects (n=6)
- Difficulty swallowing capsules (n=3)
- Other medical problems (n=9)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=2)
- Physician requested to stop (n=3)
|Intervention=Beta-carotene + Vitamin E
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=79)
- 30mg Betacarotin + 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=194)
- 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=62)
- Cardiovascular: 1
- Endocrine: 1
- Flu-like symptoms: 3
- Gastrointestinal: 31
- Genitourinary: 1
- Neurologic: 3
- Skin: 3
- Yellowing of the skin: 19
|Order number=1
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=267
|Drop-out=41 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=7)
Discontinued intervention (n=34)
- Capsule side-effects (n=6)
- Other medical problems (n=8)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=5)
- Physician requested to stop (n=2)
|Intervention=Placebos
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=77)
- 1 placebo daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=190)
- 2 placebos daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=32)
- Gastrointestinal: 23
- Genitourinary: 1
- Neurologic: 2
- Skin: 6
|Order number=2
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Acute Adverse Effects of Radiation Therapy:
most severe radiation therapy adverse effect with regards to baseline status, graded from 0 (no symptom) to 4 (severe symptom), in six sites (skin, mucosa, ear, salivary glands, pharynx and esophagus, and larynx)
|Type of measurement=RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
|Results during intervention=Side effects for '''any supplementation''' during radiotherapy (T1):

''All sides'': OR = 0.72 (95% CI: 0.52, 1.02), i.e. no significant difference between intervention and placebo arm
''Larynx, skin, mucosa, pharynx and esophagus'': no significant differences

Side effects for '''beta-carotene + Vit. E''' during radiotherapy (T1):

''All sides'': OR = 0.38 (95% CI: 0.20, 0.74), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm)
''Larynx only'': OR = 0.38 (95% CI: 0.21, 0.71), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm)
''Skin, mucosa, pharynx and esophagus'': no significant differences

Side effects for '''only Vit. E''' during radiotherapy (T1):

''All sides'': OR = 0.92 (95% CI: 0.62, 1.38), i.e. no significant difference between intervention and placebo arm
''Larynx, skin, mucosa, pharynx and esophagus'': no significant differences
|Results after intervention=Side effects for '''any supplementation''' directly post-radiotherapy (T2):

''All sides'': OR = 0.77 (95% CI: 0.54, 1.09), i.e. no significant difference between intervention and placebo arm
''Larynx, skin, mucosa, pharynx and esophagus'': no significant differences

Side effects for '''beta-carotene + Vit. E''' directly post-radiotherapy (T2):

''Total'': OR = 0.33 (95% CI: 0.17, 0.65), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm)
''Larynx only'': OR = 0.42 (95% CI: 0.23, 0.77), i.e. significant difference between intervention and placebo arm (lower risk for intervention arm)
''Skin, mucosa, pharynx and esophagus'': no significant differences

Side effects for '''only Vit. E''' directly post-radiotherapy (T2):

''Total'': OR = 1.06 (95% CI: 0.70, 1.60), i.e. no significant difference between intervention and placebo arm
''Larynx, skin, mucosa, pharynx and esophagus'': no significant differences

Side effects for '''any supplementation''' 1 month post-radiotherapy (T3):

''All sides'': OR = 1.11 (95% CI: 0.79, 1.55), i.e. no significant difference between intervention and placebo arm
''Larynx, skin, mucosa, pharynx and esophagus'': no significant differences

Side effects for '''beta-carotene + Vit. E''' 1 month post-radiotherapy (T3):

''Total'': OR = 0.98 (95% CI: 0.52, 1.87), i.e. no significant difference between intervention and placebo arm
''Larynx only'': OR = 0.61 (95% CI: 0.32, 1.17), i.e. no significant difference between intervention and placebo arm
''Skin, mucosa, pharynx and esophagus'': no significant differences

Side effects for '''only Vit. E''' 1 month post-radiotherapy (T3):

''Total'': OR = 1.17 (95% CI: 0.78, 1.74), i.e. no significant difference between intervention and placebo arm
''Larynx, skin, mucosa, pharynx and esophagus'': no significant differences
|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=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire), HNQR (Head and Neck Radiotherapy Questionnaire)
|Results during intervention=NI
|Results after intervention=Mean difference (95% CI) between intervention and placebo arm for '''any supplementation''' 1 month post-radiotherapy (T3):
- EORTC QLQ-C30 sleep disturbance: 4.05 (0.37, 8.48); p = 0.07 (p = 0.02 for '''beta-carotene + Vit. E''' )
- EORTC QLQ-C30 diarrhea: -2.74 (-4.54, -0.93); p = 0.003)
- EORTC QLQ-C30 remaining scales: no significant differences
- HNQR: no significant differences

No reported results regarding '''only Vit. E'''
|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=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome
|Outcome type=NI
|Outcome name=Recurrence rate
|Outcome specification=Local recurrence operationalized as possible indicator of compromisation of treatment (radiotherapy) efficacy;
median duration of follow-up: 51 months
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Local recurrence for '''any supplementation'''
HR = 1.37 (95% CI: 0.93, 2.02),i.e. no significant difference between intervention and placebo arm

Local recurrence for '''beta-carotene + Vit. E'''
HR = 1.56 (95% CI: 0.79, 3.07), i.e. no significant difference between intervention and placebo arm

Local recurrence for '''only Vit. E'''
HR = 1.29 (95% CI: 0.89, 2.08), i.e. no significant difference between intervention and 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=3
|Outcome topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=* Financially supported by National Cancer Institute (with funds from the Canadian Cancer Society)
* Bairati: Recipient of a Senior Scientist Award from the Fonds de Recherche en Santé du Québec
* All capsules were supplied by Roche Vitamins Inc. (Parsippany, NJ)
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|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 vote
* Comparably high compliance in both arms
* Information on the development of beta-carotene/vitamin E levels
* Low dropout (T3: 3%)
* Performance of power analyses
* Double blinding
* Intention-to-treat analysis
* Consideration of possible confounding variables (e.g. clinical or smoking status)

CONTRA:
* Possible group differences from baseline in the subgroups (beta-carotene + vitamin E/ vitamin E only, were not analyzed separately)
* Differently sized groups despite the indication of a 1:1 randomization
* Changes to the study protocol during the course of the study
* Poor report quality, sometimes contradictory information in the individual publications (see Study Note) for results
}}

Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients

2024-12-05T13:12:17Z

DDeel:

{{Reference
|Reference=Publication: Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients
}}
{{Study Note
|Study Note=Studies that look at other outcomes in the same sample are [[Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients]] and [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]].
}}
=Brief summary=
In this study by Bairati and colleagues, 540 patients with head and neck cancer in the first or second cancer stage were examined. The patients were in five different hospitals in Canada, but were all treated with radiotherapy. They were randomly divided into groups and given either vitamin E and beta-carotene or corresponding placebos. Due to concerns about the side effects of beta-carotene during the course of the study, the treatment arm was only given vitamin E from 1996 onwards and, in addition to the analyses of all 540 patients, separate calculations were made for patients who had received the vitamin combination and patients who had received vitamin E alone. The sample collected was analyzed in three different studies (see also [[Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients]] and [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]]).
The sample collected was analyzed in three different studies (see also Bairati 2005a, 2005b). In this study, the overall survival was examined. It was found that the overall survival was significantly lower in the arm taking the vitamin combination than in the placebo arm. The authors also reported more deaths in the arm receiving vitamin E alone than in the placebo arm.
Overall, the results should not be generalized. Due to the fact that beta-carotene was discontinued after a relatively short time, the sample examined up to that point was not sufficient to be able to carry out precise analyses and draw reliable conclusions. It is therefore difficult to draw conclusions about the effect of a combination of beta-carotene and vitamin E. A positive aspect of this study was the double blinding and the fact that most patients took the medication as prescribed in the study. On the negative side, however, due to the lack of some characteristics of the vitamin E arm and placebo patients, it cannot be assumed that the groups were fully comparable. In addition, further distortions cannot be ruled out due to the poor report quality.

In dieser Untersuchung von Bairati und Kollegen wurden 540 Patienten mit Kopf-Hals Karzinomen im ersten oder zweiten Krebsstadium untersucht. Die Patienten befanden sich in fünf verschiedenen Krankenhäusern in Kanada, wurden aber alle mit Radiotherapie behandelt. Man gab ihnen in zufällig aufgeteilten Gruppen entweder Vitamin E und Betacarotin oder entsprechende Placebos. Dadurch, dass es im Verlauf der Studie Bedenken bzgl. der Nebenwirkungen von Betacarotin gab, wurde der Behandlungsgruppe ab 1996 nur noch Vitamin E verabreicht und es fanden zusätzlich zu den Analysen aller 540 Patienten separate Berechnungen statt für Patienten, die die Vitaminkombination, und Patienten, die nur Vitamin E erhalten hatten.
Die erhobene Stichprobe wurde in drei verschiedenen Studien ausgewertet (siehe auch Bairati 2005a, 2005b). In dieser Studie wurden die allgemeine Überlebensdauer untersucht. Für die allgemeine Überlebensdauer fand man, dass sie in der Gruppe, welche die Vitaminkombination eingenommen hatten, bedeutsam geringer war, als in der Placebo-Gruppe. Auch für die Gruppe, welche nur Vitamin E erhielt, berichteten die Autoren mehr Todesfälle als in der Placebogruppe.
Insgesamt sollte man die Ergebnisse allerdings alle nicht verallgemeinern. Aufgrund der Tatsache, dass Betacarotin nach relativ kurzer Zeit abgesetzt wurde, reicht die bis dahin untersuchte Stichprobe nicht, um genaue Analysen durchführen zu können und gesicherte Aussagen zu treffen. Rückschlüsse auf die Wirkung einer Kombination aus Betacarotin und Vitamin E sind somit nur schwer möglich. Positiv an dieser Studie war die doppelte Verblindung und dass die meisten Patienten die Medikation so eingenommen haben, wie in der Studie vorgegeben. Negativ war jedoch, dass aufgrund des Fehlens einiger Charakteristika der Gruppe Vitamin E und Placebo-Patienten nicht von einer vollständigen Vergleichbarkeit der Gruppen ausgegangen werden kann. Außerdem können wegen der schlechten Berichtqualität weitere Verzerrungen nicht ausgeschlossen werden.

=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=- First diagnosis of stage I or II, histologically documented, squamous cell carcinoma of the tongue, gum, mouth, oropharynx, hypopharynx, pharynx, or larynx
- scheduled to be treated by radiation therapy between October 1, 1994, and June 6, 2000, in one of five radiation therapy centers in the province of Quebec, Canada
|Exclusion criteria=- Karnofsky performance score of less than 60
- multiple primary head and neck cancers or a history of cancer
- severe cardiovascular disease
- inadequate renal, hepatic, or hematologic function
- anticoagulant therapy
- pregnancy
- average daily supplement intake of β-carotene or vitamin E in the preceding year greater than 6.0 mg and 50 IU, respectively
|N randomized=540
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Main analyses conducted in two ways:
1) among all participants (any supplementation)
2) separately for the first 156 participants (combined intake of beta-carotene and Vitamin E) and for the 384 patients subsequently enrolled (only Vitamin E)

4 patients (1 in intervention arm, 3 in placebo arm) did not complete their radiation therapy as planned but were included in the analyses
|Countries of data collection=Canada
|LoE=2b Oxford 2009
|Outcome timeline=T0: before radiotherapy
T1: during radiotherapy

T2: immediately post-radiotherapy

T3: 1 month post-radiotherapy

from T4: every 6 months for 3 years, then once a year until 30.06.2003
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I or stage II cancer, n (%) of stage II disease per arm:
- intervention: 101 (37)
- placebo: 107 (40)
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=N (%) of men per arm:
- intervention: 223 (82)
- placebo: 203 (76)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) in years per arm:
- intervention: 62.9 (10.0)
- placebo: 62.3 (9.5)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=273
|Drop-out=40 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=4)
Discontinued intervention (n=36)
- Capsule side-effects (n=6)
- Difficulty swallowing capsules (n=3)
- Other medical problems (n=9)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=2)
- Physician requested to stop (n=3)
|Intervention=Beta-carotene + Vitamin E
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=79)
- 30mg Betacarotin + 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=194)
- 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=62)
- Cardiovascular: 1
- Endocrine: 1
- Flu-like symptoms: 3
- Gastrointestinal: 31
- Genitourinary: 1
- Neurologic: 3
- Skin: 3
- Yellowing of the skin: 19
|Order number=1
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=267
|Drop-out=41 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=7)
Discontinued intervention (n=34)
- Capsule side-effects (n=6)
- Other medical problems (n=8)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=5)
- Physician requested to stop (n=2)
|Intervention=Placebos
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=77)
- 1 placebo daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=190)
- 2 placebos daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=32)
- Gastrointestinal: 23
- Genitourinary: 1
- Neurologic: 2
- Skin: 6
|Order number=2
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=Separately for cause of death: any cause, initial cancer, second primary cancer, any cancer, noncancer causes

Median follow-up:
- intervention arm: 6.4 years
- placebo arm: 6.6 years
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''

Number of any cause deaths for ''any supplementation'':
- intervention arm n=102 vs. placebo arm n=77
- HR = 1.38 (95% CI: 1.03, 1.85), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)

Number of any cause deaths for ''beta-carotene + Vit. E'':
- intervention arm n=37 vs. placebo arm n=30
- HR = 1.31 (95% CI: 0.81, 2.11), i.e. no significant difference between intervention and placebo arm

Number of any cause deaths for ''only Vit. E'':
- intervention arm n=65 vs. placebo arm n=47
- HR = 1.43 (95% CI: 0.98, 2.07), i.e. no significant difference between intervention and placebo arm

No significant differences in other causes of cancer
|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=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=* Financially supported by National Cancer Institute (with funds from the Canadian Cancer Society)
* Bairati: Recipient of a Senior Scientist Award from the Fonds de Recherche en Santé du Québec
* All capsules were supplied by Roche Vitamins Inc. (Parsippany, NJ)
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|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 vote
* Comparably high compliance in both arms
* Information on the development of beta-carotene/vitamin E levels
* Low dropout (T3: 3%)
* Performance of power analyses
* Double blinding
* Intention-to-treat analysis
* Consideration of possible confounding variables (e.g. clinical or smoking status)

CONTRA:
* Possible group differences from baseline in the subgroups (beta-carotene + vitamin E/ vitamin E only, were not analyzed separately)
* Differently sized groups despite the indication of a 1:1 randomization
* Changes to the study protocol during the course of the study
* Poor report quality, sometimes contradictory information in the individual publications (see Study Note) for results
}}

Bairati et al. (2005): A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients

2024-12-05T13:11:37Z

DDeel:

{{Reference
|Reference=Publication: A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients
}}
{{Study Note
|Study Note=Studies that look at other outcomes in the same sample are [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]] and [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]].
}}
=Brief summary=
In this study by Bairati and colleagues, 540 patients with head and neck cancer in the first or second cancer stage were examined. The patients were in five different hospitals in Canada, but were all treated with radiotherapy. They were randomly divided into groups and given either vitamin E and beta-carotene or corresponding placebos. Due to concerns about the side effects of beta-carotene during the course of the study, the treatment arm was only given vitamin E from 1996 onwards and, in addition to the analyses of all 540 patients, separate calculations were made for patients who had received the vitamin combination and patients who had received vitamin E alone.
The sample collected was analyzed in three different studies (see also [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]] and [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]]). This study investigated the occurrence of secondary primary tumors and the disease-free interval. The results showed that taking the vitamin combination increased the incidence of second primary tumors in the first 3.5 years and reduced it in the following 3.5 years. The same was found for the disease-free interval. In the arm that received only vitamin E, significantly more second primary tumors were detected both in the first three and a half years after randomization and in the period thereafter in comparison to the placebo arm. While significantly more recurrences and second primary tumors were detected in the arm that received only vitamin E than in the placebo arm within the first three and a half years after randomization, there were fewer cases in this arm in the years thereafter.
Overall, the results should not be generalized. Due to the fact that beta-carotene was discontinued after a relatively short time, the sample examined up to that point was not sufficient to be able to carry out precise analyses and draw reliable conclusions. It is therefore difficult to draw conclusions about the effect of a combination of beta-carotene and vitamin E. A positive aspect of this study was the double blinding and the fact that most patients took the medication as prescribed in the study. On the negative side, however, due to the lack of some characteristics of the vitamin E arm and placebo patients, it cannot be assumed that the arms were fully comparable. In addition, further distortions cannot be ruled out due to the poor report quality.

In dieser Untersuchung von Bairati und Kollegen wurden 540 Patienten mit Kopf-Hals Karzinomen im ersten oder zweiten Krebsstadium untersucht. Die Patienten befanden sich in fünf verschiedenen Krankenhäusern in Kanada, wurden aber alle mit Radiotherapie behandelt. Man gab ihnen in zufällig aufgeteilten Gruppen entweder Vitamin E und Betacarotin oder entsprechende Placebos. Dadurch, dass es im Verlauf der Studie Bedenken bzgl. der Nebenwirkungen von Betacarotin gab, wurde der Behandlungsgruppe ab 1996 nur noch Vitamin E verabreicht und es fanden zusätzlich zu den Analysen aller 540 Patienten separate Berechnungen statt für Patienten, die die Vitaminkombination, und Patienten, die nur Vitamin E erhalten hatten.
Die erhobene Stichprobe wurde in drei verschiedenen Studien ausgewertet (siehe auch [[Bairati et al. (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients]] und [[Bairati et al. (2006): Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients]]). In dieser Studie wurde das Auftreten von sekundären Primärtumoren und das krankheitsfreie Intervall untersucht. Die Ergebnisse zeigten, dass die Einnahme der Vitaminkombination das Auftreten zweiter Primärtumore in den ersten 3.5 Jahren erhöhte und in den darauffolgenden 3.5 verringerte. Das Gleiche fand man das krankheitsfreie Intervall betreffend. In der Gruppe, die nur Vitamin E erhielt, wurden sowohl in den ersten dreieinhalb Jahren nach der Randomisierung, als auch im Zeitraum danach bedeutsam mehr zweite Primärtumore festgestellt als in der Placebogruppe. Während innerhalb der ersten dreieinhalb Jahre nach der Randomisierung in der Gruppe, die nur Vitamin E erhielt, bedeutsam mehr Rezidive und zweite Primärtumore als in der Placebogruppe festgestellt wurden, waren es in den Jahren danach weniger Fälle im dieser Gruppe.
Insgesamt sollte man die Ergebnisse allerdings alle nicht verallgemeinern. Aufgrund der Tatsache, dass Betacarotin nach relativ kurzer Zeit abgesetzt wurde, reicht die bis dahin untersuchte Stichprobe nicht, um genaue Analysen durchführen zu können und gesicherte Aussagen zu treffen. Rückschlüsse auf die Wirkung einer Kombination aus Betacarotin und Vitamin E sind somit nur schwer möglich. Positiv an dieser Studie war die doppelte Verblindung und dass die meisten Patienten die Medikation so eingenommen haben, wie in der Studie vorgegeben. Negativ war jedoch, dass aufgrund des Fehlens einiger Charakteristika der Gruppe Vitamin E und Placebo-Patienten nicht von einer vollständigen Vergleichbarkeit der Gruppen ausgegangen werden kann. Außerdem können wegen der schlechten Berichtqualität weitere Verzerrungen nicht ausgeschlossen werden

=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=- First diagnosis of stage I or II, histologically documented, squamous cell carcinoma of the tongue, gum, mouth, oropharynx, hypopharynx, pharynx, or larynx
- scheduled to be treated by radiation therapy between October 1, 1994, and June 6, 2000, in one of five radiation therapy centers in the province of Quebec, Canada
|Exclusion criteria=- Karnofsky performance score of less than 60
- multiple primary head and neck cancers or a history of cancer
- severe cardiovascular disease
- inadequate renal, hepatic, or hematologic function
- anticoagulant therapy
- pregnancy
- average daily supplement intake of β-carotene or vitamin E in the preceding year greater than 6.0 mg and 50 IU, respectively
|N randomized=540
|Analysis=PP Analysis, ITT Analysis
|Specifications on analyses=Main analyses conducted in two ways:
1) among all participants (any supplementation)
2) separately for the first 156 participants (combined intake of beta-carotene and Vitamin E) and for the 384 patients subsequently enrolled (only Vitamin E)

Analyses were performed by partitioning the time (after visual check of proportionality assumption of the models):
1) from entry until 3.5 years after randomization
2) beyond 3.5 years after randomization

4 patients (1 in intervention arm, 3 in placebo arm) did not complete their radiation therapy as planned but were included in the analyses
|Countries of data collection=Canada
|LoE=2b Oxford 2009
|Outcome timeline=T0: before radiotherapy
T1: during radiotherapy

T2: immediately post-radiotherapy

T3: 1 month post-radiotherapy

from T4: every 6 months for 3 years, then once a year until 30.06.2003
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer
|Stage cancer=Early Stage
|Cancer stage specification=Stage I or stage II cancer, n (%) of stage II disease per arm:
- intervention: 101 (37)
- placebo: 107 (40)
|Comorbidity=NI
|Current cancer therapy=Radiation therapy
|Specifications on cancer therapies=NA
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=N (%) of men per arm:
- intervention: 223 (82)
- placebo: 203 (76)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) in years per arm:
- intervention: 62.9 (10.0)
- placebo: 62.3 (9.5)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=273
|Drop-out=40 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=4)
Discontinued intervention (n=36)
- Capsule side-effects (n=6)
- Difficulty swallowing capsules (n=3)
- Other medical problems (n=9)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=2)
- Physician requested to stop (n=3)
|Intervention=Beta-carotene + Vitamin E
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=79)
- 30mg Betacarotin + 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=194)
- 400 IU Vitamin E daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=62)
- Cardiovascular: 1
- Endocrine: 1
- Flu-like symptoms: 3
- Gastrointestinal: 31
- Genitourinary: 1
- Neurologic: 3
- Skin: 3
- Yellowing of the skin: 19
|Order number=1
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=267
|Drop-out=41 (none excluded from analysis)
|Drop-out reasons=Lost to follow-up (n=7)
Discontinued intervention (n=34)
- Capsule side-effects (n=6)
- Other medical problems (n=8)
- Participation too troublesome (n=13)
- Wanted to take vitamin E (n=5)
- Physician requested to stop (n=2)
|Intervention=Placebos
|Dosage and regime=In 1996 (2 years after the start of the study) the beta-carotene intervention was discontinued due to indications of harmful effects. Therefore 2 types of "Dosage and regime" (old, i.e. before 1996 and new, i.e. after 1996) are reported.

'''OLD''' (n=77)
- 1 placebo daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy, median (range): 320 (21-609) days

'''NEW''' (n=190)
- 2 placebos daily, start with first day of radiotherapy
- Duration: up to 3 years after radiotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=N of side effects of any grade attributed to the supplementation (n=32)
- Gastrointestinal: 23
- Genitourinary: 1
- Neurologic: 2
- Skin: 6
|Order number=2
|Arm topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Tumor progression
|Outcome specification=Incidence of second primary tumors (SPT) from the day of randomization until the occurrence of the SPT/death/date of the last visit;
median follow-up: 52 months
|Type of measurement=Observation
|Results during intervention=SPT for '''any supplementation''' up to 3.5 years after randomization:
HR = 2.42 (95% CI: 1.45, 4.04), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)

SPT for '''beta-carotene + Vit. E''' up to 3.5 years after randomization:
HR = 1.51 (95% CI: 0.58, 3.98), i.e. no significant difference between intervention and placebo arm

SPT for '''only Vit. E''' up to 3.5 years after randomization:
HR = 2.88 (95% CI: 1.56, 5.31), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)

No influence of smoking status
|Results after intervention=SPT for '''any supplementation''' beyond 3.5 years after randomization:
HR = 0.57 (95% CI: 0.31, 1.07), i.e. no significant difference between intervention and placebo arm

SPT for '''beta-carotene + Vit. E''' beyond 3.5 years after randomization:
HR = 1.11 (95% CI: 0.47, 2.61), i.e. no significant difference between intervention and placebo arm

SPT for '''only Vit. E''' beyond 3.5 years after randomization:
HR = 0.41 (95% CI: 0.16, 1.03), i.e. no significant difference between intervention and placebo arm

No influence of smoking status
|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=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=Number of events (recurrence, second primary tumor), median follow-up: 52 months
|Type of measurement=Observation
|Results during intervention=DFS for '''any supplementation''' up to 3.5 years after randomization:
HR = 1.65 (95% CI: 1.21, 2.25), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)

DFS for '''beta-carotene + Vit. E''' up to 3.5 years after randomization:
HR = 1.27 (95% CI: 0.73, 2.21), i.e. no significant difference between intervention and placebo arm

DFS for '''only Vit. E''' up to 3.5 years after randomization:
HR = 1.86 (95% CI: 1.27, 2.72), i.e. significant difference between intervention and placebo arm (higher risk for intervention arm)
|Results after intervention=DFS for '''any supplementation''' beyond 3.5 years after randomization:
HR = 0.85 (95% CI: 0.48, 1.50), i.e. no significant difference between intervention and placebo arm

DFS for '''beta-carotene + Vit. E''' beyond 3.5 years after randomization:
HR = 1.11 (95% CI: 0.47, 2.61), i.e. no significant difference between intervention and placebo arm

DFS for '''only Vit. E''' beyond 3.5 years after randomization:
HR = 0.71 (95% CI: 0.33, 1.53), i.e. no significant difference between intervention and 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=2
|Outcome topic=Vitamin A (beta-carotene), Vitamin E
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=* Financially supported by National Cancer Institute (with funds from the Canadian Cancer Society)
* Bairati: Recipient of a Senior Scientist Award from the Fonds de Recherche en Santé du Québec
* All capsules were supplied by Roche Vitamins Inc. (Parsippany, NJ)
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|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 vote
* Comparably high compliance in both arms
* Information on the development of beta-carotene/vitamin E levels
* Low dropout (T3: 3%)
* Performance of power analyses
* Double blinding
* Intention-to-treat analysis
* Consideration of possible confounding variables (e.g. clinical or smoking status)

CONTRA:
* Possible group differences from baseline in the subgroups (beta-carotene + vitamin E/ vitamin E only, were not analyzed separately)
* Differently sized groups despite the indication of a 1:1 randomization
* Changes to the study protocol during the course of the study
* Poor report quality, sometimes contradictory information in the individual publications (see Study Note) for results
}}

Mondal et al. (2014): Comparative study among glutamine, acetyl-L-carnitine, vitamin-E and methylcobalamine for treatment of paclitaxel-induced peripheral neuropathy

2024-12-05T13:08:46Z

DDeel:

{{Reference
|Reference=Publication: Comparative study among glutamine, acetyl-L-carnitine, vitamin-E and methylcobalamine for treatment of paclitaxel-induced peripheral neuropathy
}}
{{Study Note}}
=Brief summary=
In this study, four different arms of cancer patients were examined, all of whom received chemotherapy. During chemotherapy, one arm received additional vitamin E, one arm vitamin B12, one arm glutamine and the last arm carnitine. Components of peripheral neuropathy (sensory function, motor function and pain), a typical side effect of chemotherapy, were examined. There were no significant differences between the vitamin E and vitamin B12 arms in terms of the onset of the three components or their progression. However, patients in the vitamin E arm reported a later onset of symptoms and a better course in all components than patients in the glutamine and carnitine arms. Points of criticism of this study are the small sample sizes in the individual arms and the lack of a control arm. It was not shown whether significantly better effects were achieved in the vitamin E arm than in the placebo/nothing at all arm.

