Skip to main content
NCBI home page
Advances in Radiation Oncology logoLink to Advances in Radiation Oncology
. 2025 Feb 1;10(4):101732. doi: 10.1016/j.adro.2025.101732

Boswellia serrata for the Management of Radiation-Induced Cerebral Edema and Necrosis: A Systematic Meta-Narrative Review of Clinical Evidence

Cas Stefaan Dejonckheere a,⁎, Davide Scafa a, Lukas Käsmann b, Thomas Zeyen c, Anna-Laura Potthoff d, Niklas Schäfer c, Johannes Weller c, Ulrich Herrlinger c, Matthias Schneider d, Hartmut Vatter d, Anca-Ligia Grosu e, Stefanie Brehmer f, Frank Anton Giordano g,h,i, Gustavo Renato Sarria a, Eleni Gkika a, Julian Philipp Layer a,j
PMCID: PMC11904484  PMID: 40092573

Abstract

Purpose

Stereotactic radiosurgery (SRS) yields excellent local control in patients with a limited number of brain metastases (BMs), but radiation-induced cerebral edema and radiation necrosis (RN) in particular may cause dose-limiting late toxicity, with the same holding true after fractionated radiation therapy for glioma. In symptomatic patients, the first-line standard of care includes corticosteroids, which may, however, be counterproductive in the evolving era of immunotherapy. Boswellic acid (BA), available as an over-the-counter dietary supplement, has been suggested as a potential corticosteroid-sparing alternative because of its anti-inflammatory and antiangiogenic effects.

Methods and Materials

We performed a comprehensive literature search of the MEDLINE, Embase, Scopus, and Cochrane databases, identifying publications reporting on the use of BA during or after brain irradiation in humans. Using the Realist and Meta-Narrative Evidence Syntheses: Evolving Standards framework, relevant data are summarized using a meta-narrative approach.

Results

Six records (3 for edema reduction in large irradiated volumes and 3 for RN after SRS) were identified, encompassing 130 patients. Roughly half of patients benefited from BA (radiographically or clinically) and about one third could successfully taper dexamethasone or prevent its long-term intake. Tolerability of BA was favorable, with mild gastrointestinal discomfort being reported most frequently. Current drawbacks include unknown optimal formulation as well as timing and dosing, a considerably large number of required daily capsules, and uncertain interactions with other drugs.

Conclusions

Overall, the clinical evidence on the use of BA for radiation-induced cerebral edema and RN is lacking and well-designed prospective trials are warranted to further investigate this potential low-cost corticosteroid-sparing option.

Introduction

Stereotactic radiosurgery (SRS) is an effective treatment option for patients with a limited number of brain metastases (BMs), yielding high local control rates with less impact on cognitive functions than whole-brain radiation therapy (WBRT).1,2 Acute tolerability of SRS is mostly excellent; however, some patients might develop late side effects such as radiation necrosis (RN).3 This radiation therapy (RT)-associated necrotic process in healthy brain tissue can cause symptoms associated with raised intracranial pressure, focal neurologic deficits, or seizures, and has an estimated prevalence of around 5% to 10% depending on RT modality and concurrent systemic treatment.4, 5, 6 Other risk factors include (cumulative) radiation dose and fractionation as well as irradiated brain volume, the latter of particular importance, eg, in diffuse glioma, where large areas of brain are treated mostly with standard fractionation.7,8 Although its exact pathophysiology remains largely unclear, vascular changes resulting from endothelial injury are thought to be responsible for RN, ultimately leading to ischemia and parenchymal necrosis mediated by proinflammatory processes.9 With a median (range) development time of 8 (6-12) months after SRS, RN is a serious cause of morbidity and reduced quality of life in cancer patients.8 Furthermore, its radiological appearance may mimic tumor recurrence, potentially necessitating additional investigations (eg, perfusion magnetic resonance imaging [MRI] sequences or amino acid positron emission tomography or even histopathological confirmation to distinguish both.10

In symptomatic patients, RN management usually includes a moderate dose of corticosteroids (eg, dexamethasone).11 In the evolving era of immunotherapy with an increasing number of RT patients receiving concomitant systemic treatment, however, corticosteroids can counteract desired proimmunogenic effects, even significantly hampering survival outcomes.12,13 Furthermore, the prolonged intake of corticosteroids is associated with a broad range of side effects, including insomnia, myopathy, insulin resistance, or iatrogenic Cushing syndrome.14 Second-line therapies for corticosteroid-refractory RN include bevacizumab, laser interstitial thermal therapy, hyperbaric oxygen therapy, or salvage surgery. Each modality has its own spectrum of potential side effects, high treatment costs, or limited availability at specialized centers only.15 With a rising incidence of RN resulting from increased SRS utilization and improved imaging workflows, there is an urgent need for effective and low-cost management options.16

