Kirste et al. (2011): Boswellia serrata Acts on Cerebral Edema in Patients Irradiated for Brain Tumors. A Prospective, Randomized, Placebo-Controlled, Double-Blind Pilot Trial

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Title	Boswellia serrata Acts on Cerebral Edema in Patients Irradiated for Brain Tumors A Prospective, Randomized, Placebo-Controlled, Double-Blind Pilot Trial
Topic	Boswellia serrata
Author	Kirste, S, Treier, M, Wehrle, SJ, Becker, G, Abdel-Tawab, M, Gerbeth, K, Hug, MJ, Lubrich, B, Grosu, AL, Momm, F
Year	2011
Journal	Wiley Online Library
DOI	https://doi.org/10.1002/cncr.25945

Brief summary

Cerebral edema is a common side effect in patients undergoing radiotherapy for brain tumors. In this study, researchers investigated the effect of Boswellia serrata H15 (BS-H15) on cerebral edema in patients undergoing radiotherapy for brain tumors. At the start of their radiotherapy, half of the patients took 4200mg/day of Boswellia serrata H15 and the other half took a placebo (consisting of lactose), which they continued throughout the duration of their radiotherapy. At the end of treatment, patients taking the BS-H15 had less cerebral edema than patients taking the sugar placebo. However, this positive effect of BS-H15 waned four weeks later. About a quarter of patients taking BS-H15 (6/22) have diarrhea during treatment.

Ein zerebrales Ödem ist eine häufige Nebenwirkung bei Patienten, die sich einer Strahlentherapie wegen Hirntumoren unterziehen. In dieser Studie untersuchten die Forscher die Wirkung von Boswellia serrata H15 (BS-H15) auf das zerebrale Ödem bei Patienten, die sich einer Strahlentherapie für Hirntumore unterziehen. Zu Beginn ihrer Strahlentherapie nahm die Hälfte der Patienten 4200mg/Tag Boswellia Serrata H15 und die andere Hälfte ein Placebo (bestehend aus der Milchzuckerlaktose) ein, dass sie während der gesamten Dauer ihrer Strahlentherapie fortsetzten. Am Ende der Behandlung hatten Patienten, die das BS-H15 einnahmen, weniger zerebrale Ödeme als Patienten, die das Zucker-Placebo einnahmen. Dieser positive Effekt des BS-H15 ließ jedoch vier Wochen später nach. Etwa ein Viertel der Patienten, die BS-H15 (6/22) einnehmen, haben während der Therapie Durchfall.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Primary brain tumor/brain metastases, Radiotherapy of whole or part of the brain (>60% of brain irradiated) with a dose of 30-60 Gray in a fractionation of 5 " 1.8-3.0 Gray/week, No former radiotherapy in the brain
Exclusion criteria	Karnofsky index <50, Dexamethasone >24 mg/day before radiotherapy
N randomized	44
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	Wilcoxon rank test 2-sided testing
Countries of data collection	Germany
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline at the beginning of radiotherapy, T1: At the end of radiotherapy, Follow-up: After 4 weeks end of radiotherapy

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Brain and Central Nervous System (CNS) Cancers - Glioblastoma
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Irradiation of the entire brain or at least 60 % with a dose of 30-60 Gray fractionated over 5 x 1.8-3.0 Gray/week
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	45 % female
Age groups	Adults (18+)
Age groups specification	Mean value (range): Intervention arm: 60 years (32-74 years), Placebo arm: 58 years (39-83 years)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	22
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Could not swallow capsules n = 1 Refused to swallow capsules n = 1
Intervention	Boswellia capsule, dried extract: H15 (350 mg; Hecht Pharma, Stinstedt, Germany)
Dosage and regime	4200 mg/day (3x4 capsules/day) Starting with the first day of radiotherapy, Ending with the last day of radiotherapy
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	6 Patients reported minor gastrointestinal discomfort, Diarrhea (level 1-2)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	22
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Refused to swallow capsules n = 1 Epileptic seizure grade 4, discontinued therapy n = 1
Intervention	Placebo capsules (Lactose)
Dosage and regime	84 capsules for 1 week (3x4 capsules/day starting with the first day of radiotherapy)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	No side effects reported.