In dieser Studie werden vier verschiedene Gruppen von Krebspatienten untersucht, die alle Chemotherapie erhielten. Während der Chemotherapie bekam eine Gruppe zusätzlich Vitamin E, eine Gruppe Vitamin B12, eine Gruppe Glutamin und die letzte Gruppe Carnitin. Betrachtet wurden Komponenten der peripheren Neuropathie (Sensorik, Motorik und Schmerz), einer typischen Nebenwirkung der Chemotherapie. Dabei fanden sich sowohl hinsichtlich des Beginns der drei Komponenten als auch bezüglich des Verlaufs keine bedeutsamen Unterschiede zwischen der Vitamin E und der Vitamin B12 Gruppe. Patienten der Vitamin E Gruppe berichteten jedoch jeweils in allen Komponenten über einen späteren Beginn der Symptome und einen besseren Verlauf als Patienten der Glutamin- und der Carnitin-Gruppe. Kritikpunkte dieser Studie sind die kleinen Stichprobengrößen in den einzelnen Gruppen und die fehlende Kontrollgruppe. Es wurde nicht gezeigt, ob in der Vitamin E Gruppe bedeutsam bessere Effekte erzielt werden, als in einer Gruppe, die ein Placebo/ überhaupt nichts bekommt.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Histology proven evidence of carcinomas of lung, breast and ovary and would be treated with 1st line or 2nd line chemotherapeutic drugs, patients receiving paclitaxel either as first line or second line chemotherapeutic drug, either as a single agent or in combinations and with baseline clinical evaluation negative for any existing peripheral neuropathy; when paclitaxel is administered as second like drug, the exact details of previous chemotherapeutic agents would be necessary; those who have already received platinum, vincristine would be included provided no peripheral neuropathy is detected at the time of enrollment
|Exclusion criteria=Patients with co‑morbidities like diabetes, autoimmune diseases which include lupus, rheumatoid arthritis, kidney disease, liver disease and thyroid (hypothyroidism, tested pre‑enrollment by thyroid‑stimulating hormone, T4, T3) and with infections like hepatitis C and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV)/AIDS (all patients would undergo laboratory confirmation for shingles, hepatitis B, C and HIV/AIDS (at any Voluntary Confidential Counselling and Testing Centre, India) prior to inclusion in study), spinal cord injuries, peripheral vascular disorders known to be associated with peripheral neuropathy; uncontrolled diabetes or compromised cardiac function or any other major organ dysfunctions, other than cancer, which would require curtailment of full doses of paclitaxel at 175 mg/m2, 3 weekly regimens
|N randomized=160
|Analysis=PP Analysis
|Specifications on analyses=Patients receiving < 4 cycles of paclitaxel or any dose curtailments were excluded from the analysis
|Countries of data collection=India
|LoE=2b Oxford 2009
|Outcome timeline=T1: after 3 chemotherapy cycles
T2: after 6 chemotherapy cycles
T3: 6 months post-chemotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Breast Cancer, Gynecologic Cancers - Ovarian Cancer, Lung Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=II – IV
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=With paclitaxel as first or second line treatment
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=44.4% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) = 54.2 (1.1) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=21
|Drop-out=Unclear per group, overall n=70
|Drop-out reasons=NI
|Intervention=Vitamin E
|Dosage and regime=Day 0 of chemotherapy: 400 mg 1x daily
Duration: until 1 month after the end of chemotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Vitamin E, Vitamin B12, Carnitine
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=-999
|Drop-out=Unclear per group, overall n=70
|Drop-out reasons=NI
|Intervention=Vitamin B12, methylcobalamin
|Dosage and regime=Oral, day 0 chemotherapy: 500 µg 3x daily
Duration: until 1 month after the end of chemotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Vitamin E, Vitamin B12, Carnitine
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=-999
|Drop-out=Unclear per group, overall n=70
|Drop-out reasons=NI
|Intervention=Acetyl-L-Carnitine (ALC)
|Dosage and regime=Day 0 chemotherapy: 250 mg 1x daily
Duration: 7 days in each chemotherapy cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=3
|Arm topic=Vitamin E, Vitamin B12, Carnitine
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=-999
|Drop-out=Unclear per group, overall n=70
|Drop-out reasons=NI
|Intervention=Glutamine
|Dosage and regime=Day 2 chemotherapy: 10 mg 3x daily
Duration: Day 2 to Day 5 in each chemotherapy cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=NI
|Order number=4
|Arm topic=Vitamin E, Vitamin B12, Carnitine
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=Toxicity of chemotherapy
Components of Peripheral Neuropathy (according to CTCAE 4.02): sensory, motor, and pain

Data collection points: Start with the first chemotherapy cycle, before each cycle, and then monthly
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events)
|Results during intervention=Onset of symptoms (Mean (95% CI), days):

Sensory
Vitamin E: 8.24 (6.87, 9.61),
Vitamin B12: 5.61 (4.50, 6.72),
Carnitine: 5.75 (4.70, 6.80),
Glutamine: 4.95 (3.94, 5.97); p < 0.001

Motor
Vitamin E: 8.38 (6.92, 9.84),
Vitamin B12: 5.78 (4.61, 6.96),
Carnitine: 5.75 (4.84, 6.66),
Glutamine: 4.95 (3.94, 5.97)

Pain
Vitamin E: 8.71 (7.64, 9.79),
Vitamin B12: 6.26 (5.10, 7.42),
Carnitine: 6.13 (5.11, 7.14),
Glutamine: 4.68 (3.53, 5.83)

--------------------------

Progression of symptoms over time
Mean (95% CI, after 3 chemotherapy cycles/ after 6 chemotherapy cycles)

Sensory
Vitamin E: 2.05 (1.66, 2.44)/2.00 (1.58, 2.42),
Vitamin B12: 1.65 (1.34, 1.96)/1.90 (1.48, 2.33),
Carnitine: 1.42 (1.09, 1.74)/1.19 (0.72, 1.66),
Glutamine: 1.09 (0.76, 1.42)/ 1.00 (0.54, 1.46)
F-Wert (ANOVA, including values from 6 month post-chemotherapy) = 1.824; p = 0.115, ns.

Motor
Vitamin E: 2.00 (1.70, 2.30)/ 1.84 (1.47, 2.21),
Vitamin B12: 1.57 (1.20, 1.93)/ 1.73 (1.39, 2.07),
Carnitine: 1.00 (0.69, 1.31)/ 0.62 (0.35, 0.89),
Glutamine: 0.91 (0.61, 1.21)/ 0.67 (0.37, 0.97),
F(ANOVA, including values from 6 month post-chemotherapy) = 2.267; p = 0.045, sign.

Pain
Vitamin E: 1.75 (1.38, 2.12)/ 1.79 (1.38, 2.20),
Vitamin B12: 1.83 (1.54, 2.11)/ 2.05 (1.70, 2.39),
Carnitine: 0.67 (0.43, 0.91)/ 0.48 (0.20, 0.75),
Glutamine: 0.27 (0.07, 0.47)/ 0.62 (0.39, 0.85),
F (ANOVA, including values from 6 month post-chemotherapy)= 3.358; p = 0.004, sign.
|Results after intervention=Mean (95% CI, 6 months after chemotherapy)

Sensory
Vitamin E: 1.72 (1.35, 2.10),
Vitamin B12: 1.60 (1.09, 2.11),
Carnitine: 0.65 (0.30, 1.00),
Glutamine: 0.58 (0.21, 0.95)
F-Wert (ANOVA, including values from after 3 chemotherapy cycles and after 6 chemotherapy cycles) = 1.824; p = 0.115, ns.

Post-Hoc Analysis:
Vitamin E vs. Vitamin B12: p = 0.446
Vitamin E vs. Carnitine: p < 0.001, sign.
Vitamin E vs. Glutamine: p = 0.002, sign.
No difference between Vit. E and Vit. B12, but Vit. E better progression than glutamine and ALC

Motor
Vitamin E: 1.39 (1.09, 1.69),
Vitamin B12: 1.40 (1.08, 1.72),
Carnitine: 0.20 (0.01, 0.39),
Glutamine: 0.32 (0.09, 0.55),
F(ANOVA, including values from after 3 chemotherapy cycles and after 6 chemotherapy cycles) = 2.267; p = 0.045, sign.

Post-Hoc Analysis:
Vitamin E vs. Vitamin B12: p = 0.227, ns.
Vitamin E vs. Carnitine: p < 0.001, sign.
Vitamin E vs. Glutamine: p < 0.001, sign.
No difference between Vit. E and Vit. B12, but Vit. E better progression than glutamine and ALC

Pain
Vitamin E: 1.33 (0.95, 1.71),
Vitamin B12: 1.30 (0.99, 1.61),
Carnitine: 0.10 (-0.04, 0.24),
Glutamine: 0.26 (0.05, 0.48),
F (ANOVA, including values from after 3 chemotherapy cycles and after 6 chemotherapy cycles)= 3.358; p = 0.004, sign.

Post-Hoc-Analysis:
Vitamin E vs. Vitamin B12: ns.; p = NI
Vitamin E vs. Carnitine: p < 0.001, sign.
Vitamin E vs. Glutamine: p < 0.001, sign.
No difference between Vit. E and Vit. B12, but Vit. E better progression than glutamine and ALC
|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=Vitamin E, Vitamin B12, Carnitine
}}
{{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=CONTRA:
* Small sample size.
* No blinding.
* No control group receiving either no intervention or placebo, only active controls whose efficacy is also not proven.
* Possible baseline differences (e.g., in pain perception) were not recorded.
* High dropout rate (overall 44%), with no information on reasons and group distribution.
* No information on compliance.
* Poor reporting quality (e.g., unclear how often patients received the intervention).
}}

Minchom et al. (2014): An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of (...)

2024-12-05T13:07:25Z

DDeel:

{{Reference
|Reference=Publication: An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of (...)
}}
{{Study Note}}
=Brief summary=
Minchom and colleagues (2014) investigated the effect of a vitamin combination of vitamin B12 and folic acid on grade 3 and 4 neutropenia, a side effect that can occur as a result of chemotherapy and consists of a decrease in the number of white blood cells in the blood and thus an increased risk of infection. They also recorded the effects of vitamin administration on the chances of survival within the first 30 days of treatment, the general survival time, the quality of life and the tolerance of the substances given. A total of 77 patients suffering from either bronchial carcinoma or mesothelioma were included in the analyses. 36 of them received the described vitamins over the period of chemotherapy until 3 weeks after its completion; the remaining 41 patients received no alternative intervention or a placebo, but were treated with chemotherapy alone. The allocation of patients was randomized. The results showed no significant differences, i.e. neither grade 3 or 4 neutropenia, survival time nor quality of life were affected by the vitamin combination. No other side effects occurred as a result of taking vitamin B12 and folic acid. A positive finding was that patients in the treatment arm complained less frequently of fatigue than those in the control arm. Difficulties with this study are its open design and the lack of a placebo for one half of the patients. In addition, there was the possibility of further supportive measures for the patients parallel to the study, the influence of which is not considered further by the authors. These unknown influences and also the problems in the design could have contributed to the failure to find an effect.

Minchom und Kollegen (2014) untersuchten die Wirkung einer Vitaminkombination aus Vitamin B12 und Folsäure auf Neutropenie 3. und 4. Grades, einer Nebenwirkung, die durch Chemotherapie auftreten kann und darin besteht, dass die Zahl der weißen Blutkörperchen im Blut abnimmt und damit das Infektionsrisiko zunimmt. Des Weiteren erfassten sie die Auswirkungen der Vitamingabe auf die Überlebenschancen innerhalb der ersten 30 Tage der Behandlung, die allgemeine Überlebenszeit, die Lebensqualität sowie die Verträglichkeit der gegebenen Stoffe. Es wurden insgesamt 77 Patienten in die Analysen eingeschlossen, die entweder an einem Bronchialkarzinom oder Mesotheliom erkrankt waren. 36 von ihnen erhielten über die Zeitspanne der Chemotherapie bis 3 Wochen nach deren Abschluss die beschriebenen Vitamine, die übrigen 41 Patienten bekamen keine alternative Intervention oder ein Placebo, sondern wurden nur durch Chemotherapie behandelt. Die Zuteilung der Patienten fand zufällig statt. Die Ergebnisse ergaben keine bedeutsamen Unterschiede, d.h. dass durch die Vitaminkombination weder die Neutropenie 3. oder 4. Grades, die Überlebensdauer, noch die Lebensqualität beeinflusst wurden. Es traten keine weiteren Nebenwirkungen durch die Einnahme von Vitamin B12 und Folsäure auf. Positiv festzustellen war, dass Patienten der behandelten Gruppe seltener über Fatigue klagten, als in der Kontroll-Gruppe. Schwierig an dieser Studie sind ihr offenes Design und das Fehlen eines Placebos für die eine Hälfte der Patienten. Außerdem gab es parallel zu der Untersuchung die Möglichkeit weiterer supportiver Maßnahmen für die Patienten, deren Einfluss von den Autoren nicht weiter beachtet wird. Diese unbekannten Einflüsse und auch die Problematik im Design könnten zum Nichtfinden eines Effektes beigetragen haben.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=- Suitability for platinum-based chemotherapy
- Histologically or cytologically confirmed NSCLC, SCLC or mesothelioma
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2
- Adequate organ function defined as an absolute neutrophil count >1.5×109/L, white cell count >3×109/L, platelet count >100×109/L, serum creatinine ≤1.25 upper level of normal, creatinine clearance >50 mL/min (EDTA) or >60 mL/min (Cockroft and Gault formula) for cisplatin or >40 mL/min for carboplatin
- Estimated life expectancy of at least 12 weeks
|Exclusion criteria=Patients having an active infection, inability or unwillingness to take vitamin supplementation, had taken any vitamins within the past 28 days or receiving concomitant radical chemotherapy and radiotherapy
or antiepileptic treatment
|N randomized=83
|Analysis=mITT Analysis
|Specifications on analyses=- Analyzed: N = 77 for primary endpoint, 78 for secondary endpoints (n=5 patients did not receive any treatment, n=1 data set missing for primary endpoint)
- 1% level of significance used because of the large number of treatment comparisons
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=Unclear, dependent on specific outcome
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Palliative
|Types of cancer=Lung Cancer - Small Cell Lung Cancer, Lung Cancer - Non-Small Cell Lung Cancer, Mesothelioma
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=- Current chemotherapy: platinum-based treatment with cisplatin (up to six cycles)
- Palliative radiation therapy permitted for irradiating small areas of painful metastases that could not be managed adequately using systemic or local analgesia
- Patients were allowed to receive full supportive care therapies concomitantly, except for growth factors as a prophylactic measure, during the study
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Overall 36% female, male/female per arm:
- intervention: 29/11
- control: 24/19
|Age groups=Adults (18+)
|Age groups specification=Age at diagnosis (years) per arm, median (IQR):
- intervention: 61 (12)
- control: 60 (14)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=40
|Drop-out=4
|Drop-out reasons=n = 4 did not received treatment
- transferred care: 1
- myocardial infarction prior to chemotherapy: 1
- became eligible for cisplatin: 2
|Intervention=Chemotherapy + Vit. B12 + folic acid
|Dosage and regime=Vit.B12: intramuscular, 1mg, before treatment and every 9 weeks until 3 weeks after last dose of chemotherapy
Folic acid: oral, 400μg daily, start at least day seven days prior to chemotherapy, duration up to 3 weeks after chemotherapy
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Occurrence of grade 3/4 nausea/vomiting, infections, diarrhea, constipation and nephrotoxicity
|Order number=1
|Arm topic=Folic acid, Vitamin B12
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=43
|Drop-out=2
|Drop-out reasons=1 patient not treated because of deteriorating renal function
1 patient had no toxicity data after first cycle of chemotherapy but had QoL and survival data
|Intervention=Chemotherapy only
|Dosage and regime=No further treatment
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=Occurrence of grade 3/4 nausea/vomiting, infections, diarrhea, constipation and nephrotoxicity
|Order number=2
|Arm topic=Folic acid, Vitamin B12
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Neutropenia
|Outcome specification=Grade 3, 4 neutropenia or death within the first 30 days of treatment
|Type of measurement=Observation, NI
|Results during intervention=NA
|Results after intervention='''Overall'''

No significant differences for grade 3/4 neutropenia or death between arms (p = 0.966)
|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=Folic acid, Vitamin B12
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=Before the start of chemotherapy, every 6 weeks during chemotherapy, then every 3 months for up to 1 year
Measures: EORTC QLQ-C30 (V.3) and Lung module QLQ-LC13
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=NA
|Results after intervention='''Overall'''

No significant differences between arms regarding change since baseline (after 6 weeks p=0.399, after 3 months p=0.943);
no difference in fatigue levels on the quality of life scales (no p-value reported)
|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=Folic acid, Vitamin B12
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=From the day of randomization until death from any cause
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''

No significant differences between arms (p = 0.41)
|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=Vitamin B12, Folic acid
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=Non-neutropenic toxicities grade 3/4, assessed before each chemotherapy cyle
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events), ECOG Performance Status Scale (Eastern Cooperative Oncology Group), Observation
|Results during intervention=NA
|Results after intervention='''Overall'''

No significant differences in occurrence of nausea/vomiting (p=0.805), infections (p=0.144), diarrhea (p=0.945), constipation (p=0.572) and nephrotoxicity (p=0.516); less frequent occurrence of fatigue in intervention arm (p = 0.003)
|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=Folic acid, Vitamin B12
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Support from the NIHR Royal Marsden Biomedical Research Centre
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
|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 vote
* Precise observation of occurring side effects
* Recording of patient compliance
* Intention-to-treat analyses
* Washout of previous vitamin intake taken into account
* Adjustment of significance level due to multiple testing
CONTRA:
* No blinding
* Not placebo controlled
* Unclear randomization, as groups are not equal in size despite 1:1 distribution
* Simultaneous offer of other supportive therapies whose influence is not considered in detail
* Stage of cancer unclear
}}

Liu et al. (2010): Influence of vitamin C on salivary absorbed dose of 131I in thyroid cancer patients: a prospective, randomized, single-blind, controlled trial

2024-12-05T13:05:21Z

DDeel:

{{Reference
|Reference=Publication: Influence of vitamin C on salivary absorbed dose of 131I in thyroid cancer patients: a prospective, randomized, single-blind, controlled trial
}}
{{Study Note}}
=Brief summary=
In this study, four different arms of thyroid cancer patients were examined, each beginning at different times to suck dissolved vitamin C in addition to radioiodine therapy to stimulate saliva flow (1, 5, 13, or 25 hours after radioiodine therapy). The aim of the vitamin C administration was to accelerate the excretion of radioiodine from the salivary glands by stimulating saliva flow, thereby protecting the salivary glands. The authors found no significant differences between the four arms regarding the radioactive exposure of the salivary glands. A drawback of this study is the absence of a control group that received no vitamin C at all. Therefore, this study only indicates that there are no differences regarding the timing of vitamin C administration.

In dieser Studie werden vier verschiedenen Gruppen mit Schilddrüsenkrebs untersucht, die zu verschiedenen Zeitpunkten beginnen, zusätzlich zur Radiojodtherapie gelöstes Vitamin C zu saugen, um den Speichelfluss zu stimulieren (1, 5, 13 oder 25 Stunden nach der Radiojodtherapie). Das Ziel der Vitamin C-Gabe war, über die Stimulation des Speichelflusses die Ausscheidung des Radiojods aus den Speicheldrüsen zu beschleunigen und damit die Speicheldrüsen zu schützen. Die Autoren fanden keine bedeutsamen Unterschiede zwischen den vier Gruppen hinsichtlich der radioaktiven Exposition der Speicheldrüsen. Ein Nachteil dieser Studie ist, dass keine Kontrollgruppe vorhanden ist, die überhaupt kein Vitamin C bekommen hat. Somit sagt diese Studie nur aus, dass es keine Unterschiede gibt, zu welchem Zeitpunkt Vitamin C gegeben wird.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=18 y old, case of recently diagnosed differentiated papillary or follicular thyroid cancer, undergone total thyroidectomy, referred to the Department of Nuclear Medicine, West China Hospital, for ablation of remnant thyroid tissue, stage pT1–T3, N0–N1, M0. For women of childbearing potential: a negative result on serum human chorionic gonadotropin pregnancy testing required
|Exclusion criteria=Presence of distant metastases; a previous history of salivary gland disorders, collagen tissue disease, diabetes, previous 131I therapy, or external radiation to the head or neck; or difficulty drinking a large amount of water.
|N randomized=80
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=China
|LoE=2b Oxford 2009
|Outcome timeline=A: 1 hour after ingestion of 131I
B: 5 hours after ingestion of 131I
C: 13 hours after ingestion of 131I
D: 25 hours after ingestion of 131I
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=NI
|Types of cancer=Head and Neck Cancers - Thyroid Cancer
|Stage cancer=Early Stage
|Cancer stage specification=pT1–T3, N0–N1, M0
|Comorbidity=NI
|Current cancer therapy=Radioiodine treatment
|Specifications on cancer therapies=Radioiodine therapy (131I)
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=Number n (Male/Female):
Arm A: 2/16
Arm B: 3/15
Arm C: 7/12
Arm D: 2/15
|Age groups=Adults (18+)
|Age groups specification=Mean (SD)
Arm A: 44 (14)
Arm B: 42 (14)
Arm C: 43 (13)
Arm D: 39 (12)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=20
|Drop-out=2
|Drop-out reasons=Did not complete salivary dosimetry measurements
|Intervention=Sucking vitamin C at 1 hour after ingestion of 131I
|Dosage and regime=100 mg every 4 h in the daytime over 6 d
|One-time application=No
|Duration in days=6
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Vitamin C
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=20
|Drop-out=2
|Drop-out reasons=Showed distant metastases on posttherapy scans
|Intervention=Sucking vitamin C at 5 hours after ingestion of 131I
|Dosage and regime=100 mg every 4 h in the daytime over 6 d
|One-time application=No
|Duration in days=6
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Vitamin C
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=20
|Drop-out=1
|Drop-out reasons=Showed distant metastases on posttherapy scans
|Intervention=Sucking vitamin C at 13 hours after ingestion of 131I
|Dosage and regime=100 mg every 4 h in the daytime over 6 d
|One-time application=No
|Duration in days=6
|Side Effects / Interactions=NI
|Order number=3
|Arm topic=Vitamin C
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=20
|Drop-out=3
|Drop-out reasons=Did not complete salivary dosimetry measurements
|Intervention=Sucking vitamin C at 25 hours after ingestion of 131I
|Dosage and regime=100 mg every 4 h in the daytime over 6 d
|One-time application=No
|Duration in days=6
|Side Effects / Interactions=NI
|Order number=4
|Arm topic=Vitamin C
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Salivary gland function
|Outcome specification=Salivary activity
|Type of measurement=Scintigraphy
|Results during intervention=No data available
|Results after intervention=No data available
|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=Vitamin C
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Salivary gland function
|Outcome specification=Salivary absorbed sose, calculated from the 131I activity administered, saliva retention time and salivary gland mass (determined by CT)
|Type of measurement=CT (Computed Tomography)
|Results during intervention=Single parotid gland: no differences between arms (p=0.37)
Single submandibular gland: no differences between arms (p=0.28)
|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=Vitamin C
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Salivary gland function
|Outcome specification=Salivary cumulated activities in first 24h after 131I ingestion divided by total cumulated activities
|Type of measurement=Scintigraphy
|Results during intervention=Parotid gland: no differences between arms (p=0.21)
Submandibular gland: no differences between arms (p=0.16)
|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=Vitamin C
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Salivary gland function
|Outcome specification=Salivary absorbed dose during the first 24 h after 131I ingestion, calculated from the 131I activity administered, saliva retention time and salivary gland mass (determined by CT)
|Type of measurement=CT (Computed Tomography)
|Results during intervention=Parotid gland: no differences between arms (p=0.32)
Submandibular gland: no differences between arms (p=0.24)
|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=Vitamin C
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This work was supported by the National Natural Science Fund of China (grants 30670585 and 30870724).
|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=?
|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:
* Low dropout
* Evenly distributed per arm

CONTRA:
* Very small sample size per arm
* No comparison sample without vitamin C
* Only a few baseline characteristics investigated (no information on cancer stage), arm differences possible.
}}

Chung et al. (2016): Randomized Trial of Vitamin C/E Complex for Prevention of Radiation- Induced Xerostomia in Patients with Head and Neck Cancer

2024-12-05T13:04:19Z

DDeel:

{{Reference
|Reference=Publication: Randomized Trial of Vitamin C/E Complex for Prevention of Radiation- Induced Xerostomia in Patients with Head and Neck Cancer
}}
{{Study Note}}
=Brief summary=
Data from 45 patients were analyzed in this study. The patients were randomly divided into groups and received either a vitamin combination of vitamin C and E or a placebo. The intake took place from one week before the concurrent radiotherapy over an average duration of three months. The effects on the patients' dry mouth (xerostomia), the general survival time and the length of the disease-free interval were observed. It was found that the group that had taken the vitamin combination showed a deterioration in their dry mouth score one month after radiotherapy treatment, but then showed a clear improvement after six months. The placebo group also showed a deterioration one month after the therapy, but remained relatively constant overall - even six months later - in their assessment of the severity of dry mouth. The same results were also confirmed by the observers. Measured by salivary scintigraphy, there were advantages for the intervention group, which indicates a positive influence of the vitamin combination on the maintenance of salivary activity. No differences were found between the groups with regard to general survival time and the length of the disease-free interval. However, most of the results describe the progression of the individual groups rather than a direct group comparison. Furthermore, significantly more patients in the vitamin group dropped out during the course of the study than in the placebo group, although the reasons for this are not explained. Due to these factors and the relatively small sample size, the results can only be trusted to a limited extent.