Boswellia serrata or Indian frankincense is an over-the-counter dietary supplement derived from the bark of a tropical tree.17 Its bioactive compound, boswellic acids (BAs), have been shown to possess anti-inflammatory properties, among other through inhibition of 5-lipoxygenase, cyclooxygenase-1, nuclear transcription factor kappa B, and tumor necrosis factor alpha.18, 19, 20 Particularly acetyl-11-keto-beta-boswellic acid (AKBA) in particular is a potent inhibitor of 5-lipoxygenase. Furthermore, in vitro studies have shown a potent inhibition of vascular endothelial growth factor-mediated angiogenesis and inhibition of cardiac graft rejection in mice to the same extent as high-dose corticosteroids.21,22

Early clinical evidence suggests beneficial effects of BA in the context of cerebral edema during and following RT, rendering it an attractive option to avoid prolonged corticosteroid intake in symptomatic patients or those likely to develop symptoms based on imaging findings (eg, large areas of edema).23 Given its low cost, general availability, and excellent safety profile, it has been commonly prescribed in brain tumor patients; however, this is largely based on anecdotal evidence. Herein, we aim to summarize the available clinical data on the use of BA in the context of cerebral edema and RN following RT (for both BMs and glioma), in preparation of a prospective clinical trial.

Methods and Materials

Search strategy

We performed a comprehensive literature search of the MEDLINE, Embase, Scopus, and Cochrane databases. All available publications from inception until October 31, 2024 matching relevant truncations related to “Boswellia” and “radiation” were screened based on title and abstract, without language restriction. Identified records were included if they reported on the use of Boswellia during or after brain irradiation in human subjects. Case reports and abstracts from scientific meetings were also considered. Additional records were identified by cross-searching the already included articles’ references, facilitated through network visualization using an artificial intelligence-powered mapping tool (ResearchRabbit by Human Intelligence Technologies Incorporated) (Fig. 1). To further extend the literature search, ClinicalTrials.gov was queried and an additional free internet search was performed. Literature research and selection were performed according to the Realist and Meta-Narrative Evidence Syntheses: Evolving Standards framework.24

Figure 1.

Figure 1

Open in a new tab

Literature research facilitated through network visualization using the artificial intelligence-powered mapping tool ResearchRabbit (Human Intelligence Technologies Incorporated).

Data collection

Following their inclusion, manuscripts, supplements, and trial protocols (where available) were read and relevant data summarized independently by 2 authors (CSD and JPL). All data were managed using Microsoft Excel version 16 (Microsoft, Redmond). Because of the overall scarcity of relevant data, reporting follows a meta-narrative approach. Grading of the level of evidence followed the 2011 Oxford Centre for Evidence-Based Medicine framework for data on prevention and therapy.25

Results

Of 26 records identified and screened, 7 were assessed for eligibility and 6 finally included in this meta-narrative review (Fig. 2).24 No ongoing trials with BA during or after brain irradiation were uncovered. Records are divided into the management of radiation-induced cerebral edema or RN, respectively.

Figure 2.

Figure 2

Open in a new tab

Flowchart of literature research and selection according to the Realist and Meta-Narrative Evidence Syntheses: Evolving Standards framework.24

Evidence in the context of radiation-induced cerebral edema

Streffer et al26 provided the first prospective evidence on BA use for cerebral edema management. Twelve patients (11 with glioma and 1 with BMs) with progressive cerebral edema (either RT-induced or secondary to tumor progression) were included and treated with 3 × 1200 mg of BA (as an H15 preparation) per day. Patients were either not taking corticosteroids or their dose had remained unaltered during the last month. Edema was successfully reduced in 2/7 (29%) patients with tumor progression-related edema and in 3/5 (60%) with treatment-related edema, with the latter improving clinically as well. In one quarter of patients, corticosteroids were reduced or completely withdrawn. No side effects related to BA intake were reported.