Outcomes

"Others" is not in the list (AQoL-8D (Assessment of Quality of Life), ASAT (Auditory Sustained Attention Test), BIA (Bioelectrical impedance analysis), BPI-SF (Brief Pain Inventory - Short Form), CTCAE (Common Terminology Criteria of Adverse Events), ESAS (Edmonton Symptom Assessment Scale), FAACT (Functional Assessment of Anorexia-Cachexia Therapy), FACIT (Functional Assessment of Chronic Illness Therapy), FLIE (Functional Living Index for Emesis), Genitourinary atrophy self-assessment tool, ...) of allowed values for the "Type of measurement" property.

"Further medication" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

Cerebral oedema

Outcome type As specificed by the authors	Primary
Outcome specification	T2-weighted magnetic resonance imaging (MRI) after therapy compared with volume at baseline
Type of measurement	MRI (Magnetic Resonance Imaging)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Volume of cerebral edema: Significantly greater reduction of edema in the boswellia arm (reduction of 75%: 60% of patients) compared to the placebo arm (reduction of 75%: 26% of patients), p=0.023, Baseline: placebo: 188.4 mL (range, 0-617.3 mL), intervention: 159.3 mL (range, 0-506.2 mL) After radiotherapy: placebo: 97.4 mL (range, 0-346.8 mL) intervention: 45.7 (range, 0-264.0 mL) Follow-up after 4 weeks: placebo: 83.3 mL (range, 0-352.7 mL), intervention: 73.9 mL (range, 0-413.1 mL)

Risk of Bias Assessment: Cochrane RoB tool 2.0
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	?

Tumor progression

Outcome type As specificed by the authors	Primary
Outcome specification	T2-weighted magnetic resonance imaging (MRI) after therapy compared with volume at baseline
Type of measurement	MRI (Magnetic Resonance Imaging)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Tumor volume: Significantly lower tumor volume in the Boswellia arm (2.9cm3) compared to the placebo arm (16.1cm3), p=0.008, Tendentially fewer patients with progressive disease in Boswellia arm (0%) compared to placebo arm (18%) Baseline: placebo: ratio = 0.11, intervention: ratio = 0.15 After radiotherapy: placebo: ratio = 0.15, intervention: ratio = 0.06

Risk of Bias Assessment: Cochrane RoB tool 2.0
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	?

Tumor response

Outcome type As specificed by the authors	Primary
Outcome specification	T2-weighted magnetic resonance imaging (MRI) after therapy compared with volume at baseline
Type of measurement	RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Tendency for fewer patients with progressive disease in boswellia (0%) compared to placebo (18%)

Risk of Bias Assessment: Cochrane RoB tool 2.0
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	?

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No difference between the 2 arms, p = .68

Risk of Bias Assessment: Cochrane RoB tool 2.0
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	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline: average score, placebo: 55.9 points, intervention: 54.3 points, After radiotherapy: placebo: 56.2 points, intervention: 58.6 points, Follow-up after 4 weeks: placebo: 53.8 points, intervention: 61.3 points

Risk of Bias Assessment: Cochrane RoB tool 2.0
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	?

Cognitive impairment

Outcome type As specificed by the authors	Secondary
Outcome specification	Mental Functioning
Type of measurement	MMSE (Mini-Mental State Exam)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Baseline: average score, placebo: 28 points, intervention: 29 points, After radiotherapy: placebo: 28 points, intervention: 27 points, Follow-up after 4 weeks: placebo: 26 points, intervention: 29 points

Risk of Bias Assessment: Cochrane RoB tool 2.0
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	?

Additional medication

Outcome type As specificed by the authors	Secondary
Outcome specification	Dexamethasone
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No differences between the groups during irradiation (boswellia: 0-84mg/week; placebo: 0-112mg/week)

Risk of Bias Assessment: Cochrane RoB tool 2.0
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	?

Funding and Conflicts of Interest

Funding	No information on financing.
Conflicts of Interest	No information on conflicts of interest.

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?