In dieser Studie wurden Daten von 45 Patienten ausgewertet. Die Patienten erhielten in zufällig aufgeteilten Gruppen entweder eine Vitaminkombination aus Vitamin C und E oder ein Placebo. Die Einnahme erfolgte ab einer Woche vor der gleichzeitig stattfindenden Radiotherapie über eine durchschnittliche Dauer von drei Monaten. Beobachtet wurden die Auswirkungen auf die Mundtrockenheit (Xerostomie) der Patienten, die allgemeine Überlebensdauer sowie die Länge des krankheitsfreien Intervalls. Man fand heraus, dass sich die Gruppe, die die Vitaminkombination genommen hatte laut den eigenen Angaben im Wert bzgl. ihrer Mundtrockenheit einen Monat nach der Radiotherapiebehandlung verschlechterte, nach sechs Monaten dann aber eine deutliche Verbesserung zeigte. Die Placebo-Gruppe zeigte einen Monat nach der Therapie zwar auch eine Verschlechterung, blieb insgesamt – auch sechs Monate danach – aber relativ konstant in ihrer Einschätzung der Stärke der Mundtrockenheit. Die gleichen Ergebnisse konnte man auch durch die Angaben der Beobachter bestätigen. Gemessen durch eine Speichel Szintigrafie, zeigten sich Vorteile für die Interventionsgruppe, was für einen positiven Einfluss der Vitaminkombination auf den Erhalt der Speicheltätigkeit spricht. Bezüglich der allgemeinen Überlebensdauer und der Länge des krankheitsfreien Intervalls ließen sich keine Unterschiede zwischen den Gruppen feststellen. In den meisten Ergebnissen werden jedoch eher die Verläufe der einzelnen Gruppen beschrieben und kein direkter Gruppenvergleich durchgeführt. Des Weiteren sind in der Vitamin-Gruppe deutlich mehr Patienten im Verlauf der Studie ausgestiegen, als in der Placebo-Gruppe, wobei die Gründe dafür nicht erläutert werden. Aufgrund dieser Faktoren sowie der relativ kleinen Stichprobengröße kann man den Ergebnissen nur bedingt vertrauen.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Diagnosed with biopsy-proven Head-Neck-Cancer, treated with >4000-cGy intensity-modulated radiotherapy
|Exclusion criteria=- Simultaneous malignancies
- Karnofsky performance score <60%
- Previous adverse reactions to the investigational product or salivary scintigraphy
- History of vitamin medication within the past 3 months OR
- Salivary gland excision during surgery
|N randomized=52
|Analysis=mITT Analysis
|Specifications on analyses=According to authors ITT analysis but loss to follow-up (n=7) not included in analyses
|Countries of data collection=NI
|LoE=2b Oxford 2009
|Outcome timeline=T0: before radiotherapy,
T1: 1 month post-radiotherapy,
T2: 6 months post-radiotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Head and Neck Cancers, Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Oropharyngeal Cancer, Head and Neck Cancers - Laryngeal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=N per arm:
- intervention: 9x stage I-II, 16x stage III-IV
- placebo: 6x stage I-II, 14x stage III-IV
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Types of radiotherapy per arm:
- intervention: 9x radiotherapy, 16x concurrent chemoradiotherapy
- placebo: 6x radiotherapy, 14x concurrent chemoradiotherapy

N for adjuvant/definitive setting per arm:
- intervention: 15/10
- placebo:9/11
|Previous cancer therapies=Surgery
|Gender=Mixed
|Gender specifications=Overall 11.1% female, male/female per arm:
- intervention: 22/3
- placebo: 18/2
|Age groups=Adults (18+)
|Age groups specification=Overall age in years, mean (SD) = 58.8 (10.5); per arm:
- intervention: 56.6 (11.3)
- placebo: 61.6 (9.6)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=26
|Drop-out=1
|Drop-out reasons=Lost to follow-up 6 month post-radiotherapy (n=1, refusal)
|Intervention=Radiotherapy + vitamin E + vitamin C
|Dosage and regime=100 IU vitamin E + 500mg vitamin C, orally, 2x daily, duration: 1 week prior to radiotherapy until 1 month after radiotherapy (average intervention period: 3 months)
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No significant adverse events or side effects related to study medication noticed/reported throughout the trial
|Order number=1
|Arm topic=Vitamin C, Vitamin E
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=26
|Drop-out=6
|Drop-out reasons=Lost to follow-up 1 month post-radiotherapy (n=2, refusal/poor compliance)
Lost to follow-up 6 month post-radiotherapy (n=4, 2x refusal/poor compliance), 2x disease recurrence)
|Intervention=Radiotherapy + placebo
|Dosage and regime=Placebo pill, orally, 2x daily, duration: 1 week prior to radiotherapy until 1 month after radiotherapy (average intervention period: 3 months)
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No significant adverse events or side effects related to study medication noticed/reported throughout the trial
|Order number=2
|Arm topic=Vitamin C, Vitamin E
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=NI
|Outcome name=Xerostomia
|Outcome specification=- Patient self-assessment by xerostomia questionnaire (XQ)
- Xerostomia score assessed by observer (XS)
- Salivary scintigraphy (maximum accumulation, ejection fraction and prestimulatory and poststimulatory oral index)
|Type of measurement=Observation, Scintigraphy, Self-developed measurement instrument
|Results during intervention=NA
|Results after intervention=T0: before radiotherapy,
T1: 1 month post-radiotherapy,
T2: 6 months post-radiotherapy

'''Xerostomia questionnaire''' (mean (SD), no group comparison reported)
Intervention arm
T0: 5.4 (4.3), T1: 8.1 (4.2), T2: 5.4 (4.0)
T0-T1: p = 0.02, T1-T2: p = 0.007
Placebo arm
T0: 4.6 (3.8), T1: 7.0 (4.5), T2: 7.0 (4.6)
T0-T1: p = 0.06 T1-T2: p = 0.97

'''Xerostomia score''' (no group comparison reported)
Intervention arm
T0: 2.8 (2.3), T1: 5.0 (2.8), T2: 3.7 (3.9)
T0-T1: p = 0.004, T1-T2: p = 0.008
Placebo arm
T0: 1.7 (1.4), T1: 3.9 (2.4), T2: 3.3 (2.3)
T0-T1: p = 0.004, T1-T2: p = 0.47

'''Salivary scintigraphy'''
No group difference for maximum accumulation, or ejection fraction at T1 or T2 (p=0.86, p=0.15; p=0.57, p=0.68),
Intervention arm showed better values before (p=0.01) and after stimulation (p=0.009) compared to placebo arm at T1
|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=Vitamin C, Vitamin E
}}
{{Outcome
|Outcome type=NI
|Outcome name=OS (Overall Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''

No significant differences between arms (p = 0.75)
|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=Vitamin C, Vitamin E
}}
{{Outcome
|Outcome type=NI
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''

No significant differences between arms (p = 0.87)
|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=Vitamin C, Vitamin E
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=National R&D Program for Cancer Control (No. 0820300), Ministry of Health and Welfare, Seoul, Republic of Korea.
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|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 vote
* Double blinding
* Intention-to-treat
CONTRA:
* No proper group comparisons between intervention and placebo arm on xerostomia questionnaire and xerostomia score
* Small sample without power analysis
* Unequal dropout (intervention arm: 4%, placebo arm: 23%)
* No validation information on the measurement instruments used
* Poor reporting quality (e.g. results reported confusingly)
}}

Rostock et al. (2013): Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Four-Arm Randomized Trial on the Effectiveness of Electroacupuncture

2024-12-02T12:31:40Z

DDeel:

{{Reference
|Reference=Publication: Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Four-Arm Randomized Trial on the Effectiveness of Electroacupuncture
}}
{{Study Note}}
=Brief summary=
In the study by Rostock and colleagues, 59 patients who were currently undergoing a rehabilitation program after chemotherapy were examined. They were randomly divided into four arms and examined over three weeks. The arms received either electroacupuncture, hydroelectric baths, a vitamin combination of vitamin B1 and B6 or placebo capsules. The symptoms of peripheral neuropathy, a disorder of one or more nerves, were assessed by the patients themselves. The neuropathy scores, the intensity of the symptoms (assessed by a neurologist) and the quality of life were also recorded. The results showed that the arms did not differ with regard to the factors examined. They all improved in their symptoms, the neuropathy value decreased, the intensity of the symptoms decreased and the quality of life tended to increase. However, the different treatment measures did not appear to have any significant reinforcing or inhibiting influence on this. The main criticism of this study is the small sample size and the fact that the patients' complaints were already low at the beginning. It is possible that this made it difficult to achieve an improvement in general and that differences could not be detected for this reason. In addition, the patients were treated in parallel with medication and therapies such as psychotherapy or sports therapy, so it remains unclear what effect these had on the results and the well-being of the patients. For this reason, the results should only be viewed critically and the effect of the combination of vitamin B1 and B6 should not be generalized.

In der Studie von Rostock und Kollegen wurden 59 Patienten untersucht, die sich gerade in einem Rehabilitationsprogramm nach einer Chemotherapie befanden. Sie wurden zufällig in vier Gruppen aufgeteilt und über drei Wochen untersucht. Die Gruppen bekamen entweder Elektroakupunktur, Hydroelektrische Bäder, eine Vitaminkombination aus Vitamin B1 und B6 oder Placebo-Kapseln. Untersucht wurden die Symptome peripherer Neuropathie, einer Störung einer oder mehrerer Nerven, die durch die Patienten selbst beurteilt wurden. Außerdem wurden die Werte der Neuropathie, die Intensität der Beschwerden (eingeschätzt durch einen Neurologen) und die Lebensqualität erhoben. Die Ergebnisse zeigten, dass sich die Gruppen hinsichtlich der untersuchten Faktoren nicht unterschieden. Sie verbesserten sich alle in ihren Symptomen, der Neuropathie-Wert sank, die Intensität der Beschwerden ließen nach und die Lebensqualität stieg tendenziell an. Die unterschiedlichen Behandlungsmaßnahmen hatten darauf aber scheinbar keinen bedeutsamen verstärkenden oder hemmenden Einfluss. Hauptkritikpunkt dieser Studie ist die geringe Stichprobengröße und die schon von zu Beginn geringen Beschwerden der Patienten. Dies kann dafür gesorgt haben, dass eine Verbesserung generell nur noch schwer möglich war und Unterschiede aus diesem Grund nicht entdeckt werden konnten. Außerdem wurden die Patienten parallel medikamentös und durch Therapien, wie bspw. Psycho- oder Sporttherapie betreut, sodass hier unklar bleibt, welchen Effekt diese auf die Ergebnisse und das Wohlbefinden der Patienten hatten. Man sollte die Ergebnisse aus diesem Grund nur kritisch betrachten und die Wirkung der Kombination von Vitamin B1 und B6 nicht verallgemeinern.

=Study Design=
Blinding: double-blind for vitamin B and placebo, open for electroacupuncture and hydroelectric baths

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

{{RCT study general properties
|Inclusion criteria=Patients in remission after chemotherapy with taxanes, platinumderivatives, or vinca alkaloids and who presented with symptoms of CIPN
|Exclusion criteria=?
|N randomized=60
|Analysis=mITT Analysis
|Specifications on analyses=n (Analysis) = 59, 1 drop-out in hydroelectric bath arm (no treatment received); "all randomized patients who received at least one study treatment were included in all (effectiveness or safety) analyses"
|Countries of data collection=Germany
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline, Day 0 of therapy
T1: Day 21, i.e. directly after treatment
T2: Follow-up, day 84 after treatment
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Breast Cancer, Gynecologic Cancers - Ovarian Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Other Cancers
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=Four patients (3 in hydroelectric bath arm, 1 in placebo arm) presented with additional neurological problems other than CIPN:
- 2 patients: facial paresis
- 1 patient: double vision
- 1 patient: one had diminished strength in the right hand
|Current cancer therapy=No therapy
|Specifications on cancer therapies=Mean times from the last chemotherapy, last surgery, or last radiotherapy were comparable between groups (all 𝑃 values >0.25)
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Female
|Gender specifications=Overall 78% female; male/female per arm:
- electroacupuncture arm: 4/10
- hydroelectric bath arm: 1/12
- vit. B arm: 5/10
- placebo arm: 3/14
|Age groups=Adults (18+)
|Age groups specification=Overall mean (SD): 52.7 (10.0) years; per arm:
- electroacupuncture arm: 49.9 (9.6)
- hydroelectric bath arm: 52.3 (11.3)
- vit. B arm: 56.3 (11.1)
- placebo arm: 52.0 (8.1)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=14
|Drop-out=3
|Drop-out reasons=- Anxious of being needled (day 1): n=1
- Lost to follow-up (day 21): n=1
- Lost to follow-up (day 84): n=1
|Intervention=Electroacupuncture
|Dosage and regime=8x ± 1 sessions for 15min

Point combinations for ...
- patients with CIPN symptoms in the lower extremities: LV3 (Taichong), SP9 (Xiongxiang), GB41 (Zulingqi),GB34 (Yanglingquan)
- patients with CIPN symptoms in the upper extremities: LI4 (Hegu), LI11 (Quchi), SI3 (Houxi), and HT3 (Shaohai)
- patients with CIPN symptoms in the upper and lower extremities: treated with complete point combination

Acupuncture needles were deeply inserted bilaterally until the deqi phenomenon was triggered; each session included 15 minutes of electrostimulation (50Hz) consisting of a combination of rectangular currents and high amplitude waves
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Vitamin B1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=13
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Hydroelectric baths
|Dosage and regime=8x ± 1 sessions for 15min

- patients dipped their arms up to a hand’s width above the elbow and their feet up to a hand’s width above the ankle into a special
water basin with water at a temperature of about 35∘
- cross-galvanisation of each individual extremity by low-frequency (50Hz) faradic current (direct current impulses) up to the individual’s sensitive
threshold (i.e., the point where the tingling feeling is considered to be just acceptable)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Vitamin B1
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=15
|Drop-out=8
|Drop-out reasons=- Study was too strenuous (day 1): n=1
- Tumor progession (day 13): n=1
- Lost to follow-up (day 21): n=2
- Lost to follow-up (day 84): n=4
|Intervention=Vitamin B Complex (vitamin B1/B6)
|Dosage and regime=100mg thiamine nitrate + 100mg pyridoxine hydrochloride, oral, 3 capsules daily
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=3
|Arm topic=Vitamin B1
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=17
|Drop-out=5
|Drop-out reasons=- Withdrawal of consent (day 1): n=1
- Lost to follow-up (day 21): n=1
- Lost to follow-up (day 84): n=3
|Intervention=Placebo
|Dosage and regime=Same form and frequency as in Vit. B arm (oral, 3 lactose capsules daily)
|One-time application=No
|Duration in days=21
|Side Effects / Interactions=NI
|Order number=4
|Arm topic=Vitamin B1
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Peripheral neuropathy
|Outcome specification=- Extension and intensity (non, mild, moderate,or severe) of CIPN complaints (numbness, swelling, tingling, pain, and subjective impairment in everyday life and at work)
- Heaviness of suffering due to CIPN complaints
- Severity of neuropathic symptoms
-> Outcome change from day 0 of treatment until day 21 (after treatment)
|Type of measurement=NRS (Numeric Rating Scale), Interview
|Results during intervention=Improvement of symptoms in all arms, no significant group difference at day 21 (directly after treatment): d = -0.3; CI: -1.4, 0.8; p = 0.705)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=1
|Outcome topic=Vitamin B1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Peripheral neuropathy
|Outcome specification=Neuropathy score (assessed by an independent neurologist)
|Type of measurement=Neurologic examination
|Results during intervention=Neuropathy score decreased in all arms during treatment (from day 0 until day 21);
no significant differences between any two arms (no p-values reported)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=2
|Outcome topic=Vitamin B1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Peripheral neuropathy
|Outcome specification=Electroneurographical tests/sensible nerve conduction studies of the median (upper extremities) and the sural nerve (lower extremities)
|Type of measurement=Neurologic examination
|Results during intervention=No significant differences between the treatment arms (from day 0 until day 21); no p-value reported
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=3
|Outcome topic=Vitamin B1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Peripheral neuropathy
|Outcome specification=Intensity of the CIPN complaints
|Type of measurement=NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria), Neurologic examination
|Results during intervention=Similar improvement in all four arms during treatment (from day 0 until day 21);
no significant differences in the four arms (no p-value reported)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=4
|Outcome topic=Vitamin B1
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Quality of life
|Outcome specification=NI
|Type of measurement=EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
|Results during intervention=Moderate increase in all four arms during treatment (from day 0 until day 21);
no significant differences in the four arms (no p-value reported)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=5
|Outcome topic=Vitamin B1
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Study was supported by the Fördergesellschaft Forschung Tumorbiologie, Freiburg, Germany, and the Karl and Veronica Carstens Foundation, Essen, Germany.
|Conflicts of Interest=According to authors no conflict of interest
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
|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 vote available
* Calculation of power analyses
* Intention-to-treat analyses
* Double-blinded if possible
CONTRA:
* Small sample size
* Low intensity of complaints, which left little room for improvement (floor effect)
* Possibility of confounding variables exists (medication and other concurrent therapies, inequality of cancer treatment medication use between arms caused by unequal distribution of cancer types (n.s.), also descriptive inequality of symptoms (n.s))
* Little detailed description of the follow-up results (overall concise results section)
}}

Publication: The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer

2024-12-02T12:27:47Z

DDeel:

{{Publication
|Title=The effect of vitamin D and E vaginal suppositories on tamoxifen-induced vaginal atrophy in women with breast cancer
|Topic=Vitamin D, Vitamin E
|Author=Keshavarzi, Z; Janghorban, R; Alipour, S; Tahmasebi, S; Jokar, A
|Year=2019
|Journal=Supportive Care in Cancer
|DOI=https://doi.org/10.1007/s00520-019-04684-6
|Authors Abstract=Purpose: Vaginal atrophy is one of the most common side effects of using tamoxifen in women with breast cancer. Hormone therapy for vaginal atrophy is prohibited in these women. The present study was conducted to investigate the effect of vitamin D and E vaginal suppositories on vaginal atrophy in women with breast cancer receiving tamoxifen.

Methods: Women under breast cancer management receiving tamoxifen and showing symptoms of vaginal atrophy were randomized triple-blind to an 8-week trial on vaginal suppository vitamin E or vitamin D or placebo administered every night before bedtime. The genitourinary atrophy self-assessment tool was administered, and pH was measured in all three groups before the intervention and at the end of weeks 2, 4, and 8 of the intervention. The Vaginal Maturation Index (VMI) was also measured before the intervention and at the end of the eighth week. Data were analyzed with paired t tests, repeated measures analysis of variance, and chi-square test.

Results: Thirty-two patients were randomized in each group. The results obtained showed an increase in the VMI by the end of the eighth week of the intervention in the groups receiving the vitamin D and E vaginal suppositories compared with the placebo group (P < 0.001). The vaginal pH also reduced in both groups compared with that in the placebo group (P < 0.001). The symptoms of self-reported genitourinary atrophy also improved in the two intervention groups compared with those in the placebo group by the end of the eighth week (P < 0.001).

Conclusion: These data support that vitamin D and E vaginal suppositories were beneficial in improving vaginal atrophy in women with breast cancer receiving tamoxifen. Given the prohibition on hormone therapy in these women, the suppositories can be used as an alternative therapy to improve these symptoms.
}}

Form:Publication

2024-11-28T14:28:57Z

DDeel:

<noinclude>
This is the "Publication" form.
To create a page with this form, enter the page name below;
if a page with that name already exists, you will be sent to a form to edit that page.

{{#forminput:form=Publication}}

</noinclude><includeonly>
<div id="wikiPreview" style="display: none; padding-bottom: 25px; margin-bottom: 25px; border-bottom: 1px solid #AAAAAA;"></div>
{{{for template|Publication|label=Publication}}}
{| class="formtable"
! Title:
| {{{field|Title|input type=text|mandatory}}}
|-
! Topic:
| {{{field|Topic|input type=text with autocomplete|mandatory|delimiter=,|values=Aloe vera,Boswellia serrata,Cannabinoids,Carnitine,Curcumin,Electroacupuncture,Enzymes (bromelain papain),Folic acid,Ginger,Ginkgo,Green tea (EGCG),Guarana,Low-carbohydrate or ketogenic diet,Lycopene,Reflexology,Resveratrol,Selenium,Vitamin A (beta-carotene),Vitamin B1,Vitamin B12,Vitamin B6,Vitamin C,Vitamin D,Vitamin E,Zeolites,Zinc,NI,?}}}
|-
! Author: {{#info: ChatGPT: “Can you rewrite this list in this style: lastname, first letter of firstname; and seperate the list by semicolon, leave second first names in, no point after initial and no space between initials” | note}}
| {{{field|Author|input type=textarea|mandatory|delimiter=;}}}

|-
! Publication year:
| {{{field|Year|input type=year|mandatory}}}
|-
! Journal:
| {{{field|Journal|input type=text|mandatory}}}
|-
! DOI: {{#info: Format as follows: ''https://doi.org/XXXXX''|note}}
| {{{field|DOI|input type=text}}}
|-
! Authors Abstract:
| {{{field|Authors Abstract|input type=textarea|mandatory|default=?}}}
|}
{{{end template}}}

'''Free text:'''
{{{standard input|free text|rows=10}}}
</includeonly>

Form:RCT Study

2024-11-28T14:28:26Z

DDeel:

<noinclude>
This is the "RCT Study" form.
To create a page with this form, enter the page name below;
if a page with that name already exists, you will be sent to a form to edit that page.

{{#forminput:form=RCT Study}}

</noinclude><includeonly>

=Publication=

{{{for template|Reference}}}
{| class="formtable"
! Publication:
| {{{field|Reference|input type=text|default=?}}}
|}

{{{for template|Study Note}}}
==Study Note==
{| class="formtable"
|{{{field|Study Note|input type=textarea|default=?}}}
|}
{{{end template}}}

=Brief summary=
{{{section|Brief summary|level=1}}}

=Study Design=
{{{section|Study Design|level=1}}}

{{{for template|Study Design (RCT)}}}
{| class="formtable"
! Prospective / Retrospective: {{#info: Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;
Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies|note}}
| {{{field|Perspective|input type=radiobutton|mandatory|default=?}}}
|-
! Monocentric / Multicentric: {{#info: Monocentric: conducted in one center/ hospital;
Multicentric: conducted in multiple centers/ hospitals|note}}
| {{{field|Centralized|input type=radiobutton|mandatory|default=?}}}
|-
! Blinding: {{#info: No: Open, all parties are aware of group assignments;
Single: one party is unaware of group assignments (generally participants);
Double: two parties are unaware of group assignments (generally the participants and the researchers);
Triple: concealing group assignment from additional parties|note}}
| {{{field|Blinding|input type=radiobutton|mandatory|default=?|values=?,No,Single,Double,Triple,NI}}}
|-
! Is randomized:
| {{{field|Is randomized|input type=checkbox|default=Yes}}}
|-
! Cross-over: {{#info: Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control|note}}
| {{{field|Cross-over|input type=checkbox|default=No}}}
|-
! Number of arms:
| {{{field|Number of arms|input type=text|mandatory|default=-999}}}
|}

=Study characteristics=
{{{section|Study characteristics|level=1}}}

{{{for template|RCT study general properties}}}
{| class="formtable"
! Inclusion criteria:
| {{{field|Inclusion criteria|input type=textarea|default=?}}}
|-
! Exclusion criteria:
| {{{field|Exclusion criteria|input type=textarea|default=?}}}
|-
! N randomized:
| {{{field|N randomized|input type=text|mandatory|default=-999}}}
|-
! Analysis: {{#info: PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.
ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.
mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.|note}}
| {{{field|Analysis|input type=checkboxes|default=?}}}
|-
! Specifications on analyses:
| {{{field|Specifications on analyses|input type=textarea|default=?}}}
|-
! Countries of data collection:
| {{{field|Countries of data collection|input type=text with autocomplete|delimiter=,|values=Afghanistan,Albania,Algeria,Andorra,Angola,Antigua & Deps,Argentina,Armenia,Australia,Austria,Azerbaijan,Bahamas,Bahrain,Bangladesh,Barbados,Belarus,Belgium,Belize,Benin,Bhutan,Bolivia,Bosnia Herzegovina,Botswana,Brazil,Brunei,Bulgaria,Burkina,Burundi,Cambodia,Cameroon,Canada,Cape Verde,Central African Rep,Chad,Chile,China,Colombia,Comoros,Congo,Congo {Democratic Rep},Costa Rica,Croatia,Cuba,Cyprus,Czech Republic,Denmark,Djibouti,Dominica,Dominican Republic,East Timor,Ecuador,Egypt,El Salvador,Equatorial Guinea,Eritrea,Estonia,Ethiopia,Europe,Fiji,Finland,France,Gabon,Gambia,Georgia,Germany,Ghana,Greece,Grenada,Guatemala,Guinea,Guinea-Bissau,Guyana,Haiti,Honduras,Hungary,Iceland,India,Indonesia,Iran,Iraq,Ireland {Republic},Israel,Italy,Ivory Coast,Jamaica,Japan,Jordan,Kazakhstan,Kenya,Kiribati,Korea North,Korea South,Kosovo,Kuwait,Kyrgyzstan,Laos,Latin America,Latvia,Lebanon,Lesotho,Liberia,Libya,Liechtenstein,Lithuania,Luxembourg,Macedonia,Madagascar,Malawi,Malaysia,Maldives,Mali,Malta,Marshall Islands,Mauritania,Mauritius,Mexico,Micronesia,Moldova,Monaco,Mongolia,Montenegro,Morocco,Mozambique,Myanmar,{Burma},Namibia,Nauru,Nepal,Netherlands,New Zealand,Nicaragua,Niger,Nigeria,North America,Norway,Oman,Pakistan,Palau,Panama,Papua New Guinea,Paraguay,Peru,Philippines,Poland,Portugal,Qatar,Romania,Russian Federation,Rwanda,St Kitts & Nevis,St Lucia,Saint Vincent & the Grenadines,Samoa,San Marino,Sao Tome & Principe,Saudi Arabia,Senegal,Serbia,Seychelles,Sierra Leone,Singapore,Slovakia,Slovenia,Solomon Islands,Somalia,South Africa,South Sudan,Spain,Sri Lanka,Sudan,Suriname,Swaziland,Sweden,Switzerland,Syria,Taiwan,Tajikistan,Tanzania,Thailand,Togo,Tonga,Trinidad & Tobago,Tunisia,Turkey,Turkmenistan,Tuvalu,Uganda,Ukraine,United Arab Emirates,United Kingdom,United Kingdom - Great Britain,United States,United States - New York,United States - Texas,Uruguay,Uzbekistan,Vanuatu,Vatican City,Venezuela,Vietnam,Yemen,Zambia,Zimbabwe,NI,?|default=?}}}
|-
! LoE: {{#info: Level of evidence|note}}
| {{{field|LoE|input type=dropdown|mandatory|default=?}}}
|-
! Outcome timeline: {{#info: Data collection times|note}}
| {{{field|Outcome timeline|input type=textarea|mandatory|default=?}}}
|}

=Characteristics of participants=
{{{section|Characteristics of participants|level=1}}}

{{{for template|Characteristics of participants}}}
{| class="formtable"
! Setting: {{#info: Refers to cancer therapy setting.
- Curative therapy: aims to completely eradicate a disease and achieve a full recovery;
- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery);
- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery);
- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease;
- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);
- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.|note}}
| {{{field|Setting|input type=checkboxes|delimiter=,|default=?|mandatory|values=?, Curative, Neo-adjuvant, Adjuvant, Palliative, Active surveillance, No therapy setting, NI}}}
|-
! Types of cancer: {{#info: "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included|note}}
| {{{field|Types of cancer|input type=text with autocomplete|mandatory|default=?|delimiter=,|values=Adrenal Cancer,Anal Cancer,Bile Duct Cancer,Bone and Soft Tissue Cancers, Bone and Soft Tissue Cancers - Osteosarcoma,Bone and Soft Tissue Cancers - Ewing Sarcoma,Bone and Soft Tissue Cancers - Chondrosarcoma,Bone and Soft Tissue Cancers - Rhabdomyosarcoma,Bone and Soft Tissue Cancers – Liposarcoma,Brain and Central Nervous System (CNS) Cancers,Brain and Central Nervous System (CNS) Cancers - Astrocytoma,Brain and Central Nervous System (CNS) Cancers - Glioblastoma,Brain and Central Nervous System (CNS) Cancers - High-Grade Glioma,Brain and Central Nervous System (CNS) Cancers - Meningioma,Breast Cancer,Breast Cancer - Ductal Carcinoma,Breast Cancer - Lobular Carcinoma,Breast Cancer - Inflammatory Breast Cancer,Breast Cancer - Triple-Negative Breast Cancer,Carcinosarcoma,Chest Cancer,Colorectal Cancer,Colorectal Cancer - Colon Cancer,Colorectal Cancer - Rectal Cancer,Eye Cancer,Eye Cancer - Retinoblastoma,Gastrointestinal Cancers,Gastrointestinal Cancers - Gallbladder Cancer,Gastrointestinal Cancers - Gastric (Stomach) Cancer,Gastrointestinal Cancers - Esophageal Cancer,Gastrointestinal Cancers - Pancreatic Cancer,Gastrointestinal Cancers - Liver Cancer,Genitourinary Cancers,Genitourinary Cancers - Bladder Cancer,Genitourinary Cancers - Kidney (Renal) Cancer,Genitourinary Cancers - Testicular Cancer,Genitourinary Cancers - Urethral Cancer,Gynecologic Cancers,Gynecologic Cancers - Ovarian Cancer,Gynecologic Cancers - Cervical Cancer,Gynecologic Cancers - Uterine Cancer,Gynecologic Cancers - Endometrial Cancer,Gynecologic Cancers - Vulvar Cancer,Head and Neck Cancers, Head and Neck Cancers - Oral Cancer,Head and Neck Cancers - Oropharyngeal Cancer,Head and Neck Cancers - Laryngeal Cancer,Head and Neck Cancers - Nasopharyngeal Cancer,Head and Neck Cancers - Tongue Cancer,Head and Neck Cancers - Thyroid Cancer,Head and Neck Cancers - Ethmoid Sinus Cancer,Hematologic Cancers, Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid), Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin),Hematologic Cancers - Multiple Myeloma,Lung Cancer,Lung Cancer - Small Cell Lung Cancer,Lung Cancer - Non-Small Cell Lung Cancer,Mesothelioma,Neuroblastoma,Prostate Cancer,Skin Cancer,Skin Cancer - Basal Cell Carcinoma,Skin Cancer - Squamous Cell Carcinoma,Skin Cancer – Melanoma,Stomach Cancer,Solid Malignancies,Thymoma and Thymic Carcinoma,Unspecified Sarcoma,Other Cancers,NI,?}}}
|-
! Cancer stage: {{#info: Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;
Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis|note}}
| {{{field|Stage cancer|input type=checkboxes|mandatory|default=?}}}
|-
! Cancer stage specification:
| {{{field|Cancer stage specification|input type=textarea|default=?}}}
|-
! Comorbidity:
| {{{field|Comorbidity|input type=textarea|default=?}}}
|-
! Current cancer therapy:
| {{{field|Current cancer therapy|input type=text with autocomplete|mandatory|default=?}}}
|-
! Specifications on cancer therapies:
| {{{field|Specifications on cancer therapies|input type=textarea|default=?}}}
|-
! Previous cancer therapies:
| {{{field|Previous cancer therapies|input type=text with autocomplete|default=?}}}
|-
! Gender:
| {{{field|Gender|input type=radiobutton|mandatory|values=?, Male, Female, Mixed, NI|default=?}}}
|-
! Gender specifications:
| {{{field|Gender specifications|input type=textarea|default=?}}}
|-
! Age groups:
| {{{field|Age groups|input type=checkboxes|values=?, Children (0-15), Adolescents and young adults (15-39), Adults (18+), Elderly (65+), NI|default=adults (18+)}}}
|-
! Age groups specification:
| {{{field|Age groups specification|input type=textarea|default=?}}}
|}

=Arms=
{{{section|Arms|level=1}}}

{{{for template|Arm|multiple}}}
'''Arm type:''' {{#info: Active control: group receives active treatment;
Passive control: for example: treatment as usual, waiting control, no treatment|note}}
{{{field|Arm type|input type=checkboxes|default=?}}}

'''Number of participants (arm):''' {{{field|Number of participants (arm)|input type=text|mandatory|default=-999}}}

'''Drop-out:''' {{#info: Number of participants who left the study for any reason or did not provide information on every data collection date|note}} {{{field|Drop-out|input type=textarea|mandatory|default=?}}}

'''Drop-out reasons:''' {{{field|Drop-out reasons|input type=textarea|default=?}}}

'''Intervention:''' {{{field|Intervention|input type=textarea|mandatory|default=?}}}

'''Dosage and regime:''' {{{field|Dosage and regime|input type=textarea|mandatory|default=?}}}