The only randomized trial was conducted by Kirste et al.27 In a double-blind placebo-controlled pilot trial, 44 patients undergoing fractionated RT of at least 60% of the brain volume received either 4200 mg BA or placebo daily during RT (25% had glioblastoma, 75% received WBRT for BMs). On its completion, a >75% reduction of cerebral edema (as assessed on T2-weighted MRI by independent neuroradiological review) was achieved in 60 versus 26% of patients receiving BA or placebo, respectively (P = .023). After 4 weeks, the difference between both groups was no longer present. Of note, initial tumor response (defined as volumetric shrinkage) was more pronounced in the BA group (P = .008), which might have contributed to the observed decrease in edema. Progression-free survival after a median follow-up time of 250 days was, however, comparable. Other radiation-related acute toxicity, cognition (mini-mental state examination), and quality of life (EORTC QLQ-C30) were not different between groups and neither was the prescription rate and cumulative dose of dexamethasone. Six patients in the BA group reported minor gastrointestinal discomfort (grade 1-2 diarrhea).

Finally, Di Pierro et al28 performed a pilot study recruiting 20 patients undergoing RT for glioblastoma. All patients were taking dexamethasone at the time of enrollment and received BA (as a lecithin-based formulation, with increased cerebral bioavailability) at a dose of 4500 mg daily, starting within the first week of RT until completion of standard temozolomide maintenance therapy, for a maximum of 34 weeks. The number of patients with reduced edema remained constant, whereas the proportion of patients with stable edema increased over time. Additionally, in a considerable number of patients, dexamethasone dose was decreased or remained unaltered. Data are summarized in Table 1.26, 27, 28

Table 1.

Overview of evidence of Boswellia in the context of radiation-induced cerebral edema

Author, year Region No. Type, LoE Entity Preparation and dose Response
Streffer et al (2001)26 Germany 12 prospective single arm, 2b glioma and BMs H15 at 1200 mg 3×/d edema reduced in 2/7 with tumor progression-related edema and in 3/5 with treatment-related leukoencephalopathy
Kirste et al (2011)27 Germany 44 randomized double-blind placebo-controlled pilot, 2b glioma and BMs H15 or placebo at 4200 mg/d during RT >75% reduction of edema in 60 versus 26% on RT completion (P = .023), initial tumor response more pronounced (P = .008)
Di Pierro et al (2019)28 Italy 20 longitudinal single arm pilot, 2b glioma lecithin-based at 4500 mg/d during RT and adjuvant TMZ number of patients with reduced edema remained constant, proportion of patients with stable edema increased
Open in a new tab

Abbreviations: BMs = brain metastases; LoE = level of evidence; RT = radiation therapy; TMZ = temozolomide.

Evidence in the context of radiation necrosis

Upadhyay et al29 report their single-institution experience with B serrata for the management of RN after SRS (median dose of 24 Gy in 3 fractions) for BMs. Fifty patients (RN grade 1, 2, and 3 in 22%, 72%, and 6%, respectively and developing after a median time of 10 months after SRS) received 4200 to 4500 mg of BA per day. Complete or partial response (as per Response Assessment in Neuro-Oncology criteria) was observed in 55% of patients. This was achieved within 1 year of initiating BA and lasted between 2 and 31 months. Of about half of the patients suffering from symptomatic RN, one third showed symptom improvement with BA alone and thus avoided corticosteroid intake. Three patients only experienced grade 1 to 2 gastrointestinal intolerance or diarrhea.

The same authors published 1 additional case report of a patient undergoing fractionated SRS of 24 Gy in 3 fractions for solitary BM from renal cell carcinoma.30 It is unclear if this patient was already included in the above-mentioned case series. Two short courses of dexamethasone (during adjuvant treatment with pembrolizumab) had been prescribed to alleviate treatment-related headaches and a brain MRI obtained 2 months after RT revealed grade 1 RN. The patient was started on 4500 mg of BA per day and follow-up imaging demonstrated a >90% reduction of fluid-attenuated inversion recovery (FLAIR) enhancement, without any new associated headaches. Mild fatigue possibly related to BA intake was noted.

Finally, Warnick recently reported a case series of 3 patients developing RN 3 to 8 months after SRS (dose, 13-25 Gy) for meningioma and BMs.31 All patients were symptomatic and had failed combinatorial treatment with pentoxifylline and vitamin E as well as corticosteroids. After starting treatment with BA at 150 mg twice daily, resolution of symptoms and associated imaging changes were noted and corticosteroids were successfully discontinued. No adverse events were reported. Data are summarized in Table 2.29, 30, 31

Table 2.

Overview of evidence of Boswellia in the context of radiation necrosis

Author, year Region No. Type, LoE Entity Preparation and dose Response
Upadhyay et al (2023)29 US 50 retrospective case series, 4 BM after SRS 4200-4500 mg/d complete or partial response in 55%, lasting 2-31 months, one-third of symptomatic patients improved clinically
Upadhyay et al (2023)30 US 1 case report, 4 BM after SRS 4500 mg/d >90% reduction of FLAIR enhancement, complete resolution of symptoms
Warnick (2023)31 US 3 retrospective case series, 4 BM and meningioma after SRS (corticosteroid-refractory) 150 mg 2×/d resolution of symptoms and associated imaging changes, corticosteroids discontinued successfully
Open in a new tab

Abbreviations: BM = brain metastasis; FLAIR = fluid-attenuated inversion recovery; LoE = level of evidence; SRS = stereotactic radiosurgery; US = United States.