'''One-time application:''' {{{field|One-time application|input type=checkbox|mandatory|default=No}}}

'''Duration in days:''' {{#info: For long-term interventions, the number of days is an estimate.
A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See ''Outcome timeline'' or ''Dosage and regime'' for further information. |note}}
{{{field|Duration in days|input type=regexp|mandatory|default=?}}}

'''Side Effects / Interactions:''' {{{field|Side Effects / Interactions|input type=textarea|mandatory|default=?}}}

'''Order number:''' {{{field|Order number|input type=text|mandatory|default=1}}}
'''Arm topic:''' {{{field|Arm topic|input type=text with autocomplete|mandatory|delimiter=,|values=Aloe vera,Boswellia serrata,Cannabinoids,Carnitine,Curcumin,Electroacupuncture,Enzymes (bromelain papain),Folic acid,Ginger,Ginkgo,Green tea (EGCG),Guarana,Low-carbohydrate or ketogenic diet,Lycopene,Reflexology,Resveratrol,Selenium,Vitamin A (beta-carotene),Vitamin B1,Vitamin B12,Vitamin B6,Vitamin C,Vitamin D,Vitamin E,Zeolites,Zinc}}}

{{{end template}}}

{{{for template|Arm Overview}}}
{{{end template}}}

=Outcomes=
{{{section|Outcomes|level=1}}}
{{{for template|Outcome|multiple}}}
'''Outcome type:''' {{#info: As specificed by the authors| note}} {{{field|Outcome type|input type=radiobutton|mandatory|default=?|values=?,Primary,Secondary,Others,NI}}}

'''Outcome name:''' {{{field|Outcome name|input type=text with autocomplete|mandatory|default=?|delimiter=,|values=Additional medication,Anorexia/Cachexia,Antibodies,Anxiety,Appetite,Arterial inflow,BMD (Bone Mineral Density),Body composition,Carnitine level,Carotenoid concentration,Cerebral oedema,CINV (Chemotherapy-Induced Nausea and Vomiting),Cognitive functioning,Cognitive impairment,Depression,Dermatitis,DFS (Disease-Free Survival),Diarrhoe,Distress,Dysgeusia,Ejection fraction,Erectile dysfunction,Erythema,Esophagitis,Fatigue,Fever,Fibrosis,Folic acid level,Functionality,Haematological indices,Haematological toxicity,Hand-foot syndrome,Hand grip strength,Hormone level,Ileus (intestinal obstruction),Incidence of acute GVHD (Graft-Versus-Host Disease),Infection,Interaction with cancer treatment,Laboratory parameters,Length of hospital stay,Lymphedema,Menopausal symptoms,Mental status/ function,Mood/Affect,Mortality rate,Mucositis,Musculoskeletal symptoms,Nausea,Nausea and Vomiting,Nerve conduction velocity,Neurotoxicity,Neutropenia,Non-haematological indices,Nutrition status,Objective signs and subjective symptoms,Oral ulcus,OS (Overall Survival),Ototoxicity,Pain,PD (Pharmacodynamics),Performance Status,Peripheral neuropathy,PFS (Progression-Free Survival),Pharyngitis,Physical functioning,PK (Pharmacokinetics),Postoperative morbidity/ complications,PSA level (Prostate-Specific Antigen),Quality of life,Recurrence rate,REE (Resting Energy Expenditure),Relaxation,RFS (Recurrence-Free Survival),Salivary gland function,Selenium level,Seroconversion,Sleep,Stomatitis,Stress,Symptom load,Taste alteration,Tea polyphenol uptake,Thromboembolic event rates,Toxicity,Treatment interruption,Tumor progression,Tumor response,Vaginal atrophy,Vitamin A level,Vitamin B6 level,Vitamin B12 level,Vitamin B17 level,Vitamin C level,Vitamin D level,Vitamin E level,Vomiting,Weight,Well-being,Wound healing,Wound odour,Xerostomia,Zinc level,Unspecified effects,NI,?}}}

'''Outcome specification:''' {{{field|Outcome specification|input type=textarea|default=?}}}

'''Type of measurement:''' {{{field|Type of measurement|input type=tokens|mandatory|default=?|delimiter=,|values=AQoL-8D (Assessment of Quality of Life),ASAT (Auditory Sustained Attention Test),Atomic absorption,Audiogram,AUSCAN (Australian/Canadian Osteoarthritis Hand Index),BCPT (Breast Cancer Prevention Symptom Scales),BDI (Beck Depression Inventory),BFI (Brief Fatigue Inventory),BIA (Bioelectrical impedance analysis),Blood Test,BPI-SF (Brief Pain Inventory - Short Form),CES-D (Center for Epidemiologic Studies - Depression Scale),Chemiluminescent immunoassay,CNPI (Checklist of Non-Verbal Pain Indicators),CSSP (Catterall Skin Scoring Profile),CT (Computed Tomography),CTCAE (Common Terminology Criteria of Adverse Events),Cystoscopy,Diary questionnaire,DXA (Dual energy X-ray Absorptiometry),Dynamometer,Echo-color Doppler,ECOG Performance Status Scale (Eastern Cooperative Oncology Group),Electronic monitoring device,Electrophysiological evaluation,ELISA protocol (Enzyme-Linked Immunoabsorbent Assay),EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire),ESAS (Edmonton Symptom Assessment Scale),FAACT (Functional Assessment of Anorexia-Cachexia Therapy),FACIT (Functional Assessment of Chronic Illness Therapy),FACT (Functional Assessment of Cancer Therapy),FGS (Hughes' Functional Grading Scale),FIQ (Fibromyalgia Impact Questionnaire),FLIE (Functional Living Index for Emesis),Genitourinary atrophy self-assessment tool,GFAAS (Graphite Furnace Atomic Absorption Spectrometry),Global Charter Fatigue Scale,HADS (Hospital Anxiety and Depression Scale),HAQ-DI (Health Assessment Questionnaire-Disability Index),HFRDIS (Hot Flash Related Daily Interference Scale),HFS (Hot Flush Score),HGST Maximum (Handgrip Strength Test),Histological examination,HNQR (Head and Neck Radiotherapy Questionnaire),HSCS (High Sensitivity Cognitive Screen),ICI Test (Intracavernosal Injection Test),IIEF (International Index of Erectile Function),Interview,KPS (Karnofsky Performance Status),LASA (Linear Analogue Self-Assessment),LENT SOMA Scale (Late Effects on Normal Tissues/ Subjective Objective Management Analysis),MADRS (Montgomery-Asberg Depression Rating Scale),MAT (Multinational Association of Supportive Care in Cancer-Antiemesis Tool),McDonald criteria,MDASI (M. D. Anderson Symptom Inventory),Measuring tape,MENQOL (Menopause-Specific Quality of Life),MFI-20 (Multidimensional Fatigue Inventory-20),MMSE (Mini-Mental State Exam),Morbidity rating scale (by Dische),MOS SF-12 (Medical Outcomes Study/ 12-Item Short Form Health Survey),MPQ-SF (McGill Pain Questionnaire - Short Form),MRI (Magnetic Resonance Imaging),MRS (Mood Rating Scale),MYCaW (Measure Yourself Concerns and Wellbeing),NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria),NCI Grading Scale (National Cancer Institute),NDS (Neurological Disability Score),Neurologic examination,Neuropathy specific question,NRS (Numeric Rating Scale),NRS (Nutritional Risk Screening),NSS (Neurological Symptom Score),Observation,OMAS (Oral Mucositis Assessment Scale),Otoacoustic Emissions Testing,PAC-QoL (Patient Assessment of Constipation - Quality of Life),PGIC (Physician Global Impression of Change),PG-SGA (Patient-Generated Subjective Global Assessment),PHLF (Post Hepatectomy Liver Failure),PHS (Cognitive subscale of the Perceived Health Scale),pH-value,Physical examination,Physical functioning (grip strength;6 minute walk;leg extension),POMS (Profile of Mood States),PoSSe (Postoperative Symptom Severity Scale),Postoperative morbidity/complications (classification according to Clavien-Dindo),PROMIS (Patient-Reported Outcomes Measurement Information System),PSQ (Patient Satisfaction Questionnaire),PSQI (Pittsburgh Sleep Quality Index),QoR-40 (Quality of Recovery-40 Questionnaire),RDS (Radiation Dermatitis Severity),RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors),Reidel-Seiffer tuning fork,Rhodes Inventory of Nausea,RPSAS (Radiation Proctopathy System Assessment Scale),RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group),Scale,SCID (Structured Clinical Interview for DSM IV),Scintigraphy,Self-developed measurement instrument,SF-36 (Short Form-36 Health Survey),SF-MPQ (Short-Form McGill Pain Questionnaire),SGIC (Subject Global Impression of Change),SI (Symptom Inventory questionnaire),SOMA (Subjective Objective Medical management and Analytic evaluation of injury),SPECT (Single Photon Emission Computed Tomography),Spectrophotometry,SPPB (Short Physical Performance Battery),STAI (State-Trait-Anxiety-Inventory),Symptom experience diary (NCCTG),Thermometer,Three-stimulus drop technique (by Henkin),Tissue testing,TMT (Trail Making Test),TNS (Total Neuropathy Score),Ultrasonography,Unspecified questionnaire,Urinalysis,VAS (Visual Analogue Scale),VMI (Vaginal Maturation Index),VNS (Verbal Numerical Scale),Volometer,Western Ontario and McMaster Osteoarthritis Index,WHO-Scale (World Health Organisation),Wound volume,NI,NA,?}}}

'''Results during intervention:''' {{#info: ''Results during intervention'' means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.|note}}
{{{field|Results during intervention|input type=textarea|mandatory|default=?}}}
'''Results after intervention:''' {{#info: ''Results after intervention'' means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.
If a categorization in ''Results during vs. after intervention'' is not possible (e.g. survival data), the results are summarized under ''Results after intervention'' under the headline "Overall".|note}}
{{{field|Results after intervention|input type=textarea|mandatory|default=?}}}
==Risk of Bias Assessment: Cochrane RoB tool 2.0==
{| class="formtable"
! Bias arising from the randomization process
| {{{field|Bias arising from the randomization process|input type=radiobutton|mandatory|default=?|values=?,low risk,some concerns,high risk,NA}}}
|-
! Bias due to deviation from intended intervention (assignment to intervention)
| {{{field|Bias due to deviation from intended intervention (assignment to intervention)|input type=radiobutton|mandatory|default=?|values=?,low risk,some concerns,high risk,NA}}}
|-
! Bias due to deviation from intended intervention (adhering to intervention)
| {{{field|Bias due to deviation from intended intervention (adhering to intervention)|input type=radiobutton|mandatory|default=NA|values=?,low risk,some concerns,high risk,NA}}}
|-
! Bias due to missing outcome data
| {{{field|Bias due to missing outcome data|input type=radiobutton|mandatory|default=?|values=?,low risk,some concerns,high risk, NA}}}
|-
! Bias in measurement of the outcome
| {{{field|Bias in measurement of the outcome|input type=radiobutton|mandatory|default=?|values=?,low risk,some concerns,high risk, NA}}}
|-
! Bias in selection of the reported result
| {{{field|Bias in selection of the reported result|input type=radiobutton|mandatory|default=?|values=?,low risk,some concerns,high risk,NA}}}
|-
! Other sources of bias
| {{{field|Other sources of bias|input type=radiobutton|mandatory|default=?|values=?,low risk,some concerns,high risk,NA}}}
|-
! Overall RoB judgment
| {{{field|Overall RoB judgment|input type=radiobutton|mandatory|default=?|values=?,low risk,some concerns,high risk,NA}}}
|}

'''Order number:''' {{{field|Order number|input type=text|mandatory|default=1}}}
'''Outcome topic:''' {{{field|Outcome topic|input type=text with autocomplete|mandatory|delimiter=,|values=Aloe vera,Boswellia serrata,Cannabinoids,Carnitine,Curcumin,Electroacupuncture,Enzymes (bromelain papain),Folic acid,Ginger,Ginkgo,Green tea (EGCG),Guarana,Low-carbohydrate or ketogenic diet,Lycopene,Reflexology,Resveratrol,Selenium,Vitamin A (beta-carotene),Vitamin B1,Vitamin B12,Vitamin B6,Vitamin C,Vitamin D,Vitamin E,Zeolites,Zinc}}}
{{{end template}}}
{{{for template|Outcome Overview}}}
{{{end template}}}

=Funding and Conflicts of Interest=
{{{section|Funding and Conflicts of Interest|level=1}}}

{{{for template|Funding and Conflicts of Interest}}}
{| class="formtable"
! Funding:
| {{{field|Funding|input type=textarea|default=?}}}
|-
! Conflicts of Interest:
| {{{field|Conflicts of Interest|input type=textarea|default=?}}}
|}
{{{end template}}}

=Further points for assessing the study=
{{{section|Further points for assessing the study|level=1}}}

{{{for template|Further points for assessing the study}}}
==Sample==
{| class="formtable"
! Power analysis performed
| {{{field|power analysis performed|input type=radiobutton|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Sample size corresponds to power analysis
| {{{field|Sample size corresponds to power analysis|input type=radiobutton|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Reasons for insufficient sample size based on power analysis
| {{{field|Reasons given for samples being too small according to power analysis|input type=textarea|mandatory|default=?}}}
|-
! If no power analysis performed: at least moderate sample size (n >= 30 per arm)
| {{{field|Samples sufficiently large|input type=radiobutton|mandatory|default=?}}}
|-
! Ethnicity mentioned
| {{{field|Ethnicity mentioned|input type=radiobutton|mandatory|default=?}}}
|}
==Alternative Explanation==
{| class="formtable"
! Other explanations for an effect besides the investigated intervention
| {{{field|Other explanations for an effect besides the investigated intervention|input type=radiobutton|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Possibility of attention effects {{#info: e.g. due to lack of a placebo arm|note}}
| {{{field|Possibility of attention effects|input type=textarea|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Possibility of placebo effects
| {{{field|Possibility of placebo effects|input type=textarea|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Other reasons
| {{{field|Other reasons|input type=textarea|mandatory|default=?}}}
|}
==Statistics==
{| class="formtable"
! Correct use of parametric and non-parametric tests {{#info: Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing|note}}
| {{{field|Correct use of parametric and non-parametric tests|input type=radiobutton|mandatory|default=?}}}
|-
! Correction for multiple testing
| {{{field|Correction for multiple testing|input type=radiobutton|mandatory|default=?}}}
|-
! Measurement of compliance
| {{{field|Measurement of compliance|input type=radiobutton|mandatory|default=?}}}
|-
! Consistent reporting in numbers (figures, flowchart, abstract, results)
| {{{field|Consistent reporting in numbers|input type=radiobutton|mandatory|default=?}}}
|-
! Comprehensive and coherent reporting
| {{{field|Comprehensive and coherent reporting|input type=radiobutton|mandatory|default=?}}}
|-
! Cross-Over study
| {{{field|Cross-over|input type=radiobutton|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Sufficient washout period
| {{{field|sufficient washout period|input type=radiobutton|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Tested for carry-over effects
| {{{field|Tested for carry-over effects|input type=radiobutton|mandatory|default=?}}}
|-
! style="text-indent:3em;" | - Tested for sequence effects
| {{{field|Were sequence effects tested|input type=radiobutton|mandatory|default=?}}}
|}
==Interpretation of results==
{| class="formtable"
! Effect sizes reported (clinical vs. statistical significance)
| {{{field|Effect sizes reported|input type=radiobutton|mandatory|default=?}}}
|-
! Side effects systematically recorded
| {{{field|Were side effects systematically recorded|input type=radiobutton|mandatory|default=?}}}
|-
! Side effects considered in result interpretation
| {{{field|Side effects taken into account in the interpretation of the results|input type=radiobutton|mandatory|default=?}}}
|-
! Ethics votum
| {{{field|Ethics / CoI / Funding|input type=radiobutton|mandatory|default=?}}}
|}
{{{end template}}}

{{{for template|Additional Notes}}}
==Additional Notes==
{| class="formtable"
|{{{field|Additional Notes|input type=textarea|default=?}}}
|}
{{{end template}}}

</includeonly>

Property:Outcome topic

2024-11-28T14:24:04Z

DDeel:

This is a property of type [[Has type::Text]].

The allowed values for this property are:
* [[Allows value::Aloe vera]]
* [[Allows value::Boswellia serrata]]
* [[Allows value::Cannabinoids]]
* [[Allows value::Carnitine]]
* [[Allows value::Curcumin]]
* [[Allows value::Electroacupuncture]]
* [[Allows value::Enzymes (bromelain papain)]]
* [[Allows value::Folic acid]]
* [[Allows value::Ginger]]
* [[Allows value::Ginkgo]]
* [[Allows value::Green tea (EGCG)]]
* [[Allows value::Guarana]]
* [[Allows value::Low-carbohydrate or ketogenic diet]]
* [[Allows value::Lycopene]]
* [[Allows value::Reflexology]]
* [[Allows value::Resveratrol]]
* [[Allows value::Selenium]]
* [[Allows value::Vitamin A (beta-carotene)]]
* [[Allows value::Vitamin B1]]
* [[Allows value::Vitamin B12]]
* [[Allows value::Vitamin B6]]
* [[Allows value::Vitamin C]]
* [[Allows value::Vitamin D]]
* [[Allows value::Vitamin E]]
* [[Allows value::Zeolites]]
* [[Allows value::Zinc]]
* [[Allows value:: NI]]
* [[Allows value:: ?]]

Property:Arm topic

2024-11-28T14:23:43Z

DDeel:

Property:Topic

2024-11-28T14:23:20Z

DDeel:

Property:Outcome name

2024-11-28T14:22:20Z

DDeel:

This is a property of type [[Has type::Text]].

The allowed values for this property are:
* [[Allows value::Additional medication]]
* [[Allows value::Anorexia/Cachexia]]
* [[Allows value::Antibodies]]
* [[Allows value::Anxiety]]
* [[Allows value::Appetite]]
* [[Allows value::Arterial inflow]]
* [[Allows value::BMD (Bone Mineral Density)]]
* [[Allows value::Body composition]]
* [[Allows value::Carnitine level]]
* [[Allows value::Carotenoid concentration]]
* [[Allows value::Cerebral oedema]]
* [[Allows value::CINV (Chemotherapy-Induced Nausea and Vomiting)]]
* [[Allows value::Cognitive functioning]]
* [[Allows value::Cognitive impairment]]
* [[Allows value::Depression]]
* [[Allows value::Dermatitis]]
* [[Allows value::DFS (Disease-Free Survival)]]
* [[Allows value::Diarrhoe]]
* [[Allows value::Distress]]
* [[Allows value::Dysgeusia]]
* [[Allows value::Ejection fraction]]
* [[Allows value::Erectile dysfunction]]
* [[Allows value::Erythema]]
* [[Allows value::Esophagitis]]
* [[Allows value::Fatigue]]
* [[Allows value::Fever]]
* [[Allows value::Fibrosis]]
* [[Allows value::Folic acid level]]
* [[Allows value::Functionality]]
* [[Allows value::Haematological indices]]
* [[Allows value::Haematological toxicity]]
* [[Allows value::Hand-foot syndrome]]
* [[Allows value::Hand grip strength]]
* [[Allows value::Hormone level]]
* [[Allows value::Incidence of acute GVHD (Graft-Versus-Host Disease)]]
* [[Allows value::Infection]]
* [[Allows value::Interaction with cancer treatment]]
* [[Allows value::Ileus (intestinal obstruction)]]
* [[Allows value::Laboratory parameters]]
* [[Allows value::Length of hospital stay]]
* [[Allows value::Lymphedema]]
* [[Allows value::Menopausal symptoms]]
* [[Allows value::Mental status/ function]]
* [[Allows value::Mood/Affect]]
* [[Allows value::Mortality rate]]
* [[Allows value::Mucositis]]
* [[Allows value::Musculoskeletal symptoms]]
* [[Allows value::Nausea]]
* [[Allows value::Nausea and Vomiting]]
* [[Allows value::Nerve conduction velocity]]
* [[Allows value::Neurotoxicity]]
* [[Allows value::Neutropenia]]
* [[Allows value::Non-haematological indices]]
* [[Allows value::Nutrition status]]
* [[Allows value::Objective signs and subjective symptoms]]
* [[Allows value::Oral ulcus]]
* [[Allows value::OS (Overall Survival)]]
* [[Allows value::Ototoxicity]]
* [[Allows value::Pain]]
* [[Allows value::PD (Pharmacodynamics)]]
* [[Allows value::Performance Status]]
* [[Allows value::Peripheral neuropathy]]
* [[Allows value::PFS (Progression-Free Survival)]]
* [[Allows value::Pharyngitis]]
* [[Allows value::Physical functioning]]
* [[Allows value::PK (Pharmacokinetics)]]
* [[Allows value::Postoperative morbidity/ complications]]
* [[Allows value::PSA level (Prostate-Specific Antigen)]]
* [[Allows value::Quality of life]]
* [[Allows value::Recurrence rate]]
* [[Allows value::REE (Resting Energy Expenditure)]]
* [[Allows value::Relaxation]]
* [[Allows value::RFS (Recurrence-Free Survival)]]
* [[Allows value::Salivary gland function]]
* [[Allows value::Seroconversion]]
* [[Allows value::Selenium level]]
* [[Allows value::Sleep]]
* [[Allows value::Stomatitis]]
* [[Allows value::Stress]]
* [[Allows value::Symptom load]]
* [[Allows value::Taste alteration]]
* [[Allows value::Tea polyphenol uptake]]
* [[Allows value::Thromboembolic event rates]]
* [[Allows value::Toxicity]]
* [[Allows value::Treatment interruption]]
* [[Allows value::Tumor progression]]
* [[Allows value::Tumor response]]
* [[Allows value::Vaginal atrophy]]
* [[Allows value::Vitamin A level]]
* [[Allows value::Vitamin B6 level]]
* [[Allows value::Vitamin B12 level]]
* [[Allows value::Vitamin B17 level]]
* [[Allows value::Vitamin C level]]
* [[Allows value::Vitamin D level]]
* [[Allows value::Vitamin E level]]
* [[Allows value::Vomiting]]
* [[Allows value::Weight]]
* [[Allows value::Well-being]]
* [[Allows value::Wound healing]]
* [[Allows value::Wound odour]]
* [[Allows value::Xerostomia]]
* [[Allows value::Zinc level]]
* [[Allows value::Unspecified effects]]
* [[Allows value::NI]]
* [[Allows value::?]]

Wyatt et al. (2012): Health-Related Quality-of-Life Outcomes: A Reflexology Trial With Patients With Advanced-Stage Breast Cancer

2024-11-28T14:10:55Z

DDeel:

{{Reference
|Reference=Publication: Health-Related Quality-of-Life Outcomes: A Reflexology Trial With Patients With Advanced-Stage Breast Cancer
}}
{{Study Note}}
=Brief summary=
Nearly 300 patients with advanced breast cancer were randomly assigned to one of three arms. The first arm received several sessions of reflexology, the second arm received the same number of regular foot massages, and the third arm received nothing in addition to conventional cancer treatment. All participants were surveyed at three points in time regarding various aspects of their psychological and physical quality of life: at the start of the study, one week after the last intervention, and six weeks after the last intervention. Statistical analyses were carried out rigorously. Initial differences between the arms were taken into account in the statistical analyses. When comparing the arm of patients who had received reflexology with the arm that had received regular foot massages, the first arm only performed better in one aspect: the patients reported less shortness of breath on one particular question. Compared to the arm that had not received any additional treatment, they performed better in two out of nine aspects: shortness of breath and overall psychological functioning, the latter resulting from the improvement in shortness of breath. In all other aspects, no differences were observed between the reflexology arm and the other two arms. It should be noted that shortness of breath was assessed with just one question. Additionally, the patients knew whether they were receiving a special treatment or not (no blinding), which means that the patients' positive or negative expectations may have influenced their well-being or perception. Furthermore, it should be noted that the arm difference presented was calculated from the average of all arm differences at the various points in time. So-called interaction effects were not presented. This means it cannot be determined whether the groups differed at specific times, i.e., whether there were short-term or very late effects. Side effects were systematically recorded. No side effects or interactions with the conventional cancer treatment were found.

Es wurden knapp 300 Patientinnen mit fortgeschrittenem Brustkrebs zufällig in eine von drei Gruppen eingeteilt. Die erste Gruppe hat mehrere Sitzungen Reflextherapie erhalten, die zweite Gruppe die gleiche Anzahl gewöhnlicher Fußmassagen und die dritte Gruppe hat nichts zusätzlich zur konventionellen Krebsbehandlung bekommen. Alle Teilnehmer wurden an drei Zeitpunkten zu verschiedenen Belangen der psychischen und physischen Lebensqualität befragt: zu Beginn der Studie, eine Woche nach der letzten Intervention und sechs Wochen nach der letzten Intervention. Die statistischen Analysen wurden nach allen Regeln der Kunst durchgeführt. Anfängliche Unterschiede zwischen den Gruppen wurden in den statistischen Analysen berücksichtigt. Im Vergleich der Gruppe der Patientinnen, die eine Reflextherapie bekommen hatte, mit der Gruppe, die gewöhnliche Fußmassagen erhalten hatte, schnitt die erste Gruppe nur hinsichtlich eines Belangs besser ab: die Patientinnen gaben in einer Frage an, weniger unter Atemnot zu leiden. Im Vergleich zur Gruppe, die keine zusätzliche Behandlung bekommen hatte, hatten sie in zwei von neun Belangen bessere Werte: ebenso Atemnot und grundsätzliches psychisches Funktionieren, wobei Letzteres durch die Verbesserung der Atemnot zustande kam. In allen weiteren Belangen zeigten sich keine Unterschiede zwischen der Reflextherapie-Gruppe und den anderen zwei Gruppen. Es ist anzumerken, dass Atemnot nur mit einer einzigen Frage erfasst wurde. Zudem wussten die Patientinnen, ob sie eine besondere Behandlung bekommen oder nicht (keine Verblindung), so dass auch die positive/negative Erwartung der Patientinnen ihr Befinden oder ihre Wahrnehmung verändert haben könnte. Weiterhin ist anzumerken, dass der dargestellte Gruppenunterschied aus dem Durchschnitt aller Gruppenunterschiede zu den verschiedenen Zeitpunkten berechnet wird. Sogenannte Interaktionseffekte wurden nicht dargestellt. D.h. es kann nicht erkannt werden, ob sich die Gruppen zeitweise unterschieden haben, also ob es kurzfristige oder sehr späte Effekte gab. Nebenwirkungen wurden systematisch erhoben. Es wurden keine Nebenwirkungen oder Wechselwirkungen mit der konventionellen Krebsbehandlung gefunden.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=21 years or older; having a diagnosis of stage III or IV breast cancer, metastasis, or recurrence; being able to perform basic activities of daily living; being cognitively intact and without a documented diagnosis of mental illness; being able to speak and understand English; having access to a telephone; being able to hear normal conversation; receiving chemotherapy at intake into the study; and having a score of 11 or lower on the Palliative Prognostic Score (Pirovano et al., 1999), which indicates a 30% probability of having a life expectancy of at least three months
|Exclusion criteria=Receiving hospice care at intake, residing in a nursing home or similar care facility, being bedridden, regularly using CAM similar to those used in the protocol (e.g., reflexology, foot massage, pedicure with massage), and participating in an experimental chemotherapy protocol.
|N randomized=286
|Analysis=ITT Analysis
|Specifications on analyses=Chi-square test
|Countries of data collection=United States
|LoE=1b Oxford 2009
|Outcome timeline=Before randomization:
T1: 1 week after the last intervention;

T2: 6 weeks after the last intervention
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Palliative
|Types of cancer=Breast Cancer
|Stage cancer=Advanced Stage, ?
|Cancer stage specification=Andvanced stage (III-IV, metastatic or recurrent)
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Hormone therapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=Diverse
|Gender=Female
|Gender specifications=100 % female
|Age groups=Adults (18+)
|Age groups specification=Mean = 56 years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=95
|Drop-out=N=0
|Drop-out reasons=NA
|Intervention=Reflexology
|Dosage and regime=30min., 1x week, 4 weeks in total
|One-time application=No
|Duration in days=4
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Reflexology
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=95
|Drop-out=N=0
|Drop-out reasons=NA
|Intervention=Foot massage (LFM)
|Dosage and regime=30min., 1x week, 4 weeks in total
|One-time application=No
|Duration in days=4
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Reflexology
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=96
|Drop-out=N=0
|Drop-out reasons=NA
|Intervention=Conventional therapy, control arm
|Dosage and regime=30min., 1x week, 4 weeks in total
|One-time application=No
|Duration in days=4
|Side Effects / Interactions=NI
|Order number=3
|Arm topic=Reflexology
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Breast cancer-specific QOL with FACT-B: physical, emotional, social, functional, breast cancer-specific concerns subscales and total scale
|Type of measurement=FACT (Functional Assessment of Cancer Therapy)
|Results during intervention=NA
|Results after intervention=No sig. differences between the arms (reflexology arm/control arm: 0.387 [2.194]; p= 0.86, reflexology arm/control arm: NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=1
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Unspecified effects
|Outcome specification=Dyspnea with a single item from the FACT-B other concerns subscale
|Type of measurement=FACT (Functional Assessment of Cancer Therapy)
|Results during intervention=NA
|Results after intervention=Sig. better values in reflexology arm than control arm (β= 0.39 [0.13]; p<0.01, reflexology arm: Mean-T1=3.33, Mean-T2=3.36, control arm: Mean-T1 (1 week after last intervention)=3.1 M-T2 (6 weeks after last intervention)=2.9, effect T1 (1 week after last intervention)= 0.36, effect T2 (6 weeks after last intervention)= 0.51).
Sig. better values in reflexology arm than in foot massage arm (β=NI; p=0.02, foot massage arm: Mean-T1 (1 week after last intervention)=3.1, Mean-T2 (6 weeks after last intervention) =3.03, effect T1 (1 week after last intervention) =NI, effect T2 (6 weeks after last intervention=NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=2
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Nausea
|Outcome specification=Nausea with single item from the FACT-B physical subscale
|Type of measurement=FACT (Functional Assessment of Cancer Therapy)
|Results during intervention=NA
|Results after intervention=No sig. differences between the arms (reflexology arm/control arm: β=0.212[0.124], p=0.089, reflexology arm/foot massage arm: NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=3
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Physical functioning
|Outcome specification=Physical function level with SF-36: physical function subscale
|Type of measurement=SF-36 (Short Form-36 Health Survey)
|Results during intervention=NA
|Results after intervention=Sig. higher (better) values for reflexology arm than control arm (ß= 5.527 [2.728]; p=0.04, reflexology arm: Mean-T1 (1 week after last intervention)= 58.6, Mean-T2 (6 weeks after last intervention) =59.2, control arm: Mean-T1 (1 week after last intervention)= 54.9 Mean-T2 (6 weeks after last intervention)= 51.6, effect T1 (1 week after last intervention=0.21, effect T2 (6 weeks after last intervention) = 0.44).
No sig. difference between reflexology arm and control arm (NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=4
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Fatigue
|Outcome specification=Fatigue severity with single item from the BFI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=NA
|Results after intervention=No sig. difference between the arms (reflexology arm/control arm: ß= -0.335 [3.81]; p=0.38, reflexology arm/foot massage: NI).
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=5
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Fatigue
|Outcome specification=Disruption of daily activities due to fatigue with single item from the BFI
|Type of measurement=BFI (Brief Fatigue Inventory)
|Results during intervention=NA
|Results after intervention=No sig. differences between the arms (reflexology arm/control arm: ß= -2.87 [0.389]; p=0.46; reflexology arm/foot massage arm: NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=6
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Pain intensity with a single item from the Brief Pain Inventory-Short Form
|Type of measurement=BPI-SF (Brief Pain Inventory - Short Form)
|Results during intervention=NA
|Results after intervention=No sig. differences between the arms (reflexology arm/control arm: ß= -2.87 [0.389]; p=0.46; reflexology arm/foot massage arm: NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=7
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Depression
|Outcome specification=NA
|Type of measurement=CES-D (Center for Epidemiologic Studies - Depression Scale)
|Results during intervention=NA
|Results after intervention=No sig. differences between the arms (reflexology arm/control arm: ß= -0.487 [1.21]; p=0.69; reflexology arm/foot massage arm: NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=8
|Outcome topic=Reflexology
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Anxiety
|Outcome specification=NA
|Type of measurement=STAI (State-Trait-Anxiety-Inventory)
|Results during intervention=NA
|Results after intervention=No sig. differences between the arms (reflexology arm/control arm: ß= -0.886 [1.259]; p=0.48; reflexology arm/foot massage arm: NI)
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=9
|Outcome topic=Reflexology
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This work was supported by a grant (#R01 CA104883) from the National Institutes of Health (NIH), National Cancer Institute. The Branch Reflexology Institute and Biostatistics, Epidemiology, and Research Design (BERD) Core of the Center for Clinical and Translational Sciences (CCTS) is primarily funded by an NIH Clinical and Translational Science Award grant (UL1 RR024148), awarded to the University of Texas Health Science Center at Houston in 2006. Wyatt can be reached at gwyatt@msu.edu, with copy to editor at ONFEditor@ons.org
|Conflicts of Interest=NI
}}
=Further points for assessing the study=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
}}
{{Additional Notes
|Additional Notes=PRO:
Large, multicenter sample;
Statistical model with repeated measures (no multiple testing), intention-to-treat analysis and covariates (group differences from baseline in depression and anxiety were controlled);
Survey of NW not with CTCAE, but systematically with own criteria

CONTRA:
No blinding when conducting the study, although this would have been possible (subjective outcomes)

Dyspnoea, which is also the mediator for the effects of physical function (outcome 4), was itself only measured with a single item (internal validity).

No indication of the specific results of the group comparisons between arm A and arm B (i.e. the comparisons with the active control group), except for the one significant effect on dyspnoea (reduced reporting)
}}

Tan et al. (2018): Bromelain has significant clinical benefits after extraction of the third molar during chemotherapy in patients with hematologic tumor

2024-11-28T14:04:22Z

DDeel:

{{Reference
|Reference=Publication: Bromelain has significant clinical benefits after extraction of the third molar during chemotherapy in patients with hematologic tumor
}}
{{Study Note}}
=Brief summary=
This study included 72 patients with blood cancer. A common feature of all patients was that their wisdom teeth had been surgically removed to prevent infection during or before chemotherapy. In the patients included, access to the wisdom teeth was more difficult as they were still partially in the bone. One arm of 36 people also received enzyme therapy (bromelain) in tablet form, which was started one day before the planned procedure and continued up to and including three days after the procedure. The other arm received cold and warm compresses instead of tablets. The question of this study is whether enzyme intake can alleviate the side effects of tooth extraction, such as pain, swelling and restricted mouth opening. In addition, the quality of life and satisfaction of the patients was assessed. The authors were able to identify advantages in all areas, i.e. less patient discomfort and greater satisfaction in the enzyme arm. The enzyme arm also achieved better values in the area of quality of life. The authors are therefore in favour of enzyme therapy for blood cancer patients during wisdom tooth removal. The study has a very small number of patients with little information about the disease of the test subjects. No correction for multiple testing was performed and the randomisation process is insufficiently described.

In dieser Studie wurden 72 Patienten mit Blutkrebs eingeschlossen. Als gemeinsames Merkmal hatten alle Patienten eine operative Entfernung der Weisheitszähne, welche zur Vermeidung von Infektionen während bzw. vor der Chemotherapie durchgeführt wurde. Bei den eingeschlossenen Patienten war der Zugang zu den Weisheitszähnen erschwert, da sie sich noch zum Teil im Knöchernen befunden haben. Eine Arm mit 36 Personen erhielt dabei zusätzlich eine Enzymtherapie (Bromelain) in Tablettenform, die einen Tag vor dem geplanten Eingriff begonnen wurde und sich bis einschließlich drei Tage nach dem Eingriff fortsetzte. Der andere Arm erhielt hingegen kalte und warme Kompressen anstelle von Tabletten. Die Fragestellung dieser Studie ist nun, ob durch die Enzymeinnahme die Nebenwirkungen der Zahnextraktion, wie Schmerzen, Schwellungen und eine eingeschränkte Mundöffnung gemildert werden können. Zusätzlich wurde die Lebensqualität bzw. Zufriedenheit der Patienten erhoben. Die Autoren konnten dabei in allen Bereichen Vorteile, also geringere Beeinträchtigungen der Patienten und eine höhere Zufriedenheit in der Enzymgruppe feststellen. Auch im Bereich Lebensqualität erzielte der Enzymarm bessere Werte. Die Autoren sprechen sich daher für eine Enzymtherapie bei Blutkrebspatienten während der Weisheitszahnentfernung aus. Die Studie hat eine sehr geringe Patientenanzahl mit wenigen Informationen über die Erkrankung der Probanden. Es wurde keine Korrektur für multiples Testen durchgeführt und der Randomisierungsprozess ist unzureichend beschrieben.

=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=Diagnosis of hematological tumor; white blood cell count 3–12×109/l, platelet count ≥60×109 /l, absolute neutrophil count ≥109 /l; average score of the difficulty of mandibular impacted third molar extraction ≥14, patients had difficulties with tooth extraction; informed consent form signed by patients
|Exclusion criteria=Contraindications of surgery; long-term administration of medication, recent administration of glucocorticoids, antibiotics, or anodyne; recurrent pericoronitis of the impacted tooth; moderate caries of the wisdom tooth and adjacent teeth; periapical periodontitis, pulpitis, or periodontitis
|N randomized=72
|Analysis=ITT Analysis
|Specifications on analyses=All participants analysed; no drop-outs
|Countries of data collection=China
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline

T1: 1 day after surgery

T2: 3 days after surgery

T3: 7 days after surgery (+quality of life)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid)
|Stage cancer=NI
|Cancer stage specification=Hematological tumor classification in enyzme arm; control arm:

Acute lymphoblastic leukemia: 13 (36.11%); 12 (33.33%)

Acute non-lymphocytic leukemia: 11 (30.56%); 9 (25.00%)

Aplastic anemia: 5 (13.89%); 6 (16.67%)

Non-Hodgkin's lymphoma: 4 (11.11%); 5 (13.89%)

Langerhans cell histocytosis: 3 (8.33%); 4 (11.11%)
|Comorbidity=NI
|Current cancer therapy=Chemotherapy
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Enzyme arm: 22 male (61%); 14 female (39%)

Control arm: 20 male (56%%); 16 female (44%)
|Age groups=Adults (18+)
|Age groups specification=Mean age (SD) per arm:
Enzyme arm: 24.35 (5.57) years

Control arm: 23.76 (5.48) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=36
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Enzymes
|Dosage and regime=Oral intake of 3 x 30,000 units of enteric-coated capsules of bromelain daily, starting one day before the surgery up to and including three days after the surgery

+ all patients: sugery: third molar extraction was performed under local anesthesia
|One-time application=No
|Duration in days=5
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Enzymes (bromelain papain)
}}
{{Arm
|Arm type=Active control
|Number of participants (arm)=36
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Cold-Hot-Compress
|Dosage and regime=Cold-hot compress for two days after surgery

+ all patients: surgery: third molar extraction was performed under local anesthesia
|One-time application=No
|Duration in days=2
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Enzymes (bromelain papain)
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Score range = 0 (no pain) to 10 (intolerable severe pain)

No pain: 0–1 points for no pain or little pain or pain hard to feel;

Mild: 2–3 points for tolerable pain that did not affect sleep;

Moderate: 3–6 points for pain that altered normal daily activities and sleep;

Severe: ≥7 points for intolerable pain, patients took ibuprofen sustained release capsule or return for a visit
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=The pain decreased in both arms from day 1 to day 7 after surgery.

Day 1: Enzyme arm = 5.35(1.14); control arm = 6.06(1.23) p =0.013

Day 3: Enzyme arm = 4.06(1.13); control arm = 4.73(1.25) p =0.019

Day 7: Enzyme arm = 2.23(1.02) ; control arm = 2.76(1.17) p=0.044
|Results after intervention=The enzyme arm exhibited significantly lower scores at each time point compared to the control arm (p=0.013-0.044)
|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=Enzymes (bromelain papain)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Postoperative morbidity/ complications
|Outcome specification='''Side effects of tooth extraction: Swelling'''

Value difference of CT+ ME before and after surgery indicated the swelling degree:

CT distance: distance of the skin surface from the tragion (T point) on the affected side of the cheek to the cheilion (C point) on the same side;
ME distance: distance on the skin surface from the external canthus point on the same side (E point) to the mandibular angle point (M point)
|Type of measurement=Observation
|Results during intervention=Day 1: Enzyme arm = 2.23(0.34) ;control arm = 2.85(0.43) p<0.0001

Day 3: Enzyme arm = 1.23(0.13) ;control arm = 1.98(0.27) p<0.0001

Day 7: Enzyme arm = 0.23(0.11) ;control arm = 1.01(0.37) p<0.0001
|Results after intervention=The enzyme arm exhibited significantly lower swelling than the control arm at each time point (p<0.0001).
|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=Enzymes (bromelain papain)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Postoperative morbidity/ complications
|Outcome specification='''Side effects of tooth extraction: Mouth opening'''

Distance from the upper central incisor margin to the lower at the biggest positive mouth opening state before and after surgery; distance differences before and after surgery indicated the limitation of mouth opening degree.
|Type of measurement=Observation
|Results during intervention=Day 1: Enzyme arm = 2.15±0.34 ;control arm = 2.76±0.53 p<0.0001

Day 3: Enzyme arm = 1.16±0.33 ;control arm = 1.83±0.45 p<0.0001

Day 7: Enzyme arm = 0.43±0.12 ;control arm = 1.16±0.27 p<0.0001
|Results after intervention=The enzyme arm exhibited significantly lower scores than the control arm at each time point.
|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=Enzymes (bromelain papain)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Quality of life
|Outcome specification=Modified postoperative symptom severity scale (PoSSe): Patients were scored in 7 dimensions

(food, language, feeling, swelling, pain, nausea, and daily living) one week after surgery
|Type of measurement=PoSSe (Postoperative Symptom Severity Scale)
|Results during intervention=NA
|Results after intervention=The comparison of quality of life for the two arms showed that the enzyme arm scored better than the control arm in all items:

Items in enzyme arm; control arm:

Food: 5.76(2.78); 7.96(2.18) p=0.0004

Language: 1.17(0.63); 2.57(0.93) p<0.0001

Feeling: 0.83(0.36); 1.44(0.76) p<0.0001

Swelling: 3.28(1.57); 4.76(2.06) p=0.0010

Pain: 4.16(2.01); 6.23(1.01) p<0.0001

Nausea: 0.21(0.12); 0.91(0.21) p<0.0001

Daily living: 1.38(0.34); 3.38(0.54) p<0.0001
|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=Enzymes (bromelain papain)
}}
{{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:
* Ethics vote available
* Detailed specification of statistical parameters

CONTRA:
* Small number of study participants
* No information on drop-out or attrition: ‘If participants suffered from side effects, they stopped treatment and discontinued participation in the study.’
* The authors state that the study was double-blinded, but this is not possible due to the different treatment methods of the two arms
* Endpoint 4 not independent of endpoints 1, 2 and 3
* No correction for multiple testing (cumulative α-error possible)
* Unclear randomisation process (‘we randomly divided’)
}}

Koyama et al. (2017): Intravenous Carnitine Administration in Addition to Parenteral Nutrition With Lipid Emulsion May Decrease the Inflammatory Reaction in Postoperative Surgical Patients

2024-11-28T14:00:03Z

DDeel:

{{Reference
|Reference=Publication: Intravenous Carnitine Administration in Addition to Parenteral Nutrition With Lipid Emulsion May Decrease the Inflammatory Reaction in Postoperative Surgical Patients
}}
{{Study Note}}
=Brief summary=
The study investigated the influence of carnitine on the inflammatory and insulin response in patients following surgery for gastric or colorectal cancer. Eight patients were randomly assigned to the control group, who received the usual parenteral nutrition after colorectal cancer surgery. In the intervention group, the 8 patients were also given carnitine. The administration took place in both groups over 4 days after surgery and showed no differences in laboratory values, insulin response or other characteristics between the two groups. The additional administration of carnitine does not appear to have any health benefits for the target group, but the results should be interpreted with caution due to the small sample size.

Die Studie untersuchte den Einfluss von Carnitin auf die Entzündungs- und Insulinreaktion bei Patienten nach einer Operation aufgrund eines Magen – oder Kolorektalen Karzinoms. Es wurden 8 Patienten zufällig in die Kontrollgruppe eingeteilt, diese erhielten die übliche Gabe an parentaler Ernährung nach der Operation des Darmkrebses. In der Interventionsgruppe wurde den 8 Patienten zusätzlich Carnitin verabreicht. Die Gabe erfolgte in beiden Gruppen über 4 Tage nach der Operation und zeigte keine Unterschiede in den Laborwerten, der Insulin Reaktion oder anderen Merkmalen zwischen den beiden Gruppen. Die zusätzliche Gabe von Carnitin scheint der Zielgruppe keine gesundheitlichen Vorteile zu bringen, aufgrund der kleinen Stichprobe sind die Ergebnisse aber mit Vorsicht zu interpretieren.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=Preoperative gastric or colorectal cancer patients without distant metastasis
|Exclusion criteria=Liver dysfunction, respiratory dysfunction, cardiac dysfunction, renal failure, ongoing infection, history of recent immunosuppressive or immunologic disease (including preoperative chemo-therapy and/or radiation therapy), or diabetes mellitus
|N randomized=16
|Analysis=ITT Analysis
|Specifications on analyses=ITT not specified, but no drop-out reported.
|Countries of data collection=Japan
|LoE=2b Oxford 2009
|Outcome timeline=T0: preoperative phase
T1: 1 day after surgery
T2-T7: Day 2-7 after surgery

Blood samples at T0, T1, T3 and T4; carnitine concentration at T0, T1, T3, T7; C-reactive protein (CRP) at T3 and T7, urine samples at T3 and T7
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Colorectal Cancer, Gastrointestinal Cancers - Gastric (Stomach) Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Stage I-III
|Comorbidity=NI
|Current cancer therapy=Surgery
|Specifications on cancer therapies=Open or Laparoscopic surgery for gastric or colorectal cancer

+ Peripheral postoperative parenteral nutrition (PPN): glucose, amino acid, lipid emulsion
|Previous cancer therapies=No therapy
|Gender=Mixed
|Gender specifications=43.8% female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD): 68 (9.6) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=8
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Carnitin + PPN

+ Additional administration of solutions to supply water and electrolytes possible. No oral nutrition until day 4 and oral water intake from day 2.
|Dosage and regime=Peripheral PN (PPN) 100ml (20% lipid emulsion) + carnitine, IV, -1st postoperative day OP to day 4, average administration: 72.6mg/kg daily (SD = 37.3)
Duration: 4 days
|One-time application=No
|Duration in days=4
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Carnitine
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=-999
|Drop-out=0
|Drop-out reasons=NA
|Intervention=PPN

+ Additional administration of solutions to supply water and electrolytes possible. No oral nutrition until day 4 and oral water intake from day 2.
|Dosage and regime=Peripheral PN (PPN) 100ml (20% lipid emulsion)
|One-time application=No
|Duration in days=4
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Carnitine
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Reduction of complication rates
|Outcome specification=Reduction of complication rates: infectious, mechanical, overall after surgery
|Type of measurement=NI
|Results during intervention=No differences between the arms for complications (in both arms n=2 each; p=0.715) or type of complication (p>0.05)
|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=Carnitine
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=This work was supported financially by Grants-in-Aid for Science Research from the Ministry of Education, Science, Sports and Culture, Japan (Project no. 15K10047).
|Conflicts of Interest=According to authors no conflict of interest.
}}
=Further points for assessing the study=

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

CONTRA:
* At baseline: BMI, TLC, and ChE significantly higher in intervention arm (p < 0.05).
* Measurements of individual variables taken on different days.
* Unclear temporal definition of preoperative phase.
* 14 out of 16 participants had colorectal cancer, mostly stage I.
* Very brief data presentation.
* Very small sample size.
* Short intervention phase.
* BMI: significant preoperative difference between groups, with the difference on postoperative day 7 even larger but no longer significant.
* No reporting of significance values when no difference was found.
}}

Beer et al. (2007): Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators

2024-11-28T13:57:12Z

DDeel:

{{Reference
|Reference=Publication: Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators
}}
=Brief summary=
This study investigated the effectiveness of vitamin D in combination with docetaxel (a chemotherapeutic agent) in prostate cancer patients. One arm received docetaxel and vitamin D and the other arm docetaxel and placebo. There were no differences between the arms in terms of treatment response rate and time to disease progression, but patients in the vitamin D arm lived longer on average. In addition, although there were no fewer side effects overall in the vitamin D arm, there were fewer serious side effects than in the other arm. Positive aspects of this study are the large sample size and the double blinding (observers/patients do not know which arm they belong to). However, a major criticism of this study is that the vitamin D level was not recorded and taken into account. Thus, there is no verification of whether there was a vitamin D deficiency at the beginning of the study and whether the vitamin D treatment worked (i.e. that patients in the vitamin D arm had higher levels due to vitamin D supplementation).

In dieser Studie wurde die Wirksamkeit von Vitamin D in Kombination mit Docetaxel (ein Chemotherapeutikum) bei Prostatakrebspatienten untersucht. Ein Arm bekam Docetaxel und Vitamin D und der andere Arm Docetaxel und Placebo. Es zeigten sich keine Unterschiede zwischen den Armen hinsichtlich der Ansprechrate der Behandlung und der Zeit bis zum Krankheitsfortschreiten, aber der Vitamin-D Arm lebten die Patienten im Durchschnitt länger. Zudem traten im Vitamin-D-Arm zwar insgesamt nicht weniger Nebenwirkungen auf, aber es gab weniger schwerwiegende Nebenwirkungen als im anderen Arm. Positiv an dieser Studie sind die große Stichprobe und die doppelte Verblindung (Beobachter/Patienten wissen nicht, welchem Arm sie angehören). Ein großer Kritikpunkt dieser Studie ist jedoch, dass der Vitamin D Spiegel nicht erhoben und berücksichtigt wurde. Somit gibt es keine Überprüfung, ob zu Beginn der Studie ein Vitamin D Mangel bestand und ob die Vitamin D Behandlung funktioniert hat (d.h. dass Patienten im Vitamin-D-Arm durch Vitamin D Präparat einen höheren Spiegel hatten).

=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=Men with histopathologically or cytologically proven metastatic adenocarcinoma of the prostate with evidence of progression (the development of new metastatic lesions or rising PSA) despite standard hormonal management (orchiectomy, gonadotropin-releasing hormone agonist or antagonist including withdrawal of antiandrogens, if applicable; 6 weeks for bicalutamide, 4 weeks for flutamide or nilutamide) were eligible;
serum PSA ≥ 5.0 ng/mL, serum testosterone level ≤ 50 ng/dL, Eastern Cooperative Oncology Group performance status ≤ 2, life expectancy ≥ 3 months, age ≥ 18 years, patient agreement to use adequate contraception, and patient ability to give informed consent.
|Exclusion criteria=Active malignancy within 5 years (except nonmelanoma skin cancer), significant active medical illness that would preclude protocol treatment, a history of hypercalcemia or vitamin D toxicity, or hospitalization for treatment of angina, myocardial infarction, or congestive heart failure in the previous 12 months;
kidney stones (calcium salt) within 5 years, hypersensitivity to calcitriol or drugs formulated with polysorbate-80, grade 2 or higher peripheral neuropathy, neutrophil count less than 1,500/mm3 , platelet count lower than 100,000/ mm3 , serum creatinine more than upper limit of normal (ULN), serum calcium more than ULN, conjugated bilirubin more than ULN, alkaline phosphatase more than 4 x ULN (patients with known bone involvement and a normal conjugated bilirubin, ALT, and AST were not excluded), ALT or AST more than 2.0 x ULN when alkaline phosphatase is less than 2.5 x ULN, ALT or AST more than 1.5 x ULN when alkaline phosphatase is more than 2.5 x ULN,
prior investigational therapy or use of calcitriol within 30 days, prior chemotherapy for prostate cancer except for adjuvant therapy more than 12 months before enrollment, prior chemotherapy with docetaxel, treatment with radiotherapy within 4 weeks or treatment with other radiopharmaceuticals within 8 weeks
|N randomized=250
|Analysis=ITT Analysis
|Specifications on analyses=Primary analysis for efficacy was on the intention to treat population and toxicity was evaluated in the as-treated population. These two populations were identical.
|Countries of data collection=NI
|LoE=1b Oxford 2009
|Outcome timeline=Every 4 weeks
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=Metastatic adenocarcinoma of the prostate with evidence of progression
|Comorbidity=No
|Current cancer therapy=Chemotherapy, Hormone therapy
|Specifications on cancer therapies=Weekly docetaxel 36 mg/m2 intravenously and dexamethasone (4 mg orally 12 hours before, 1 hour before, and 12 hours after docetaxel administration)
|Previous cancer therapies=No therapy
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median (range): 68 (45-87)
Placebo arm: median (range): 70 (47-92)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=125
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcitriol
|Dosage and regime=DN-101 (45 μg) orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No increase in toxicity was seen with the addition of DN-101 to docetaxel
|Order number=1
|Arm topic=Vitamin D
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=125
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Placebo orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=?
|Order number=1
|Arm topic=Vitamin D
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=PSA level (Prostate-Specific Antigen)
|Outcome specification=PSA response (≥ 50% PSA reduction, confirmed at least 4 weeks later)
|Type of measurement=Blood Test
|Results during intervention=Within 6 months of enrollment: no significant differences in PSA decline;
at any time while on study: PSA decline achieved in 52% of placebo- treated patients and 63% of DN-101-treated patients (p = .07);
median time to PSA response was 5.3 months in placebo-treated patients and 2.9 months in DN-101-treated patients (p = .06)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Tumor response
|Outcome specification=Tumor response rate
|Type of measurement=RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=low risk
|Order number=2
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=PSA (defined by consensus criteria), tumor, and clinical progression-free survival (defined as either tumor progression, occurrence of a skeletal-related event, or death from any cause)
|Type of measurement=Observation
|Results during intervention=No significant differences in median duration of PSA progression-free survival;
median duration of tumor progression-free survival and median duration of clinical progression-free survival could not be reliably assessed due to the lack of regularly scheduled tumor imaging
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=EFS (Event-Free Survival)
|Outcome specification=Defined as the time from random assignment to a skeletal-related event or death from any cause, skeletal-related events were defined as pathologic bone fracture, spinal cord compression, surgery to the bone, or radiation to the bone
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After adjustment for baseline characteristics of hemoglobin and Eastern Cooperative Oncology Group performance status, overall survival showed a promising improvement in intervention arm over the placebo arm with a HR of 0.67 (95% CI, 0.45 to 0.97; p = .04)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=All adverse events are reported regardless of perceived relationship to treatment
|Type of measurement=Observation
|Results during intervention=The incidence of any grade 3 or 4 adverse events was not significantly different;
serious adverse events, generally those requiring hospitalization, were observed in 41% of placebo-treated patients and 27% of DN-101-treated patients (p = .023);

Among the grade 3 or 4 nonhematologic toxicities, the most common were fatigue (16% placebo; 8% DN-101), infection (13% placebo; 8% DN- 101), and hyperglycemia (12% placebo; 6% DN-101)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=low risk
|Order number=6
|Outcome topic=Vitamin D
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Some authors receive honoraria/research funding from various pharmaceutical companies or they advise them
|Conflicts of Interest=According to information financial conflicts of interest may exist
}}
=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
|Possibility of placebo effects=No
|Other reasons=We do not know whether the arms had baseline values without significant differences in vitamin D levels.
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=NI
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Double blinding
* Large sample according to power analysis
* Low dropout (8%) and intention-to-treat analysis

CONTRA:
* Vitamin D levels not assessed
* Group differences not excluded
* Fewer endpoints calculated for PFS than specified in the protocol

Beer et al. (2007): Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators

2024-11-28T13:57:03Z

DDeel:

{{Reference
|Reference=Publication: Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators
}}
{{Study Note}}
=Brief summary=
This study investigated the effectiveness of vitamin D in combination with docetaxel (a chemotherapeutic agent) in prostate cancer patients. One arm received docetaxel and vitamin D and the other arm docetaxel and placebo. There were no differences between the arms in terms of treatment response rate and time to disease progression, but patients in the vitamin D arm lived longer on average. In addition, although there were no fewer side effects overall in the vitamin D arm, there were fewer serious side effects than in the other arm. Positive aspects of this study are the large sample size and the double blinding (observers/patients do not know which arm they belong to). However, a major criticism of this study is that the vitamin D level was not recorded and taken into account. Thus, there is no verification of whether there was a vitamin D deficiency at the beginning of the study and whether the vitamin D treatment worked (i.e. that patients in the vitamin D arm had higher levels due to vitamin D supplementation).