Discussion

Radiation-induced cerebral edema and RN can be clinically challenging and the latter poses a dose-limiting late toxicity of RT. Accurate diagnosis requires expertise and its management might be difficult, especially in corticosteroid-refractory patients. BA has been used for several decades in traditional ayurvedic medicine to treat a wide variety of inflammatory disorders.32 Randomized evidence showing beneficial effects is currently available for asthma, rheumatoid arthritis, Crohn's disease, osteoarthritis, and collagenous colitis, without any serious adverse events being reported.33 Of note, BA doses are usually lower for these indications. Its first use in the context of glioma was reported in 1997 by Böker and Winking,23 who described a dose-dependent perifocal edema reduction if taken 7 days preoperatively, with associated improvement of symptoms. In our meta-narrative review, we summarize the clinical evidence of BA in the context of radiation-induced cerebral edema and RN. Overall, few trials are available, with evidence stemming from case reports, retrospective series, and 1 small randomized trial, representing only 130 patients in total. The overall level of evidence thus remains low (Tables 1 and 2). Roughly half of patients benefited from BA intake, either radiographically or clinically, and about one third could successfully taper dexamethasone or prevent its (long-term) intake. Tolerability of BA was excellent, with only few side effects reported. Mild gastrointestinal discomfort was reported most commonly and easily reversible after discontinuation of BA. Interestingly, 2 trials also reported some form of tumor response after BA therapy.27,31 This implies an antitumor effect of BA beyond a mere reduction of associated vasogenic edema. Antitumor properties have also been described by other authors; Yadav et al34,35 reported BA-induced tumor and metastases growth inhibition in a mouse model of colorectal cancer and similar results were reported for glioblastoma, especially in combination with RT. Effects are thought to be mediated through downregulation of inflammatory, proliferative, invasive or angiogenic pathways. The latter is in line with clinical studies on targeting the postradiogenic tumor revascularization, suggesting a clinical relevance of the compound's antivasculogenic properties.36, 37, 38 Based on the data presented here, BA appears effective for both radiation-induced edema with or without necrosis. Of note, commercially available supplements with a mixture of different BAs have been shown to promote certain tumor properties in pediatric high-grade glioma cells.39 This implies that caution should be taken and pure formulations are possibly to be preferred in the context of further investigations. Because of the heterogeneity of included patients, dosing schedules, and indications, it is difficult to assess the optimal timing for the initiation of BA at this time. Whether preventive of therapeutic use holds most promise is unclear for now. Exploiting its broad anti-inflammatory properties, the greatest benefits of BA are likely to be observed in patients with otherwise refractory edema or necrosis, as these are generally self-limiting, but potentially interfering with the assessment of drug response. Whether BA should be given upfront to patients at risk or when tapering corticosteroids requires further investigation. The early administration of BA (ie, in asymptomatic patients, based on radiological findings) would, however, be of interest in order to potentially prevent (long-term) corticosteroid intake. Given its broad availability as well as a favorable toxicity and cost profile, hurdles are low for treating physicians as well as patients to consider BA as a first-line treatment before prescription of corticosteroids. Patients should, however, always be informed about the low level of evidence for this medication.

BA has also been investigated in the context of other radiation-related toxicities. Togni et al40 investigated a topical BA-based cream for the prevention of radiation dermatitis, a very common side effect of RT, which so far lacks sufficiently evidence-based pharmaceutical prevention and management options.41,42 In a randomized double-blind placebo-controlled trial (n = 114), patients undergoing normofractionated adjuvant breast RT received either Boswellia or an unspecified base cream twice daily during RT. The experimental arm showed lower rates of clinician-assessed erythema intensity on treatment completion (22% versus 49%; P = .009), corroborated by an objective skin analysis. Furthermore, the need for topical corticosteroids was lower in the BA group (25% versus 63%; P < .001). The frankincense-like smell of the BA cream could potentially have introduced bias and the absence of patient-reported outcomes limits generalizability of these results.43 In recent animal models, BA has been shown to expedite wound healing and anecdotal evidence exists for the treatment of radiation-induced trismus.44,45