In dieser Studie wurde die Wirksamkeit von Vitamin D in Kombination mit Docetaxel (ein Chemotherapeutikum) bei Prostatakrebspatienten untersucht. Ein Arm bekam Docetaxel und Vitamin D und der andere Arm Docetaxel und Placebo. Es zeigten sich keine Unterschiede zwischen den Armen hinsichtlich der Ansprechrate der Behandlung und der Zeit bis zum Krankheitsfortschreiten, aber der Vitamin-D Arm lebten die Patienten im Durchschnitt länger. Zudem traten im Vitamin-D-Arm zwar insgesamt nicht weniger Nebenwirkungen auf, aber es gab weniger schwerwiegende Nebenwirkungen als im anderen Arm. Positiv an dieser Studie sind die große Stichprobe und die doppelte Verblindung (Beobachter/Patienten wissen nicht, welchem Arm sie angehören). Ein großer Kritikpunkt dieser Studie ist jedoch, dass der Vitamin D Spiegel nicht erhoben und berücksichtigt wurde. Somit gibt es keine Überprüfung, ob zu Beginn der Studie ein Vitamin D Mangel bestand und ob die Vitamin D Behandlung funktioniert hat (d.h. dass Patienten im Vitamin-D-Arm durch Vitamin D Präparat einen höheren Spiegel hatten).

=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=Men with histopathologically or cytologically proven metastatic adenocarcinoma of the prostate with evidence of progression (the development of new metastatic lesions or rising PSA) despite standard hormonal management (orchiectomy, gonadotropin-releasing hormone agonist or antagonist including withdrawal of antiandrogens, if applicable; 6 weeks for bicalutamide, 4 weeks for flutamide or nilutamide) were eligible;
serum PSA ≥ 5.0 ng/mL, serum testosterone level ≤ 50 ng/dL, Eastern Cooperative Oncology Group performance status ≤ 2, life expectancy ≥ 3 months, age ≥ 18 years, patient agreement to use adequate contraception, and patient ability to give informed consent.
|Exclusion criteria=Active malignancy within 5 years (except nonmelanoma skin cancer), significant active medical illness that would preclude protocol treatment, a history of hypercalcemia or vitamin D toxicity, or hospitalization for treatment of angina, myocardial infarction, or congestive heart failure in the previous 12 months;
kidney stones (calcium salt) within 5 years, hypersensitivity to calcitriol or drugs formulated with polysorbate-80, grade 2 or higher peripheral neuropathy, neutrophil count less than 1,500/mm3 , platelet count lower than 100,000/ mm3 , serum creatinine more than upper limit of normal (ULN), serum calcium more than ULN, conjugated bilirubin more than ULN, alkaline phosphatase more than 4 x ULN (patients with known bone involvement and a normal conjugated bilirubin, ALT, and AST were not excluded), ALT or AST more than 2.0 x ULN when alkaline phosphatase is less than 2.5 x ULN, ALT or AST more than 1.5 x ULN when alkaline phosphatase is more than 2.5 x ULN,
prior investigational therapy or use of calcitriol within 30 days, prior chemotherapy for prostate cancer except for adjuvant therapy more than 12 months before enrollment, prior chemotherapy with docetaxel, treatment with radiotherapy within 4 weeks or treatment with other radiopharmaceuticals within 8 weeks
|N randomized=250
|Analysis=ITT Analysis
|Specifications on analyses=Primary analysis for efficacy was on the intention to treat population and toxicity was evaluated in the as-treated population. These two populations were identical.
|Countries of data collection=NI
|LoE=1b Oxford 2009
|Outcome timeline=Every 4 weeks
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Prostate Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=Metastatic adenocarcinoma of the prostate with evidence of progression
|Comorbidity=No
|Current cancer therapy=Chemotherapy, Hormone therapy
|Specifications on cancer therapies=Weekly docetaxel 36 mg/m2 intravenously and dexamethasone (4 mg orally 12 hours before, 1 hour before, and 12 hours after docetaxel administration)
|Previous cancer therapies=No therapy
|Gender=Male
|Gender specifications=100% male
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: median (range): 68 (45-87)
Placebo arm: median (range): 70 (47-92)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=125
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Calcitriol
|Dosage and regime=DN-101 (45 μg) orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=No increase in toxicity was seen with the addition of DN-101 to docetaxel
|Order number=1
|Arm topic=Vitamin D
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=125
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Placebo orally (high concentration formulation of calcitriol), weekly for 3 consecutive weeks of a 4-week cycle
|One-time application=No
|Duration in days=-999
|Side Effects / Interactions=?
|Order number=1
|Arm topic=Vitamin D
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=PSA level (Prostate-Specific Antigen)
|Outcome specification=PSA response (≥ 50% PSA reduction, confirmed at least 4 weeks later)
|Type of measurement=Blood Test
|Results during intervention=Within 6 months of enrollment: no significant differences in PSA decline;
at any time while on study: PSA decline achieved in 52% of placebo- treated patients and 63% of DN-101-treated patients (p = .07);
median time to PSA response was 5.3 months in placebo-treated patients and 2.9 months in DN-101-treated patients (p = .06)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=NA
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Tumor response
|Outcome specification=Tumor response rate
|Type of measurement=RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=low risk
|Order number=2
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=PSA (defined by consensus criteria), tumor, and clinical progression-free survival (defined as either tumor progression, occurrence of a skeletal-related event, or death from any cause)
|Type of measurement=Observation
|Results during intervention=No significant differences in median duration of PSA progression-free survival;
median duration of tumor progression-free survival and median duration of clinical progression-free survival could not be reliably assessed due to the lack of regularly scheduled tumor imaging
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=3
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=EFS (Event-Free Survival)
|Outcome specification=Defined as the time from random assignment to a skeletal-related event or death from any cause, skeletal-related events were defined as pathologic bone fracture, spinal cord compression, surgery to the bone, or radiation to the bone
|Type of measurement=Observation
|Results during intervention=No significant differences
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=4
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=OS (Overall Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=After adjustment for baseline characteristics of hemoglobin and Eastern Cooperative Oncology Group performance status, overall survival showed a promising improvement in intervention arm over the placebo arm with a HR of 0.67 (95% CI, 0.45 to 0.97; p = .04)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=high risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Order number=5
|Outcome topic=Vitamin D
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Toxicity
|Outcome specification=All adverse events are reported regardless of perceived relationship to treatment
|Type of measurement=Observation
|Results during intervention=The incidence of any grade 3 or 4 adverse events was not significantly different;
serious adverse events, generally those requiring hospitalization, were observed in 41% of placebo-treated patients and 27% of DN-101-treated patients (p = .023);

Among the grade 3 or 4 nonhematologic toxicities, the most common were fatigue (16% placebo; 8% DN-101), infection (13% placebo; 8% DN- 101), and hyperglycemia (12% placebo; 6% DN-101)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=low risk
|Bias in selection of the reported result=low risk
|Other sources of bias=NA
|Overall RoB judgment=low risk
|Order number=6
|Outcome topic=Vitamin D
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Some authors receive honoraria/research funding from various pharmaceutical companies or they advise them
|Conflicts of Interest=According to information financial conflicts of interest may exist
}}
=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
|Possibility of placebo effects=No
|Other reasons=We do not know whether the arms had baseline values without significant differences in vitamin D levels.
|Correct use of parametric and non-parametric tests=Yes
|Correction for multiple testing=No
|Measurement of compliance=No
|Consistent reporting in numbers=Yes
|Comprehensive and coherent reporting=Yes
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=Yes
|Side effects taken into account in the interpretation of the results=No
|Ethics / CoI / Funding=NI
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Blinding reliable=?
|Check whether blinding was successful=?
|mono- or multicentric=?
}}
{{Additional Notes}}
PRO:
* Ethics vote
* Double blinding
* Large sample according to power analysis
* Low dropout (8%) and intention-to-treat analysis

CONTRA:
* Vitamin D levels not assessed
* Group differences not excluded
* Fewer endpoints calculated for PFS than specified in the protocol

Lin et al. (2009): Effects of zinc supplementation on the survival of patients who received concomitant chemotherapy and radiotherapy for advanced nasopharyngeal carcinoma: follow-up of a double-blind randomized study with subgroup analysis

2024-11-28T13:54:39Z

DDeel:

{{Reference
|Reference=Publication: Effects of zinc supplementation on the survival of patients who received concomitant chemotherapy and radiotherapy for advanced nasopharyngeal carcinoma: follow-up of a double-blind randomized study with subgroup analysis
}}
{{Study Note
|Study Note=This study is a follow-up of [[Lin et al. (2006): Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study]] and a subgroup-analysis of [[Lin et al. (2008): Effects of zinc supplementation on clinical outcomes in patients receiving radiotherapy for head and neck cancers: a double-blinded randomized study]].
}}
=Brief summary=
This study was dedicated to the investigation of 34 patients with nasopharyngeal carcinoma who were removed from a larger sample of a 2006 study to investigate the effect of zinc on overall survival and time interval to local tumor recurrence or distant metastasis after 5 years. The results suggest that zinc had a positive effect on overall survival, time to tumor recurrence or metastasis, and time to local tumor progression. Methodologically, however, this study must be viewed critically, as it only included a very small sample and did not make sure before the analyses whether the conditions for the respective calculations were valid. In addition, in their study from the previous year, Lin and colleagues found exactly opposite results with regard to the same examination points in the total sample of 97 patients, namely that zinc had no effect on the general survival time or the time until the occurrence of local or distant metastases. For this reason, it remains unclear to what extent the findings of the subsample analyzed here can be transferred and applied to other types of cancer.

Diese Studie widmete sich der Untersuchung von 34 Patienten mit Nasopharynxkarzinom, die aus einer größeren Stichprobe einer Untersuchung aus dem Jahr 2006 herausgenommen wurden, um den Effekt von Zink auf die allgemeine Überlebensdauer und die Zeitintervalle bis zu einem lokalen Wiederauftreten des Tumors oder einem Auftreten entfernter Metastasen nach 5 Jahren zu untersuchen. Die Ergebnisse legen nahe, dass Zink die allgemeine Überlebensdauer, das Zeitintervall bis zu einem Wiederauftreten eines Tumors oder Metastasen und die Zeitspanne bis zum Fortschreiten des lokalen Tumors positiv beeinflusste. Methodisch muss man diese Studie jedoch kritisch betrachten, da sie eine nur sehr kleine Stichprobe einschließt und sich vor den Analysen nicht vergewissert, ob die Voraussetzungen für die jeweiligen Berechnungen gelten. Hinzu kommt, dass Lin und Kollegen in ihrer Studie aus dem Vorjahr gemessen an der Gesamtstichprobe von 97 Patienten bezüglich der gleichen Untersuchungspunkte genau gegensätzliche Ergebnisse fanden, nämlich dass Zink keine Auswirkungen auf die allgemeine Überlebensdauer oder die Zeitspanne bis zum Auftreten lokaler oder entfernter Metastasen hatte. Aus diesem Grund bleibt unklar, inwiefern man die Befunde der hier analysierten Teilstichprobe übertragen und auch auf andere Krebsarten beziehen kann.

=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=Aged >18 years, pathologically established stages III and IV advanced nasopharyngeal carcinoma (NPC), concomitant chemotherapy and radiotherapy (CCRT)
|Exclusion criteria=Previous radiotherapy for head and neck cancer, double cancers, diabetes mellitus
|N randomized=34
|Analysis=ITT Analysis
|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients of the subgroup analysis were evaluated at the end of the study.
|Countries of data collection=Taiwan
|LoE=2b Oxford 2009
|Outcome timeline=Follow-up period of 5 years (followed up on once a month during the first year of study and then every 3 months thereafter)
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Head and Neck Cancers - Nasopharyngeal Cancer
|Stage cancer=Advanced Stage
|Cancer stage specification=stages III (n=5) and IV (n=29)
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Daily fraction was 180 cGy to 200 cGy in five weekly fractions,
total dose prescribed was 7,000 cGy;

No significant difference in the radiation dose, fraction, and duration was identified between intervention and placebo arm; all patients received concomitant chemotherapy with 5-fluorouracil and cis-platinum
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Intervention arm: n=14 male, n=3 female
Placebo arm: n=13 male, n=4 female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: mean (SD): 49.53 (13.75)
Placebo arm: mean (SD): 50.88 (10.01)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=17
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Zinc
|Dosage and regime=Oral zinc (25 mg Pro-Z), three capsules per day
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=1
|Arm topic=Zinc
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=17
|Drop-out=0
|Drop-out reasons=NA
|Intervention=Placebo
|Dosage and regime=Three capsule containing soybean oil per day
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=2
|Arm topic=Zinc
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=The period between the time of treatment and the time of death;

Subgroup analysis: no significant difference between the arms for the 5-year OS among the patients with stages III to IV head and neck cancers other than nasopharyngeal carcinoma (p = .357)
|Type of measurement=?
|Results during intervention=NA
|Results after intervention=Median follow-up duration was 32 months (6–68 months): patients in the intervention arm have better rates of OS than those in placebo arm (p = .044)
|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=Zinc
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=Between the time of first treatment and the time of local recurrence or distant metastases;

Subgroup analysis: no significant difference between the arms for the 5-year DFS among the patients with stages III to IV head and neck cancers other than nasopharyngeal carcinoma (p = .752)
|Type of measurement=?
|Results during intervention=NA
|Results after intervention=Median follow-up duration was 32 months (6–68 months): patients in the intervention arm have better rates of DFS than those in placebo (p = .033)
|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=Zinc
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=More specifically: LFS (Local-Free Survival), between the time of the first treatment and the time when local tumor progression was documented
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Median follow-up duration was 32 months (6–68 months): patients in the intervention arm have better rates of LFS than those in intervention arm (p = .007);

Subgroup analysis: no significant difference between the arms for the 5-year LFS among the patients with stages III to IV head and neck cancers other than nasopharyngeal carcinoma (p = .467)
|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=Zinc
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=MFS (Metastases-Free Survival)
|Outcome specification=More specifically: MFS (Metastases-Free Survival), between the time of the first treatment and the time when distant metastases occurred
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Median follow-up duration was 32 months (6–68 months): no significant differences
|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=Zinc
}}
{{Outcome
|Outcome type=Others
|Outcome name=Zinc level
|Outcome specification=?
|Type of measurement=Blood Test
|Results during intervention=The difference of pretreatment serum zinc levels between the arms was not statistically significant,
significant differences posttreatment with higher levels in the intervention arm (mean (SD): 138.76 (32.71) vs. 114.06 (26.08), p = .023)
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=5
|Outcome topic=Zinc
}}
{{Outcome
|Outcome type=Others
|Outcome name=Nutrition status
|Outcome specification=Serum transferrin level
|Type of measurement=Blood Test
|Results during intervention=No statistically difference between the two patient arms pre-treatment and post-treatment
|Results after intervention=NI
|Bias arising from the randomization process=?
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=?
|Bias in measurement of the outcome=?
|Bias in selection of the reported result=?
|Other sources of bias=?
|Overall RoB judgment=?
|Order number=6
|Outcome topic=Zinc
}}
{{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=NI
|Reasons given for samples being too small according to power analysis=NI
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=NI
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=NI
|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=
PRO:
* Ethics vote available
* Double blinding
* Given comparability of the groups (also regarding the zinc level)

CONTRA:
* Lack of clarity about the time of randomization (already in the 2006 study or again after 5 years?)
* Small sample (no testing of normal distribution)
* Results only reported in a short sentence stating the p-values, MFS is only taken up again in the discussion section - but represents the endpoint that was the only one that did not become significant (focus on significant results)
* Report on NW is not comprehensible ("none of the commonly reported side effects accompanied by orally administered Zinc was observed among patients in the control group")

Lin et al. (2008): Effects of zinc supplementation on clinical outcomes in patients receiving radiotherapy for head and neck cancers: a double-blinded randomized study

2024-11-28T13:28:21Z

DDeel:

{{Reference
|Reference=Publication: Effects of zinc supplementation on clinical outcomes in patients receiving radiotherapy for head and neck cancers: a double-blinded randomized study
}}
{{Study Note
|Study Note=This study is a follow-up of [[Lin et al. (2006): Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study]].
}}
=Brief summary=
In this study, Lin and colleagues investigated the effect of zinc during radiotherapy treatment on overall survival time, the time intervals until local recurrence of the tumor, local recurrence of metastases and the occurrence of distant metastases in head and neck carcinoma patients. Half of the patients were given zinc, the other half a placebo consisting of soybean oil. It was found that the administration of zinc had no effect on the general lifespan or the time until the appearance of local or distant metastases and that there were no significant differences between the zinc and placebo arms. Only cancer growth tended to be delayed by zinc, although this was particularly true for patients with stage III-IV cancer and receiving chemotherapy at the same time as radiotherapy. Accordingly, the results of the study can only be generalized to a very limited extent, as many analyses were only calculated for very specific subgroups (such as stage III-IV cancer patients receiving chemotherapy at the same time). The extent to which the various subgroups are comparable and the size of each arm remains unclear. Furthermore, the results described focus strongly on those that showed a difference due to the administration of zinc. The three other factors investigated remain relatively unnoticed in the evaluation, but their results indicate that zinc has no positive influence on the lifespan or growth of distant metastases in head and neck cancer patients.

Lin und Kollegen untersuchten in dieser Studie die Wirkung von Zink während der Radiotherapie-Behandlung auf die allgemeine Überlebenszeit, die Zeitintervalle bis zu einem lokalen Wiederauftreten des Tumors, einem lokalen Wiederauftreten von Metastasen und dem Auftreten entfernter Metastasen bei Kopf-Hals- Karzinom Patienten. Eine Hälfte der Patienten bekam dafür Zink, die andere ein, aus Sojabohnenöl bestehendes, Placebo verabreicht. Es stellte sich heraus, dass die Gabe von Zink keine Auswirkungen auf die allgemeine Lebenszeit oder die Dauer bis zum Auftreten lokaler oder entfernter Metastasen hatte und es zwischen dem Zink- und Placebo-Arm zu keinen bedeutsamen Unterschieden kam. Allein das Krebswachstum konnte durch Zink tendenziell hinausgezögert werden, wobei dies v.a. für Patienten mit einem Krebsstadium von III-IV und gleichzeitig zur Radiotherapie stattfindender Chemotherapie galt. Dementsprechend lassen sich die Ergebnisse der Studie nur sehr beschränkt verallgemeinern, da viele Analysen für nur ganz bestimmte Teilgruppen berechnet wurden (wie Krebspatienten im Stadium III-IV und gleichzeitig erhaltener Chemotherapie). Inwiefern die verschiedenen Teilgruppen vergleichbar sind und welche Größe sie jeweils umfassten bleibt dabei unklar. Des Weiteren konzentrieren sich die beschrieben Ergebnisse stark aus solche, die einen Unterschied durch die Gabe von Zink erbrachten. Die drei weiteren untersuchten Faktoren bleiben in der Auswertung relativ unbeachtet, deuten in ihren Ergebnissen aber darauf hin, dass Zink keinen positiven Einfluss bei Kopf-Hals-Karzinom Patienten auf die Lebensspanne oder das Wachstum entfernter Metastasen hat.

=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=Aged >18 years, had a radiotherapy field covering more than one-third of the buccal mucosa
|Exclusion criteria=Previous radiotherapy of the head and neck; diabetes mellitus
|N randomized=100
|Analysis=PP Analysis
|Specifications on analyses=NI
|Countries of data collection=Taiwan
|LoE=2b Oxford 2009
|Outcome timeline=T0: after radiotherapy
Follow-Up: every 3 months after therapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative, Adjuvant
|Types of cancer=Head and Neck Cancers
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Stages I-IV and primary and recurrent tumors
|Comorbidity=NI
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=Intervention arm: Dose of radiotherapy (cGy): 6,824 (463.5), Placebo arm: Dose of radiotherapy (cGy): 6,651 (1,056.3);

Intervention arm: Duration of radiotherapy: 56 (8.7), Placebo arm: Duration of radiotherapy: 54 (11.8);

Intervention arm: concurrent chemotherapy: 20 (41), Placebo arm: concurrent chemotherapy: 20 (42)
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Intervention arm: n=40 (81.6%) male, n=9 (18.4%) female
Placebo arm: n=43 (89.6%) male, n=5 (10.4%) female
|Age groups=Adults (18+)
|Age groups specification=Intervention arm: mean (SD): 50 (11)
Placebo arm: mean (SD): 51 (11)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=50
|Drop-out=1
|Drop-out reasons=Voluntary withdrawal
|Intervention=Zinc
|Dosage and regime=Oral zinc (25 mg Pro-Z), three capsules per day
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=1
|Arm topic=Zinc
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=50
|Drop-out=2
|Drop-out reasons=Voluntary withdrawal
|Intervention=Placebo
|Dosage and regime=Three capsule containing soybean oil per day
|One-time application=No
|Duration in days=56
|Side Effects / Interactions=No side effects
|Order number=2
|Arm topic=Zinc
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=Time from the first day of treatment to death
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Median duration of follow-up was 22.3 months (1- 47 months): no significant differences
|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=Zinc
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=The date of the first treatment to local recurrence or distant metastases
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No significant differences between intervention and 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=3
|Outcome topic=Zinc
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=More specifically: LFS (Local-Free Survival), from the date of the first treatment until the date local tumor progression was documented
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Patients with recurrent disease had significantly worse LFS than patients with primary disease (HR, 2.23; 95% CI, 1.17–4.26, p = 0.015) and worse LFS than patients with primary Stages I–II disease (HR, 9.4; 95% CI, 1.22–72.39, p = 0.031),
completion of radiotherapy was a significantly beneficial factor for LFS (HR, 6.84; 95% CI, 2.62–17.86, p < 0.001);

Univariate analysis for patients receiving concurrent chemoradiotherapy: poorer prognosis of patients with recurrent disease than for those with primary disease (HR, 5.25; 95% CI, 2.06–13.42, p = 0.001),
better LFS with completion of radiotherapy (HR, 12.49; 95% CI, 2.4–65, p = 0.003),
worse LFS of patients in placebo arm than patients in intervention arm (HR, 3.01; 95% CI, 1.1–8.23, p = 0.032);

Multivariate analysis: placebo arm (HR, 5.25; 95% CI, 1.73–15.88, p = 0.003) and recurrent disease (HR, 8.83; 95% CI, 3.13–24.88, p < 0.001) emerged as independent predictors of poor LFS
|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=Zinc
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=DFS (Disease-Free Survival)
|Outcome specification=More specifically: MFS (Metastases-Free Survival), from the date of the first treatment until the date distant metastases occurred
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=No significant differences
|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=Zinc
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Sponsored by the Chi-Mei Foundation Medical Center (CMFHR9201)
|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=?
|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 vote available
* Given comparability of the two groups in all important characteristics and zinc levels
* Large sample size
* Double blinding

CONTRA:
* No information on reasons for attrition (3%)
* Selectively reported: Reference is made to the tables for the results, the focus in the results section is only on endpoint 2, lack of information on statistical parameters (focus on significant results)
* Multiple testing in repeatedly different group comparisons, whereby it is not clear how many patients the individual groups comprise in each case
* Results of significant subgroup analyses are only mentioned for the first time in the discussion section
* No mention of reasons for exclusion of patients

Van Zandwijk et al. (2000): EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients With Head and Neck Cancer or Lung Cancer

2024-11-28T13:22:43Z

DDeel:

{{Reference
|Reference=Publication: EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients With Head and Neck Cancer or Lung Cancer
}}
=Brief summary=
In this study, 4 groups of head and neck tumor or lung cancer patients after radiotherapy and/or tumor surgery were compared with each other. One group received vitamin A, one group received N-acetylcysteine (NAC, a chemical agent with mucolytic properties), one group received vitamin A and NAC and a control group received nothing except radiotherapy/surgery. Comparing the two groups that received vitamin A with the other two groups, there were no significant differences in the occurrence of first events such as recurrence, second primary tumor or death, in overall survival over a five-year period and in the time until the occurrence of second primary tumors. However, the fewest second primary tumors occurred in the group that had only received radiotherapy and/or surgery. Significantly more adverse events were reported in the groups receiving vitamin A than in the group receiving NAC alone. A disadvantage of this study is that there was no blinding (i.e. investigators/patients know which group they belong to), that there were more treatment dropouts in the vitamin A groups and that the reporting quality in this study was poor in some cases. Among other things, the results were reported in a very confusing and mixed way.

In dieser Studie werden vier Gruppen mit Kopf-Hals-Tumor- oder Lungenkrebs-Patienten nach Radiotherapie und/oder Tumoroperation miteinander verglichen. Eine Gruppe bekam Vitamin A, eine Gruppe N-Acetylcystein (NAC, ein chemischer Wirkstoff mit schleimlösenden Eigenschaften), eine Gruppe Vitamin A und NAC und eine Kontrollgruppe nichts außer Radiotherapie/Operation. Vergleicht man jeweils die beiden Gruppen, die Vitamin A bekommen haben, mit den anderen beiden Gruppen, fanden sich keine bedeutsamen Unterschiede bezüglich des Auftreten erster Ereignisse wie Rezidiv, zweiter Primärtumor oder Tod, bezüglich des Gesamtüberlebens in einem Zeitraum von fünf Jahren und bezüglich des Zeitraums bis zum Auftreten von zweiten Primärtumoren. Die wenigsten zweiten Primärtumoren tauchten jedoch in der Gruppe auf, die nur Radiotherapie und/oder Operation erhalten hatten. In den Gruppen mit Vitamin A wurden bedeutsam mehr unerwünschte Nebenwirkungen berichtet als in der Gruppe, die nur NAC erhalten hat. Ein Nachteil dieser Studie ist, dass keine Verblindung stattfand (d.h. Untersuchter/Patienten wissen, welcher Gruppe sie angehören), dass es in den Vitamin A Gruppen mehr Therapieabbrecher gegeben hat und dass die Berichtqualität in dieser Studie teilweise schlecht war. So waren unter anderen die Ergebnisse sehr verwirrend und durcheinander berichtet.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=- Non-small-cell lung cancer (stages pT1–2, N0–1, and T3N0), cancer of the larynx (Tis, T1–3, and N0–1), or cancer of the oral cavity (T1–2 and N0–1)
- Performance status 0–2
- Treated with curative intent
|Exclusion criteria=Patients with recurrent disease, synchronous multiple tumors, previous malignant disease, abnormal liver or renal function, hypertriglyceridemia, hypercholesterolemia, diabetes mellitus, hypertension, and recent or active peptic ulcer
|N randomized=2592
|Analysis=PP Analysis
|Specifications on analyses=Event-free survival, time to second primary tumor, and survival curves were constructed by the Kaplan–Meier technique and were compared by the log-rank test. The interaction between the effects of N-acetylcysteine and those of retinyl palmitate was tested with a proportional hazards model. Also, analyses of four arms were performed.
|Countries of data collection=Italy, Netherlands
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
Follop-up: at least 2 years after randomization
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Laryngeal Cancer, Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Per arm, n stage I/n stage II/n stage III:
- vit. A: 395/167/85
- NAC: 371/176/95
- vit. A + NAC: 376/182/85
- control: 382/184/77
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=3.4% of patients received chemotherapy in addition to local treatment

Time between radiotherapy/surgery and randomization (month)
- vit. A group: < 2: 51%; 2-12: 32%, > 12: 17%
- NAC group: < 2: 52%; 2-12: 30%, > 12: 17%, missing: 1%
- vit. A and NAC group: < 2: 49%; 2-12: 36%, > 12: 15%
- control group: < 2: 49%; 2-12: 34%, > 12: 17%
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Mixed
|Gender specifications=13% female, n (male/female) per arm:
- vit. A: 563/84
- NAC: 556/86
- vit. A + NAC: 560/83
- control: 559/82
|Age groups=Adults (18+)
|Age groups specification=Median (range): 61 (19-91), per arm:
- vit. A: Median 61 (23-83)
- NAC: 61 (28–86)
- vit. A + NAC: 61 (23–83)
- control: 60 (19-91)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=638
|Drop-out=12 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=Vitamine A (retinyl palmitate)
|Dosage and regime=1st year: retinyl palmitate (300,000 IU) 1x/day
2nd year: retinyl palmitate (150,000 IU) 1x/day
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=Typical: mucocutaneous side effects (dryness, desquamation, itching, bleeding, hair loss)

Severe side effects (grade 3/4)
- Gastrointestinal: 32
- Skin: 50
- Malaise: 5
- Temporary increase in liver enzymes: 2
- Hypercholesterolemia: 2
- Bone pain: 2
- Other: 15
|Order number=1
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=637
|Drop-out=8 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=N-acetylcysteine (NAC)
|Dosage and regime=600mg NAC 1x/day
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=Typical: symptoms of the digestive tract (especially dyspepsia)

Severe side effects (grade 3/4)
- Gastrointestinal: 44
- Skin: 11
- Malaise: 2
- Temporary increase in liver enzymes: 1
- Other: 3
|Order number=2
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=640
|Drop-out=9 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=Vitamine A (retinyl palmitate) and N-acetylcysteine (NAC) combined
|Dosage and regime=- Retinyl palmite (300 000 IU daily for 1 year followed by 150 000 IU for the 2nd year)
- N-acetylcysteine (600 mg daily for 2 years)
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=Typical: mucocutaneous side effects (dryness, desquamation, itching, bleeding, hair loss), symptoms of the digestive tract (especially dyspepsia)

Severe side effects (grade 3/4)
- Gastrointestinal: 47
- Skin: 43
- Malaise: 1
- Temporary increase in liver enzymes: 3
- Hypercholesterolemia 3
- Bone pain 2
- Other: 8
|Order number=3
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=633
|Drop-out=15 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=None
|Dosage and regime=NA
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=NA
|Order number=4
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=No recurrence/SPT/death
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''
No significant difference for number of first events (recurrence/SPT/death) within 5 years between (vit. A group and vit. A+NAC group) vs. (NAC group and control group): p=0.672
|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=Vitamin A (beta-carotene)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''
No significant difference for number of deaths within 5 years between (vit. A group and vit. A+NAC group) vs. (NAC group and control group): p=0.925

Interaction (for NAC) not significant, i.e. no influence of NAC on results
|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=Vitamin A (beta-carotene)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Tumor progression
|Outcome specification=Time to second primary tumor (SPT)
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''
- No significant difference for number of SPTs between (vit. A group and vit. A+NAC group) vs. (NAC group and control group) controlled for NAC: p=0.173

- No significant difference for number of tobacco-associated SPTs between (vit. A group and vit. A+NAC group) vs. (NAC group and control group) controlled for NAC: p=0.978

- Interaction with NAC: p = 0.039 i.e. difference between vit. A vs. no vit. A in terms of time period differed depending on whether NAC was additionally given or not

- When comparing all four arms, number of SPT in arm D lowest: SPT in general p = 0.025, tobacco-associated SPT p = 0.174
|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=Vitamin A (beta-carotene)
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funded by the European Organization for Research and Treatment of Cancer (EORTC), the Netherlands Cancer Institute, the European Commision

Financial support for the meetings: Zambon (Italy) Provision of the preparations: N-acetylcysteine: Zambon; retinyl palmitate: MUCOS Pharma GmbH & Co. KG (Germany)
|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:
* Large sample according to power analysis
CONTRA:
* No blinding
* No p-values for baseline group differences -> at least descriptively partially different
* More treatment dropouts in vitamin A groups (vit. A: 26%/vit. A+NAC: 25% vs. NAC: 18%; p < 0.001)
* Very unclear reporting, only very few p-values reported overall
}}

Van Zandwijk et al. (2000): EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients With Head and Neck Cancer or Lung Cancer

2024-11-28T13:22:37Z

DDeel:

{{Reference
|Reference=Publication: EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients With Head and Neck Cancer or Lung Cancer
}}
{{Study Note}}
=Brief summary=
In this study, 4 groups of head and neck tumor or lung cancer patients after radiotherapy and/or tumor surgery were compared with each other. One group received vitamin A, one group received N-acetylcysteine (NAC, a chemical agent with mucolytic properties), one group received vitamin A and NAC and a control group received nothing except radiotherapy/surgery. Comparing the two groups that received vitamin A with the other two groups, there were no significant differences in the occurrence of first events such as recurrence, second primary tumor or death, in overall survival over a five-year period and in the time until the occurrence of second primary tumors. However, the fewest second primary tumors occurred in the group that had only received radiotherapy and/or surgery. Significantly more adverse events were reported in the groups receiving vitamin A than in the group receiving NAC alone. A disadvantage of this study is that there was no blinding (i.e. investigators/patients know which group they belong to), that there were more treatment dropouts in the vitamin A groups and that the reporting quality in this study was poor in some cases. Among other things, the results were reported in a very confusing and mixed way.

In dieser Studie werden vier Gruppen mit Kopf-Hals-Tumor- oder Lungenkrebs-Patienten nach Radiotherapie und/oder Tumoroperation miteinander verglichen. Eine Gruppe bekam Vitamin A, eine Gruppe N-Acetylcystein (NAC, ein chemischer Wirkstoff mit schleimlösenden Eigenschaften), eine Gruppe Vitamin A und NAC und eine Kontrollgruppe nichts außer Radiotherapie/Operation. Vergleicht man jeweils die beiden Gruppen, die Vitamin A bekommen haben, mit den anderen beiden Gruppen, fanden sich keine bedeutsamen Unterschiede bezüglich des Auftreten erster Ereignisse wie Rezidiv, zweiter Primärtumor oder Tod, bezüglich des Gesamtüberlebens in einem Zeitraum von fünf Jahren und bezüglich des Zeitraums bis zum Auftreten von zweiten Primärtumoren. Die wenigsten zweiten Primärtumoren tauchten jedoch in der Gruppe auf, die nur Radiotherapie und/oder Operation erhalten hatten. In den Gruppen mit Vitamin A wurden bedeutsam mehr unerwünschte Nebenwirkungen berichtet als in der Gruppe, die nur NAC erhalten hat. Ein Nachteil dieser Studie ist, dass keine Verblindung stattfand (d.h. Untersuchter/Patienten wissen, welcher Gruppe sie angehören), dass es in den Vitamin A Gruppen mehr Therapieabbrecher gegeben hat und dass die Berichtqualität in dieser Studie teilweise schlecht war. So waren unter anderen die Ergebnisse sehr verwirrend und durcheinander berichtet.

=Study Design=

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

{{RCT study general properties
|Inclusion criteria=- Non-small-cell lung cancer (stages pT1–2, N0–1, and T3N0), cancer of the larynx (Tis, T1–3, and N0–1), or cancer of the oral cavity (T1–2 and N0–1)
- Performance status 0–2
- Treated with curative intent
|Exclusion criteria=Patients with recurrent disease, synchronous multiple tumors, previous malignant disease, abnormal liver or renal function, hypertriglyceridemia, hypercholesterolemia, diabetes mellitus, hypertension, and recent or active peptic ulcer
|N randomized=2592
|Analysis=PP Analysis
|Specifications on analyses=Event-free survival, time to second primary tumor, and survival curves were constructed by the Kaplan–Meier technique and were compared by the log-rank test. The interaction between the effects of N-acetylcysteine and those of retinyl palmitate was tested with a proportional hazards model. Also, analyses of four arms were performed.
|Countries of data collection=Italy, Netherlands
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline
Follop-up: at least 2 years after randomization
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=No therapy setting
|Types of cancer=Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Laryngeal Cancer, Lung Cancer - Non-Small Cell Lung Cancer
|Stage cancer=Early Stage, Advanced Stage
|Cancer stage specification=Per arm, n stage I/n stage II/n stage III:
- vit. A: 395/167/85
- NAC: 371/176/95
- vit. A + NAC: 376/182/85
- control: 382/184/77
|Comorbidity=NI
|Current cancer therapy=No therapy
|Specifications on cancer therapies=3.4% of patients received chemotherapy in addition to local treatment

Time between radiotherapy/surgery and randomization (month)
- vit. A group: < 2: 51%; 2-12: 32%, > 12: 17%
- NAC group: < 2: 52%; 2-12: 30%, > 12: 17%, missing: 1%
- vit. A and NAC group: < 2: 49%; 2-12: 36%, > 12: 15%
- control group: < 2: 49%; 2-12: 34%, > 12: 17%
|Previous cancer therapies=Surgery, Chemotherapy, Radiation therapy
|Gender=Mixed
|Gender specifications=13% female, n (male/female) per arm:
- vit. A: 563/84
- NAC: 556/86
- vit. A + NAC: 560/83
- control: 559/82
|Age groups=Adults (18+)
|Age groups specification=Median (range): 61 (19-91), per arm:
- vit. A: Median 61 (23-83)
- NAC: 61 (28–86)
- vit. A + NAC: 61 (23–83)
- control: 60 (19-91)
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=638
|Drop-out=12 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=Vitamine A (retinyl palmitate)
|Dosage and regime=1st year: retinyl palmitate (300,000 IU) 1x/day
2nd year: retinyl palmitate (150,000 IU) 1x/day
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=Typical: mucocutaneous side effects (dryness, desquamation, itching, bleeding, hair loss)

Severe side effects (grade 3/4)
- Gastrointestinal: 32
- Skin: 50
- Malaise: 5
- Temporary increase in liver enzymes: 2
- Hypercholesterolemia: 2
- Bone pain: 2
- Other: 15
|Order number=1
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=637
|Drop-out=8 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=N-acetylcysteine (NAC)
|Dosage and regime=600mg NAC 1x/day
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=Typical: symptoms of the digestive tract (especially dyspepsia)

Severe side effects (grade 3/4)
- Gastrointestinal: 44
- Skin: 11
- Malaise: 2
- Temporary increase in liver enzymes: 1
- Other: 3
|Order number=2
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=640
|Drop-out=9 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=Vitamine A (retinyl palmitate) and N-acetylcysteine (NAC) combined
|Dosage and regime=- Retinyl palmite (300 000 IU daily for 1 year followed by 150 000 IU for the 2nd year)
- N-acetylcysteine (600 mg daily for 2 years)
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=Typical: mucocutaneous side effects (dryness, desquamation, itching, bleeding, hair loss), symptoms of the digestive tract (especially dyspepsia)

Severe side effects (grade 3/4)
- Gastrointestinal: 47
- Skin: 43
- Malaise: 1
- Temporary increase in liver enzymes: 3
- Hypercholesterolemia 3
- Bone pain 2
- Other: 8
|Order number=3
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm
|Arm type=Passive control
|Number of participants (arm)=633
|Drop-out=15 (no clear indication of exact numbers)
|Drop-out reasons=No clear indication of exclusion reasons
|Intervention=None
|Dosage and regime=NA
|One-time application=No
|Duration in days=730
|Side Effects / Interactions=NA
|Order number=4
|Arm topic=Vitamin A (beta-carotene)
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=PFS (Progression-Free Survival)
|Outcome specification=No recurrence/SPT/death
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''
No significant difference for number of first events (recurrence/SPT/death) within 5 years between (vit. A group and vit. A+NAC group) vs. (NAC group and control group): p=0.672
|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=Vitamin A (beta-carotene)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=OS (Overall Survival)
|Outcome specification=NI
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''
No significant difference for number of deaths within 5 years between (vit. A group and vit. A+NAC group) vs. (NAC group and control group): p=0.925

Interaction (for NAC) not significant, i.e. no influence of NAC on results
|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=Vitamin A (beta-carotene)
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Tumor progression
|Outcome specification=Time to second primary tumor (SPT)
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention='''Overall'''
- No significant difference for number of SPTs between (vit. A group and vit. A+NAC group) vs. (NAC group and control group) controlled for NAC: p=0.173

- No significant difference for number of tobacco-associated SPTs between (vit. A group and vit. A+NAC group) vs. (NAC group and control group) controlled for NAC: p=0.978

- Interaction with NAC: p = 0.039 i.e. difference between vit. A vs. no vit. A in terms of time period differed depending on whether NAC was additionally given or not

- When comparing all four arms, number of SPT in arm D lowest: SPT in general p = 0.025, tobacco-associated SPT p = 0.174
|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=Vitamin A (beta-carotene)
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funded by the European Organization for Research and Treatment of Cancer (EORTC), the Netherlands Cancer Institute, the European Commision

Financial support for the meetings: Zambon (Italy) Provision of the preparations: N-acetylcysteine: Zambon; retinyl palmitate: MUCOS Pharma GmbH & Co. KG (Germany)
|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:
* Large sample according to power analysis
CONTRA:
* No blinding
* No p-values for baseline group differences -> at least descriptively partially different
* More treatment dropouts in vitamin A groups (vit. A: 26%/vit. A+NAC: 25% vs. NAC: 18%; p < 0.001)
* Very unclear reporting, only very few p-values reported overall
}}

Jeon et al. (2016): Effect of intravenous high dose Vitamin C on postoperative pain and morphine use after laparoscopic colectomy: A randomized controlled trial

2024-11-28T13:19:59Z

DDeel:

{{Reference
|Reference=Publication: Effect of intravenous high dose Vitamin C on postoperative pain and morphine use after laparoscopic colectomy: A randomized controlled trial
}}
{{Study Note}}
=Brief summary=
In this study, colorectal cancer patients were examined in the first 24 hours after surgical removal of the colon. One group received an additional intravenous injection of vitamin C during the operation and the other group only a placebo. The vitamin C group reported less pain at rest after the operation (both groups reported similar pain ratings during coughing) and two hours after the operation the vitamin C group needed less morphine. This difference disappeared 6 and 24 hours after surgery. Apart from this, the vitamin C group needed fewer additional opiates postoperatively. The two groups did not differ in terms of perceived fatigue, reported nausea and vomiting and length of hospital stay after surgery. A major criticism of this study is that in most cases the authors did not indicate whether the patients differed in terms of the characteristics examined at the beginning of the study. For example, when recording pain, it is important to know whether the patients had a generally high or low sensitivity to pain.

In dieser Studie wurden Darmkrebspatienten in den ersten 24 Stunden nach der operativen Entfernung des Dickdarms untersucht. Eine Gruppe bekam während der Operation zusätzlich intravenös Vitamin C gespritzt und die andere Gruppe nur ein Placebo. Die Vitamin C Gruppe berichtete nach der Operation im Ruhezustand weniger Schmerzen (Während Husten gaben beide Gruppe ähnliche Schmerzeinstufungen an) und zwei Stunden nach der Operation brauchte die Vitamin C Gruppe weniger Morphium. Dieser Unterschied verschwand 6, bzw. 24 Stunden nach der Operation. Abgesehen davon brauchte die Vitamin C Gruppe weniger zusätzliche Opiate postoperativ. Die beiden Gruppen unterschieden sich nicht hinsichtlich der eingeschätzten Erschöpfung, der berichteten Übelkeit und Erbrechen und der Aufenthaltsdauer im Krankenhaus nach der Operation. Ein großer Kritikpunkt an dieser Studie ist, dass die Autoren in den meisten Fällen nicht angegeben haben, ob sich die Patienten hinsichtlich untersuchter Merkmale schon zu Beginn der Studie unterschieden haben. So ist es z.B. bei der Erfassung der Schmerzen wichtig zu wissen, ob es Patienten mit einer generell hohen oder niedrigen Schmerzempfindlichkeit sind.

=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=Colon cancer patients aged 20 to 75 years, scheduled for elective laparoscopic colectomy
under general anesthesia
|Exclusion criteria=Patients with history of allergy to systemic opioids, substance use disorder, coagulopathy, chronic opioid use, sleep apnea, and analgesic use within 24 h
|N randomized=100
|Analysis=PP Analysis, ITT Analysis
|Countries of data collection=Korea South
|LoE=1b Oxford 2009
|Outcome timeline=T0: Baseline (pre-/peri-op)
T1: 2h post-op
T2: 6h post-op
T3: 24h post-op
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=NI
|Types of cancer=Colorectal Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=Surgery
|Specifications on cancer therapies=Elective laparoscopic colectomy
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Per group
- placebo: 29 male, 21 female
- intervention: 28 male, 22 female
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) per group:
- placebo: 64.5 (10.6) years
- intervention: 65.4 (9.6) years
}}
=Arms=

{{Arm
|Arm type=Placebo
|Number of participants (arm)=48
|Drop-out=2
|Drop-out reasons=Not arm specified: complications (anastomotic leak and additional ileostomy)
|Intervention=Saline 50 mL
|Dosage and regime=Intravenous, 30 minutes
|One-time application=Yes
|Duration in days=1
|Side Effects / Interactions=NI
|Order number=2
|Arm topic=Vitamin C
}}
{{Arm
|Arm type=Intervention
|Number of participants (arm)=49
|Drop-out=1
|Drop-out reasons=Not arm specified: complications (anastomotic leak and additional ileostomy)
|Intervention=Ascorbic acid
|Dosage and regime=50mg/kg (ascorbic acid 10 g/20 mL) mixed with normal saline for a total injection volume of 50 mL; intravenous, 30 minutes
|One-time application=Yes
|Duration in days=1
|Side Effects / Interactions=NI
|Order number=1
|Arm topic=Vitamin C
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=At rest and while coughing
Pain at 2h, 6h and 24h
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=NA
|Results after intervention=Estimated mean (SD) from graphic:
2, 6 and 24h post-op: at rest significantly lower in intervention compared to placebo; p's<0.05 (no values reported, only graphs)

While coughing: no significant difference at any time point; p's>0.05
|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=Vitamin C
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Additional medication
|Outcome specification=Consumption in mg at 2h, 6h and 24h
|Type of measurement=Observation
|Results during intervention=NA
|Results after intervention=Morphine use (in mg) at 2h was significantly lower in intervention arm (p<0.05), no significant difference between the two arms at 6h and 24h (p's>0.05).
|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=Vitamin C
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Fatigue
|Outcome specification=Fatigue at baseline and at 2h, 6h and 24h
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=NA
|Results after intervention=No difference between groups in postoperative fatigue scores (p's>0.05)
|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=Vitamin C
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Additional medication
|Outcome specification=Frequency of postoperative rescue analgesics
|Type of measurement=Observation
|Results during intervention=?
|Results after intervention=Rescue analgesics were required more frequently in the placebo arm; significant difference compared to intervention arm (p = 0.00).

Frequency as Mean(SD):
Intervention: 0.8(0.8)
Placebo: 1.4(1.0)
|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=Vitamin C
}}
{{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=?
|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=Large sample according to power analysis, double-blinded, exact results could only be taken from the graph, no information on whether the arms differed in terms of pain perception at the beginning of the study, only the difference between A and B was considered at all time points, no development over time

PRO
* Ethics vote
* Adequate randomization
* Double blinding
* Sample size according to power analysis
* Low dropout
CONTRA
* Except fatigue, no baseline values for investigated outcomes (e.g. pain), group differences possible
* Multiple testing (no models over time)
* Poor report quality (figures for endpoints can only be taken from graph)
}}

Jameson, MB

2024-11-28T13:17:40Z

DDeel: Created page with "{{Author}}"

Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies

2024-11-26T17:18:10Z

DDeel:

{{Reference
|Reference=Publication: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies
}}
{{Study Note
|Study Note=This is the second study [[Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]]

First study: [[Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].
}}
=Brief summary=
Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one arm (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other arm a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients, who then showed an improvement in pain perception of at least 15%, were then randomly divided into two arms to receive either Sativex® or a placebo.
In the first study 399 and in the second study (after division into arms) 206 patients were included. After five weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the first study did the Sativex® arm show improvement in some of the questionnaires (personal and physician-assessed improvement). In the second study, there were no differences between the arms in the questionnaires.

Both studies are characterised by a large sample size and a well thought-out statistical analysis. However, as the studies were conducted in centres all over the world, it should be noted that it cannot be assumed that all patients received the same basic care (especially in opioid care). In addition, both studies were funded by a pharmaceutical industry.

In diesem Artikel wurden zwei Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der zweiten Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten, die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten, wurden anschließend zufällig in zwei Gruppen eingeteilt, um entweder weiterhin Sativex® oder ein Placebo zu bekommen.
In der ersten Studie wurden 399 und in der zweiten Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach fünf Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der ersten Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der zweiten Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.
Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden, ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.

=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 incurable stage of cancer; ≥18years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
|Exclusion criteria=Baseline use of morphine at >500mg 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 including recreational use of cannabis product
|N randomized=399
|Analysis=ITT Analysis
|Specifications on analyses=Procedure
Part A: all received Sativex® for 10 days, then 4 days therapy at adjusted dose; patients who showed an improvement of at least 15% for pain (NRS) entered Part B: randomized in A or B with intervention for 5 weeks, follow-up 2 weeks later

Discussed is part B of the study.
|Countries of data collection=Australia, Bulgaria, Germany, Hungary, India, Israel, Italy, Lithuania, Poland, Romania, Spain, Taiwan, United Kingdom
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: after 3 weeks (day 22)

T2: after 5 weeks (day 36)

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

{{Characteristics of participants
|Setting=NI
|Types of cancer=Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Chest Cancer, Eye Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Prostate Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, Skin Cancer, Bone and Soft Tissue Cancers, Gastrointestinal Cancers - Esophageal Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Part A

Female = 176 (43.6%)

Part B

Sativex = 40 (38.8%) female

Placebo = 48 (46.6%) female
|Age groups=Adults (18+)
|Age groups specification=Part A
Mean (SD) age: 61.2 (11.2) years

Part B

Mean (SD) age per arm:

Sativex = 61.4 (10.9) years

Placebo = 61.6 (11.8) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=103
|Drop-out=Discontinued n=25

Died during study n=23

Study completed n=78
|Drop-out reasons=Adverse Events n=21

Withdrew consent n=2

Withdrawn by investigator n=1

Lack of efficacy n=1

Died during treatment n=23

Died post-treatment but before follow-up n=8

Died post follow-up n=3
|Intervention=Sativex
|Dosage and regime=Sativex® (nabiximol, THC 27 mg/mL, CBD 25 mg/mL) via oral spray (self-applied by patient);
week 1: dose finding; week 2-5: stable dose, max. 10 sprays

* Part A: first week average number of sprays: 3.6; second week: 6.4
* Part B: average daily number: 6.5
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Part A

Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n=128, 31.7%, somnolence (n=42, 10.4%), nausea (n=21, 5.2%) and dizziness (n=21, 5.2%)

Part B

Overall 72% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=16, 15.5%; somnolence (n=6, 5.8%)

More than twice as many patients in Sativex arm discontinued study due to side effects (n=14, 13.6% vs. n=6, 5.8%); no statistical comparison given)

None of the deaths related to intervention
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=103
|Drop-out=Discontinued n=15

Died during study n=9

Study completed n=88
|Drop-out reasons=Adverse Events n=13

Withdrawn by investigator n=1

Lack of efficacy n=1

Died during treatment n=9
|Intervention=Placebo
|Dosage and regime=Week 1: dose finding; week 2-5: stable dose, max. 10 sprays

* Part A: first week average number of sprays: 3.6, second week: 6.4
* Part B: average daily number: 6.3
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=''Part A''

Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n=128, 31.7%, somnolence (n=42, 10.4%), nausea (n=21, 5.2%) and dizziness (n=21, 5.2%)

''Part B''

Overall 62% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=12, 11.7%; somnolence n=0
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Change in NRS value for moderate pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Deterioration in both arms after 5 weeks:
* Sativex arm: from 3.2 to 3.7, Placebo arm: 3.1 to 3.6. (treatment effect -0.02; 95% CI: -0.42, 0.38; p = 0.917)
* No differences for individual subgroups (no US patients in this study)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=Median improvement in pain with NRS in %
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=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 arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Sleep
|Outcome specification=Extent of sleep disturbance (assessed with NRS)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Additional medication
|Outcome specification=General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|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=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (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=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
|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=* high drop-out due to side effects or withdrawal of consent in Phase A
* not fitting the inclusion criteria (failure to demonstrate a 15% improvement in average pain NRS score during titration)
|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=* More and cannabinoid typical side effects in intervention arms, knowledge of assignment could have influenced the result.
* 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=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=?
|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
* Arms comparable at baseline
* Power analysis conducted
* Multiple testing controlled for endpoints pain and sleep disruption
* Intent-to-Treat analysis performed

CONTRA:
* High dropout rate (due to study discontinuation or death)
* No information on whether centers were comparable in patient treatment; particularly, "optimal" opioid treatment may vary between countries
* Multiple testing only controlled for pain and sleep disruption
}}

Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies

2024-11-26T17:14:08Z

DDeel:

{{Reference
|Reference=Publication: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies
}}
{{Study Note
|Study Note=This is the first study [[Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].

Second study: [[Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].
}}
=Brief summary=
Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one arm (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other arm a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients, who then showed an improvement in pain perception of at least 15%, were then randomly divided into two arms to receive either Sativex® or a placebo.

In the first study 399 and in the second study (after division into arms) 206 patients were included. After five weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the first study did the Sativex® arm show improvement in some of the questionnaires (personal and physician-assessed improvement). In the second study, there were no differences between the arms in the questionnaires.

Both studies are characterised by a large sample size and a well thought-out statistical analysis. However, as the studies were conducted in centres all over the world, it should be noted that it cannot be assumed that all patients received the same basic care (especially in opioid care). In addition, both studies were funded by a pharmaceutical industry.

In diesem Artikel wurden zwei Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der zweiten Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten, die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten, wurden anschließend zufällig in zwei Gruppen eingeteilt, um entweder weiterhin Sativex® oder ein Placebo zu bekommen.

In der ersten Studie wurden 399 und in der zweiten Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach fünf Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der ersten Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der zweiten Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.

Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden, ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.

=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 incurable stage of cancer; ≥ 18 years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤ 4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤ 8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
|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 including recreational use of cannabis product
|N randomized=399
|Analysis=ITT Analysis
|Specifications on analyses=n = 2 no intervention received

Wilcoxon rank-sum test was conducted for percent improvement in average pain NRS score (from baseline to end of treatment in study 1, and from eligibility
pre-treatment baseline to end of treatment in study 2).
Analysis of covariance (ANCOVA) was applied on the primary and the key secondary efficacy endpoints, including percent improvement, average pain/worst pain/sleep disruption scores, with corresponding baseline value as a covariate and treatment group as a factor. The time-course of these four efficacy endpoints from week 1 through week 5 was also analysed using Mixed-Effect Model Repeat Measurement (MMRM) on the ITT analysis set in both studies.

For both study 1 and study 2, the primary endpoint and the key secondary endpoints were tested with their Type I error controlled by use of a hierarchical gate-keeping procedure.

In each study, p-values from Wilcoxon rank-sum tests on percent improvement and ANCOVA on average pain/worst pain/sleep disruption scores were used for the hierarchical gate-keeping procedure in the sequence of the primary endpoint and the key secondary endpoints. No adjustments for covariates were made for the analyses of the other secondary endpoints in both studies with analysis of variance (ANOVA), including PGIC, SGIC or PSQ, and daily total, maintenance, and breakthrough opioid dose. Subgroup analyses for region (United States and rest of world (ROW)) were performed for the primary and the key secondary endpoints.
|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 (day 22)

T2: after 5 weeks (day 36)

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

{{Characteristics of participants
|Setting=NI
|Types of cancer=Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Prostate Cancer, Lung Cancer, Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Chest Cancer, Eye Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, Genitourinary Cancers - Kidney (Renal) Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Skin Cancer, Bone and Soft Tissue Cancers, Gastrointestinal Cancers - Esophageal Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=Mean (SD) time since cancer diagnosis per arm:

Sativex = 4.1 (4.2) years

Placebo = 3.5 (5.0) years
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Male, n(%) per arm:

Sativex = 106 (53.0)

Placebo = 97 (48.7)

Female, n(%) per arm:

Sativex = 194 (47.0)

Placebo = 102 (51.3)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age per arm:

Sativex = 60 (11) years

Placebo = 59.6 (11) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=200
|Drop-out=64
|Drop-out reasons=Side effects (n = 38, 19%); consent withdrawn (n = 19, 9.5%); death (n = 20, 10%)
|Intervention=Sativex
|Dosage and regime=Sativex® (Nabiximol, THC 27 mg/mL, CBD 25 mg/mL) via oral spray (self-applied by patient)
* week 1: dose finding; week 2-5: stable dose, max. 10 sprays
* first week mean number of sprays: 3.7, stabilized over 4 weeks (6.3 sprays per day)
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Overall 68% at least one event; assessed as probably intervention-associated with frequency ≥ 5%:
Total n=64 (32.2%), of which somnolence n=18 (9%), dizziness n=15 (7.5%), nausea n=10 (5%)

2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)

None of the deaths related to intervention
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=199
|Drop-out=41
|Drop-out reasons=Side effects (n = 29, 14.6%), consent withdrawn (n = 8, 4%), death (n = 25, 68%)
|Intervention=Placebo
|Dosage and regime=First week mean number of sprays 3.7, stabilized over 4 weeks (7.4 sprays per day)
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Overall 64% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n=41 (20.7%), of which somnolence n=6 (3%), dizziness n=6 (3%), nausea n=8 (4%)

2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)

None of the deaths related to intervention
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Median improvement in pain with NRS in %
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significant difference after 5 weeks
* Sativex arm = 7.2% vs. placebo arm = 9.5% (median difference = −1.84%; CI: −6.19%, 1.50%; p=0.274, not significant)

Subgroup analysis with US population
* shows effects for Sativex arm (p=0.03), especially for patients under 65 years of age
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 average pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No differences between arms after 5 weeks (no p-value)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=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 differences between arms after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Extent of sleep disturbance (assessed with NRS)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No differences between arms after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Results during intervention=No differences between arms after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|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=Results:
* Higher change in SGIC for global impression and better change assessed by physician in 'general functional ability' of Sativex arm compared to placebo arm
* Scores in SGIC better in Sativex arm at week 3 (p = 0.041), 5 (p = 0.022) and last visit (p = 0.022)
* PGIC better at week 5 (p=0.037) compared to placebo arm
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
|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=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* More and cannabinoid typical side effects in intervention arms, knowledge of assignment could have influenced the result.
* 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=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
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethical approval obtained
* Arms comparable at baseline
* Power analysis conducted
* Multiple testing controlled for endpoints pain and sleep disruption
* Intent-to-Treat analysis performed

CONTRA:
* High dropout rate (due to study discontinuation or death)
* No information on whether centers were comparable in patient treatment; particularly, "optimal" opioid treatment may vary between countries
* Multiple testing only controlled for pain and sleep disruption
}}

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

2024-11-26T17:10:58Z

DDeel:

{{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 two 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 (each THC 2.5mg/CBD 2.5mg) 3x daily from 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 and placebo arm (31% vs. 7%, p=0.002):
* Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03)
* No differences for disorientation (p=0.5) and anxiety (p=1.00)
* No cannabinoid-related serious adverse events 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 and placebo arm (31% vs. 7%, p=0.002):
* Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03)
* No differences for disorientation (p=0.5) and anxiety (p=1.00)
* No cannabinoid-related serious adverse events 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
}}

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

2024-11-26T17:10:47Z

DDeel:

{{Reference
|Reference=Publication: Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial
}}
{{Study Note}}
=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 two 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 (each THC 2.5mg/CBD 2.5mg) 3x daily from 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 and placebo arm (31% vs. 7%, p=0.002):
* Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03)
* No differences for disorientation (p=0.5) and anxiety (p=1.00)
* No cannabinoid-related serious adverse events 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 and placebo arm (31% vs. 7%, p=0.002):
* Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03)
* No differences for disorientation (p=0.5) and anxiety (p=1.00)
* No cannabinoid-related serious adverse events 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
}}

Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies

2024-11-26T17:05:51Z

DDeel:

{{Reference
|Reference=Publication: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies
}}
{{Study Note
|Study Note=This is the second study [[Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]]

First study: [[Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].
}}
=Brief summary=
Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one arm (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other arm a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients, who then showed an improvement in pain perception of at least 15%, were then randomly divided into two arms to receive either Sativex® or a placebo.
In the first study 399 and in the second study (after division into arms) 206 patients were included. After five weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the first study did the Sativex® arm show improvement in some of the questionnaires (personal and physician-assessed improvement). In the second study, there were no differences between the arms in the questionnaires.

Both studies are characterised by a large sample size and a well thought-out statistical analysis. However, as the studies were conducted in centres all over the world, it should be noted that it cannot be assumed that all patients received the same basic care (especially in opioid care). In addition, both studies were funded by a pharmaceutical industry.

In diesem Artikel wurden zwei Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der zweiten Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten, die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten, wurden anschließend zufällig in zwei Gruppen eingeteilt, um entweder weiterhin Sativex® oder ein Placebo zu bekommen.
In der ersten Studie wurden 399 und in der zweiten Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach fünf Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der ersten Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der zweiten Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.
Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden, ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.

=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 incurable stage of cancer; ≥18years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
|Exclusion criteria=Baseline use of morphine at >500mg 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 including recreational use of cannabis product
|N randomized=399
|Analysis=ITT Analysis
|Specifications on analyses=Procedure
Part A: all received Sativex® for 10 days, then 4 days therapy at adjusted dose; patients who showed an improvement of at least 15% for pain (NRS) entered Part B: randomized in A or B with intervention for 5 weeks, follow-up 2 weeks later

Discussed is part B of the study.
|Countries of data collection=Australia, Bulgaria, Germany, Hungary, India, Israel, Italy, Lithuania, Poland, Romania, Spain, Taiwan, United Kingdom
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: after 3 weeks (day 22)

T2: after 5 weeks (day 36)

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

{{Characteristics of participants
|Setting=NI
|Types of cancer=Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Chest Cancer, Eye Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Prostate Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, Skin Cancer, Bone and Soft Tissue Cancers, Gastrointestinal Cancers - Esophageal Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Part A

Female = 176 (43.6%)

Part B

Sativex = 40 (38.8%) female

Placebo = 48 (46.6%) female
|Age groups=Adults (18+)
|Age groups specification=Part A
Mean (SD) age: 61.2 (11.2) years

Part B

Mean (SD) age per arm:

Sativex = 61.4 (10.9) years

Placebo = 61.6 (11.8) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=103
|Drop-out=Discontinued n=25

Died during study n=23

Study completed n=78
|Drop-out reasons=Adverse Events n=21

Withdrew consent n=2

Withdrawn by investigator n=1

Lack of efficacy n=1

Died during treatment n=23

Died post-treatment but before follow-up n=8

Died post follow-up n=3
|Intervention=Sativex
|Dosage and regime=Sativex® (nabiximol, THC 27 mg/mL, CBD 25 mg/mL) via oral spray (self-applied by patient)
Week 1: dose finding; week 2-5: stable dose, max. 10 sprays

* Part A: first week average number of sprays = 3.6; second week = 6.4
* Part B: average daily number = 6.5
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Part A

Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n = 128, 31.7%, somnolence (n = 42, 10.4%), nausea (n = 21, 5.2%) and dizziness (n = 21, 5.2%)

Part B

Overall 72% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n = 16, 15.5%; somnolence (n = 6, 5.8%)

More than twice as many patients in Sativex arm discontinued study due to side effects (n = 14, 13.6% vs. n = 6, 5.8%); no statistical comparison given)

None of the deaths related to intervention
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=103
|Drop-out=Discontinued n=15

Died during study n=9

Study completed n=88
|Drop-out reasons=Adverse Events n=13

Withdrawn by investigator n=1

Lack of efficacy n=1

Died during treatment n=9
|Intervention=Placebo
|Dosage and regime=Week 1: dose finding; week 2-5: stable dose, max. 10 sprays

Part A

First week average number of sprays = 3.6, Second week = 6.4

Part B

Average daily number = 6.3
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Part A

Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n = 128, 31.7%, somnolence (n = 42, 10.4%), nausea (n = 21, 5.2%) and dizziness (n = 21, 5.2%)

Part B

Overall 62% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n = 12, 11.7%; somnolence n = 0
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Change in NRS value for moderate pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Deterioration in both arms after 5 weeks:
* Sativex arm: from 3.2 to 3.7, Placebo arm: 3.1 to 3.6. (treatment effect -0.02; 95% CI: -0.42, 0.38; p = 0.917)
* No differences for individual subgroups (no US patients in this study)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=Median improvement in pain with NRS in %
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=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 arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Sleep
|Outcome specification=Extent of sleep disturbance (assessed with NRS)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Additional medication
|Outcome specification=General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|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=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (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=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
|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=* high drop-out due to side effects or withdrawal of consent in Phase A
* not fitting the inclusion criteria (failure to demonstrate a 15% improvement in average pain NRS score during titration)
|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=* More and cannabinoid typical side effects in intervention arms, knowledge of assignment could have influenced the result.
* 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=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=?
|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
* Arms comparable at baseline
* Power analysis conducted
* Multiple testing controlled for endpoints pain and sleep disruption
* Intent-to-Treat analysis performed

CONTRA:
* High dropout rate (due to study discontinuation or death)
* No information on whether centers were comparable in patient treatment; particularly, "optimal" opioid treatment may vary between countries
* Multiple testing only controlled for pain and sleep disruption
}}

Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies

2024-11-26T17:05:01Z

DDeel:

{{Reference
|Reference=Publication: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies
}}
{{Study Note
|Study Note=This is the second study [[Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]]

First study: [[Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].
}}
=Brief summary=
Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one arm (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other arm a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients, who then showed an improvement in pain perception of at least 15%, were then randomly divided into two arms to receive either Sativex® or a placebo.
In the first study 399 and in the second study (after division into arms) 206 patients were included. After five weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the first study did the Sativex® arm show improvement in some of the questionnaires (personal and physician-assessed improvement). In the second study, there were no differences between the arms in the questionnaires.

Both studies are characterised by a large sample size and a well thought-out statistical analysis. However, as the studies were conducted in centres all over the world, it should be noted that it cannot be assumed that all patients received the same basic care (especially in opioid care). In addition, both studies were funded by a pharmaceutical industry.

In diesem Artikel wurden zwei Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der zweiten Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten, die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten, wurden anschließend zufällig in zwei Gruppen eingeteilt, um entweder weiterhin Sativex® oder ein Placebo zu bekommen.
In der ersten Studie wurden 399 und in der zweiten Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach fünf Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der ersten Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der zweiten Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.
Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden, ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.

=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 incurable stage of cancer; ≥18years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
|Exclusion criteria=Baseline use of morphine at >500mg 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 including recreational use of cannabis product
|N randomized=399
|Analysis=ITT Analysis
|Specifications on analyses=Procedure
Part A: all received Sativex® for 10 days, then 4 days therapy at adjusted dose; patients who showed an improvement of at least 15% for pain (NRS) entered Part B: randomized in A or B with intervention for 5 weeks, follow-up 2 weeks later

Discussed is part B of the study.
|Countries of data collection=Australia, Bulgaria, Germany, Hungary, India, Israel, Italy, Lithuania, Poland, Romania, Spain, Taiwan, United Kingdom
|LoE=Level 2 Oxford 2011
|Outcome timeline=T0: baseline

T1: after 3 weeks (day 22)

T2: after 5 weeks (day 36)

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

{{Characteristics of participants
|Setting=NI
|Types of cancer=Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Breast Cancer, Chest Cancer, Eye Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Prostate Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, Skin Cancer, Bone and Soft Tissue Cancers, Gastrointestinal Cancers - Esophageal Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=NI
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Part A

Female = 176 (43.6%)

Part B

Sativex = 40 (38.8%) female

Placebo = 48 (46.6%) female
|Age groups=Adults (18+)
|Age groups specification=Part A
Mean (SD) age: 61.2 (11.2) years

Part B

Mean (SD) age per arm:

Sativex = 61.4 (10.9) years

Placebo = 61.6 (11.8) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=103
|Drop-out=Discontinued n=25

Died during study n=23

Study completed n=78
|Drop-out reasons=Adverse Events n=21

Withdrew consent n=2

Withdrawn by investigator n=1

Lack of efficacy n=1

Died during treatment n=23

Died post-treatment but before follow-up n=8

Died post follow-up n=3
|Intervention=Sativex
|Dosage and regime=Sativex® (nabiximol, THC 27 mg/mL, CBD, 25 mg/mL) via oral spray (self-applied by patient)

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

* Part A: first week average number of sprays = 3.6; second week = 6.4
* Part B: average daily number = 6.5
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Part A

Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n = 128, 31.7%, somnolence (n = 42, 10.4%), nausea (n = 21, 5.2%) and dizziness (n = 21, 5.2%)

Part B

Overall 72% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n = 16, 15.5%; somnolence (n = 6, 5.8%)

More than twice as many patients in Sativex arm discontinued study due to side effects (n = 14, 13.6% vs. n = 6, 5.8%); no statistical comparison given)

None of the deaths related to intervention
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=103
|Drop-out=Discontinued n=15

Died during study n=9

Study completed n=88
|Drop-out reasons=Adverse Events n=13

Withdrawn by investigator n=1

Lack of efficacy n=1

Died during treatment n=9
|Intervention=Placebo
|Dosage and regime=Week 1: dose finding; week 2-5: stable dose, max. 10 sprays

Part A

First week average number of sprays = 3.6, Second week = 6.4

Part B

Average daily number = 6.3
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Part A

Overall 60% at least one event, assessed as probably intervention-associated with frequency ≥ 5%: Total n = 128, 31.7%, somnolence (n = 42, 10.4%), nausea (n = 21, 5.2%) and dizziness (n = 21, 5.2%)

Part B

Overall 62% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n = 12, 11.7%; somnolence n = 0
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Change in NRS value for moderate pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=Deterioration in both arms after 5 weeks:
* Sativex arm: from 3.2 to 3.7, Placebo arm: 3.1 to 3.6. (treatment effect -0.02; 95% CI: -0.42, 0.38; p = 0.917)
* No differences for individual subgroups (no US patients in this study)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=Median improvement in pain with NRS in %
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=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 arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Sleep
|Outcome specification=Extent of sleep disturbance (assessed with NRS)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Additional medication
|Outcome specification=General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Results during intervention=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|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=No arm differences after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=?
|Bias due to deviation from intended intervention (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=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=6
|Outcome topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
|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=* high drop-out due to side effects or withdrawal of consent in Phase A
* not fitting the inclusion criteria (failure to demonstrate a 15% improvement in average pain NRS score during titration)
|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=* More and cannabinoid typical side effects in intervention arms, knowledge of assignment could have influenced the result.
* 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=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=?
|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
* Arms comparable at baseline
* Power analysis conducted
* Multiple testing controlled for endpoints pain and sleep disruption
* Intent-to-Treat analysis performed

CONTRA:
* High dropout rate (due to study discontinuation or death)
* No information on whether centers were comparable in patient treatment; particularly, "optimal" opioid treatment may vary between countries
* Multiple testing only controlled for pain and sleep disruption
}}

Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies

2024-11-26T17:03:03Z

DDeel:

{{Reference
|Reference=Publication: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies
}}
{{Study Note
|Study Note=This is the first study [[Fallon et al. (2017) I: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].

Second study: [[Fallon et al. (2017) II: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies]].
}}
=Brief summary=
Two studies were reported in this article. Both studies included patients with various advanced cancers who suffered from pain despite optimized opioid therapy. In both studies, one arm (randomized) received Sativex® (containing THC and CBD) daily for 35 days and the other arm a placebo. The first 14 days were used to adjust the dose, which varied from patient to patient throughout the study. In both studies, the percentage improvement in pain perception was measured, as well as the change in average pain, the value of the worst pain, the extent of sleep disturbance, the amount of opioids taken and several questionnaires on the patient's own satisfaction, their own assessment of the change and constipation. A special feature of the second study was that all patients included were initially given Sativex® for 14 days. All patients, who then showed an improvement in pain perception of at least 15%, were then randomly divided into two arms to receive either Sativex® or a placebo.

In the first study 399 and in the second study (after division into arms) 206 patients were included. After five weeks, there was no significant difference in the percentage improvement in pain perception, change in mean pain, score of worst pain, extent of sleep disturbance or amount of opioid intake. Only in the first study did the Sativex® arm show improvement in some of the questionnaires (personal and physician-assessed improvement). In the second study, there were no differences between the arms in the questionnaires.

Both studies are characterised by a large sample size and a well thought-out statistical analysis. However, as the studies were conducted in centres all over the world, it should be noted that it cannot be assumed that all patients received the same basic care (especially in opioid care). In addition, both studies were funded by a pharmaceutical industry.

In diesem Artikel wurden zwei Studien berichtet. Beide Studien schlossen Patienten mit verschiedenen fortgeschrittene Krebsarten ein, welche trotz optimierter Opioid Therapie unter Schmerz leiden. In beiden Studien bekam (zufällig eingeteilt) eine Gruppe täglich Sativex® (enthält THC und CBD) für 35 Tage und die andere ein Placebo. Die ersten 14 Tage dienten der Einstellung der Dosis und diese war über die Studie unterschiedlich von Patient zu Patient. Gemessen wurde in beiden Studien die prozentuale Verbesserung des Schmerzempfindens, sowie die Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung, Menge der Einnahme von Opioiden sowie einige Fragebögen zur eigenen Zufriedenheit, der eigenen Einschätzung der Veränderung und Verstopfung. Besonderheit der zweiten Studie war, dass zunächst alle eingeschlossenen Patienten für 14 Tage Sativex® bekamen. Alle Patienten, die danach eine Verbesserung des Schmerzempfindens von mindestens 15% zeigten, wurden anschließend zufällig in zwei Gruppen eingeteilt, um entweder weiterhin Sativex® oder ein Placebo zu bekommen.

In der ersten Studie wurden 399 und in der zweiten Studie (nach Aufteilung in Gruppen) 206 Patienten eingeschlossen. Nach fünf Wochen zeigte sich kein bedeutsamer Unterschied in der prozentualen Besserung des Schmerzempfindens, sowie Veränderung des mittleren Schmerzes, Wert des schlimmsten Schmerzes, Ausmaß von Schlafstörung oder Menge der Einnahme von Opioiden. Einzig in der ersten Studie zeigten sich für die Sativex® Gruppe Verbesserung in einigen der Fragebögen (persönliche und vom Arzt eingeschätzte Besserung). In der zweiten Studie zeigten sich in den Fragebögen keine Unterschiede zwischen den Gruppen.

Beide Studien zeichnen sich durch eine große Stichprobe und eine durchdachte statistische Analyse aus. Da die Studien in Zentren über die ganze Welt durchgeführt wurden, ist jedoch zu beachten, dass nicht davon ausgegangen werden kann, dass alle Patienten die gleiche Grundversorgung (insbesondere in der Opioidversorgung) bekamen. Zudem wurden beide Studien von einer Pharmaindustrie finanziert.

=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 incurable stage of cancer; ≥ 18 years of age; clinical diagnosis of cancer-related pain unalleviated by an optimized maintenance dose of Step 3 opioid therapy; ≤ 4 opioid breakthrough analgesic episodes per day (averaged over the 3 days); stable maintenance opioid therapy dose; average pain ≥ 4 and ≤ 8 on a 0–10 NRS; average pain scores on the NRS that did not change by more than 2 points from the beginning to end of screening (i.e. no more than a 2-point difference between the highest and lowest scores, with all scores remaining between 4 and 8
|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 including recreational use of cannabis product
|N randomized=399
|Analysis=ITT Analysis
|Specifications on analyses=n = 2 no intervention received

Wilcoxon rank-sum test was conducted for percent improvement in average pain NRS score (from baseline to end of treatment in study 1, and from eligibility
pre-treatment baseline to end of treatment in study 2).
Analysis of covariance (ANCOVA) was applied on the primary and the key secondary efficacy endpoints, including percent improvement, average pain/worst pain/sleep disruption scores, with corresponding baseline value as a covariate and treatment group as a factor. The time-course of these four efficacy endpoints from week 1 through week 5 was also analysed using Mixed-Effect Model Repeat Measurement (MMRM) on the ITT analysis set in both studies.

For both study 1 and study 2, the primary endpoint and the key secondary endpoints were tested with their Type I error controlled by use of a hierarchical gate-keeping procedure.

In each study, p-values from Wilcoxon rank-sum tests on percent improvement and ANCOVA on average pain/worst pain/sleep disruption scores were used for the hierarchical gate-keeping procedure in the sequence of the primary endpoint and the key secondary endpoints. No adjustments for covariates were made for the analyses of the other secondary endpoints in both studies with analysis of variance (ANOVA), including PGIC, SGIC or PSQ, and daily total, maintenance, and breakthrough opioid dose. Subgroup analyses for region (United States and rest of world (ROW)) were performed for the primary and the key secondary endpoints.
|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 (day 22)

T2: after 5 weeks (day 36)

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

{{Characteristics of participants
|Setting=NI
|Types of cancer=Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Gallbladder Cancer, Gastrointestinal Cancers - Liver Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Stomach Cancer, Gastrointestinal Cancers, Prostate Cancer, Lung Cancer, Genitourinary Cancers - Bladder Cancer, Brain and Central Nervous System (CNS) Cancers, Chest Cancer, Eye Cancer, Gynecologic Cancers - Cervical Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Uterine Cancer, Genitourinary Cancers, Head and Neck Cancers, Hematologic Cancers, Genitourinary Cancers - Kidney (Renal) Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Skin Cancer, Bone and Soft Tissue Cancers, Gastrointestinal Cancers - Esophageal Cancer, Other Cancers
|Stage cancer=Advanced Stage
|Cancer stage specification=Mean (SD) time since cancer diagnosis per arm:

Sativex = 4.1 (4.2) years

Placebo = 3.5 (5.0) years
|Comorbidity=Pain that could not be improved even with optimized opioid therapy (NRS ≥ 4 and ≤ 8)
|Current cancer therapy=NI
|Specifications on cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender specifications=Male, n(%) per arm:

Sativex = 106 (53.0)

Placebo = 97 (48.7)

Female, n(%) per arm:

Sativex = 194 (47.0)

Placebo = 102 (51.3)
|Age groups=Adults (18+)
|Age groups specification=Mean (SD) age per arm:

Sativex = 60 (11) years

Placebo = 59.6 (11) years
}}
=Arms=

{{Arm
|Arm type=Intervention
|Number of participants (arm)=200
|Drop-out=64
|Drop-out reasons=Side effects (n = 38, 19%); consent withdrawn (n = 19, 9.5%); death (n = 20, 10%)
|Intervention=Sativex
|Dosage and regime=Sativex® (Nabiximol, THC 27 mg/mL, CBD 25 mg/mL) via oral spray (self-applied by patient)
* week 1: dose finding; week 2-5: stable dose, max. 10 sprays
* first week mean number of sprays = 3.7, stabilized over 4 weeks (6.3 sprays per day)
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Overall 68% at least one event; assessed as probably intervention-associated with frequency ≥ 5%:
Total n = 64 (32.2%), of which somnolence n = 18 (9%), dizziness n = 15 (7.5%), nausea n = 10 (5%)

2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)

None of the deaths related to intervention
|Order number=1
|Arm topic=Cannabinoids
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=199
|Drop-out=41
|Drop-out reasons=Side effects (n = 29, 14.6%), consent withdrawn (n = 8, 4%), death (n = 25, 68%)
|Intervention=Placebo
|Dosage and regime=First week mean number of sprays 3.7, stabilized over 4 weeks (7.4 sprays per day)
|One-time application=No
|Duration in days=36
|Side Effects / Interactions=Overall 64% at least one event; assessed as probably intervention-associated with frequency ≥ 5%: Total n = 41 (20.7%), of which somnolence n = 6 (3%), dizziness n = 6 (3%), nausea n = 8 (4%)

2 severe side effects associated with intervention: 1x constipation (with 360mg/day morphine equivalents), 1x moderate disorientation and somnolence on day 4 (with 2.5 daily sprays of Sativex)

None of the deaths related to intervention
|Order number=2
|Arm topic=Cannabinoids
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Pain
|Outcome specification=Median improvement in pain with NRS in %
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No significant difference after 5 weeks
* Sativex arm = 7.2% vs. placebo arm = 9.5% (median difference = −1.84%; CI: −6.19%, 1.50%; p=0.274, not significant)

Subgroup analysis with US population
* shows effects for Sativex arm (p=0.03), especially for patients under 65 years of age
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 average pain
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No differences between arms after 5 weeks (no p-value)
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=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 differences between arms after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=3
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=Extent of sleep disturbance (assessed with NRS)
|Type of measurement=NRS (Numeric Rating Scale)
|Results during intervention=No differences between arms after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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=4
|Outcome topic=Cannabinoids
}}
{{Outcome
|Outcome type=Secondary
|Outcome name=Pain
|Outcome specification=General intake, appropriate opioid intake for breakthrough pain and total opioid intake per day in morphine equivalents
|Type of measurement=Observation
|Results during intervention=No differences between arms after 5 weeks (no p-value).
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 topic=Cannabinoids
}}
{{Outcome
|Outcome type=Others
|Outcome name=Quality of life
|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=Results:
* Higher change in SGIC for global impression and better change assessed by physician in 'general functional ability' of Sativex arm compared to placebo arm
* Scores in SGIC better in Sativex arm at week 3 (p = 0.041), 5 (p = 0.022) and last visit (p = 0.022)
* PGIC better at week 5 (p=0.037) compared to placebo arm
|Results after intervention=NI
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|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 topic=Cannabinoids
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{Funding and Conflicts of Interest
|Funding=Funding for the study was obtained from Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
|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=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* More and cannabinoid typical side effects in intervention arms, knowledge of assignment could have influenced the result.
* 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=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
}}
{{Additional Notes
|Additional Notes=PRO:
* Ethical approval obtained
* Arms comparable at baseline
* Power analysis conducted
* Multiple testing controlled for endpoints pain and sleep disruption
* Intent-to-Treat analysis performed

CONTRA:
* High dropout rate (due to study discontinuation or death)
* No information on whether centers were comparable in patient treatment; particularly, "optimal" opioid treatment may vary between countries
* Multiple testing only controlled for pain and sleep disruption
}}

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

2024-11-26T16:58:13Z

DDeel:

{{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 radiotherapy: 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=0.32), anxiety (p=0.92) and xerostomia (p=0.83)
|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=Placebo tablets
* once a day before radiotherapy in the first week
* twice a day in the second week
* third week until end of radiotherapy: 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=0.32), anxiety (p=0.92) and xerostomia (p=0.83)
|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=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
|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
}}

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

2024-11-26T16:56:56Z

DDeel:

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

2024-11-26T16:56:47Z

DDeel:

{{Reference
|Reference=Publication: Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial
}}
{{Study Note}}
=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 radiotherapy: 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=0.32), anxiety (p=0.92) and xerostomia (p=0.83)
|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=Placebo tablets
* once a day before radiotherapy in the first week
* twice a day in the second week
* third week until end of radiotherapy: 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=0.32), anxiety (p=0.92) and xerostomia (p=0.83)
|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=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
|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
}}

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

2024-11-26T16:50:07Z

DDeel:

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

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

=Study Design=

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

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

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

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

Start: day 0 radiotherapy

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

Start: day 0 radiotherapy

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

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

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

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

* Grade 4: Intervention arm and Placebo arm: 0

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

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

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

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

* 21 days: Intervention arm: 9 (47.4%), Placebo arm: 6 (33.3%)
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Burning Sensation in the mouth
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=Significant difference between intervention vs. placebo arm in mean (SD):
intervention 3.7 (2.1) vs. placebo 7.9 (2.0); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Erythema
|Outcome specification=Oral mucosal erythema
|Type of measurement=Observation
|Results during intervention=Significant difference between intervention vs. placebo arm for max. size in mm (mean (SD)):
intervention 4.9 (2.2) vs. placebo 8.9 (2.7); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Oral ulcus
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=Significant difference between intervention vs. placebo arm for max. size in mm (mean (SD)):
intervention 1.3 (2.7) vs. placebo 6.4 (4.2); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

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

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

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

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

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

2024-11-26T16:49:49Z

DDeel:

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

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

=Study Design=

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

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

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

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

Start: day 0 radiotherapy

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

Start: day 0 radiotherapy

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

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

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

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

* Grade 4: Intervention arm and Placebo arm: 0

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

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

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

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

* 21 days: Intervention arm: 9 (47.4%), Placebo arm: 6 (33.3%)
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=1
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Mucositis
|Outcome specification=Burning Sensation in the mouth
|Type of measurement=VAS (Visual Analogue Scale)
|Results during intervention=Significant difference between intervention vs. placebo arm in mean (SD):
intervention 3.7 (2.1) vs. placebo 7.9 (2.0); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=2
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Erythema
|Outcome specification=Oral mucosal erythema
|Type of measurement=Observation
|Results during intervention=Significant difference between intervention vs. placebo arm for max. size in mm (mean (SD)):
intervention 4.9 (2.2) vs. placebo 8.9 (2.7); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=3
|Outcome topic=Curcumin
}}
{{Outcome
|Outcome type=Primary
|Outcome name=Oral ulcus
|Outcome specification=NA
|Type of measurement=Observation
|Results during intervention=Significant difference between intervention vs. placebo arm for max. size in mm (mean (SD)):
intervention 1.3 (2.7) vs. placebo 6.4 (4.2); p < 0.001
|Results after intervention=NA
|Bias arising from the randomization process=some concerns
|Bias due to deviation from intended intervention (assignment to intervention)=low risk
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=some concerns
|Other sources of bias=some concerns
|Overall RoB judgment=some concerns
|Order number=4
|Outcome topic=Curcumin
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

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

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

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

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

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

2024-11-26T16:44:21Z

DDeel:

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

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

=Study Design=

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

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

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

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

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

Start: Day 1 radiotherapy, 6 times daily

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

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

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

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

''Cases of intolerable mucositis:''

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

Number of days lost: mean (SD)

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

Weight loss: mean (SD)

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

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

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

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

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

2024-11-26T16:43:56Z

DDeel:

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

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

=Study Design=

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

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

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

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

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

Start: Day 1 radiotherapy, 6 times daily

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

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

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

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

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

Number of days lost: mean (SD)

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

Weight loss: mean (SD)

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

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

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

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

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

2024-11-26T16:43:28Z

DDeel:

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

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

=Study Design=

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

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

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

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

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

Start: Day 1 radiotherapy, 6 times daily

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

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

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

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

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

Number of days lost: mean (SD)

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

Weight loss: mean (SD)

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

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

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

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

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

2024-11-26T16:40:17Z

DDeel:

{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 and placebo arm; 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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 and placebo arm ; 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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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

2024-11-26T16:38:52Z

DDeel:

{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 and placebo arm; 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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 and placebo arm ; 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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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

2024-11-26T16:36:59Z

DDeel:

{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 and placebo arm; 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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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

2024-11-26T16:36:01Z

DDeel:

{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 (mean(SD)=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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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 topic=Selenium
}}
{{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.
}}