Optimal timing and dosing of BA require further investigation. Reported trials used 3600 to 4500 mg daily in divided doses. A direct comparison of formulations is challenging, as Boswellia is comprised of a mixture of several BAs, with a differing relative weight across the different preparations. AKBA is the most potent inhibitor of 5-lipoxygenase, which should be considered when choosing an appropriate extract (eg, 5-Loxin provides 30% AKBA by weight). Sterk et al46 reported an extreme increase in bioavailability with 387% plasma concentration over time if BA was taken with a fatty meal (consisting of eggs fried in butter, bacon, fried potatoes, toast with butter, and whole milk). A reduced BA dose of 150 mg twice daily combined with a fatty snack (eg, cheese or peanut butter) resulted in good edema control in corticosteroid-refractory patients in the case series by Warnick.31 BA is a lipophilic compound and thus depends heavily on bile acids for its appropriate uptake. This implies that fasting should be avoided and absorption can be further optimized by concomitant fat intake, for which a fatty snack seems to suffice and should be recommended to patients. The lecithin-based formulation (as used by Di Pierro et al28) led to a doubling of the cerebral bioavailability in comparison with the free H15 formulation used in other trials. The rather large number of required capsules might hamper patient's compliance, especially if prescribed in addition to (poly-)chemotherapy and associated standard supportive care. Furthermore, potential interactions with other drugs have to be considered, as BA modulates P-glycoprotein and multidrug resistance-associated protein 2 or might inhibit platelet aggregation. The clinical significance of these interactions remains, however, largely unclear at this time.47, 48, 49 Considering all these unanswered questions, a drug absorption study to determine the optimal timing, dosing, and fat intake would be justified.

Other treatment options for RN that are being used despite limited evidence include pentoxifylline (a methylxanthine derivative that increases tissue oxygenation by decreasing blood viscosity), edaravone and vitamin E (both scavengers of free radicals). Reported efficacy seems similar to that of BA, with roughly half of patients benefiting, yet randomized data are still largely lacking.50,51 Similar modes of action are proposed for hyperbaric oxygen therapy.15,52 Costs and side effects should be considered.

Current evidence on the effects of BA in radiation-induced edema and necrosis is limited by selection and detection bias and a lack of high-level randomized evidence. The paucity of data prevents a meaningful meta-analysis at this time. The current narrative summary might serve as a starting point for a future prospective trial. In designing such study, population and indication, (patient-reported) endpoints, and intervention as well as placebo control should be considered carefully. The recently proposed International Stereotactic Radiosurgery Society grading system for RN might be of added value in this context, as it considers previous lines of treatment (Table 3).15

Table 3.

Common Toxicity Criteria for Adverse Events versus International Stereotactic Radiosurgery Society grading system for radiation necrosis.

Grade CTCAE ISRS
1 asymptomatic; clinical or diagnostic observations only; intervention not indicated asymptomatic and no prior corticosteroid administration
2 moderate symptoms; corticosteroids indicated symptomatic and no prior corticosteroid administration
3 severe symptoms; medical intervention indicated symptomatic and corticosteroid-refractory
4 life-threatening consequences; urgent intervention indicated symptomatic with neurologic impairment, progressive radiation necrosis despite a trial of noninvasive treatments, dependency on high doses of corticosteroid
5 death
Open in a new tab

Abbreviations: CTCAE = Common Toxicity Criteria for Adverse Events; ISRS = International Stereotactic Radiosurgery Society.

Conclusions

The overall level of clinical evidence on the use of BA for radiation-induced cerebral edema and RN is very low, yet encouraging further assessment. Advantages include its low cost, general availability, and favorable safety profile. A lecithin-based formulation with a high relative weight of AKBA, administered with a fatty snack, is recommended. Current drawbacks are the unknown optimal formulation as well as timing and dosing, inconvenient galenics, and uncertain interactions with other drugs. The true role of BA in the management of radiation-induced cerebral edema and necrosis, as a single or add-on treatment, remains to be elucidated and should be the subject of prospective trials.

Disclosures

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

Sources of support: This work had no specific funding.

All data generated and analyzed during this study are included in this published article.

References

  • 1.Chao ST, De Salles A, Hayashi M, et al. Stereotactic radiosurgery in the management of limited (1-4) brain metasteses: systematic review and International Stereotactic Radiosurgery Society practice guideline. Neurosurgery. 2018;83:345–353. doi: 10.1093/neuros/nyx522. [DOI] [PubMed] [Google Scholar]
  • 2.Wiegreffe S, Sarria GR, Layer JP, et al. Incidence of hippocampal and perihippocampal brain metastases and impact on hippocampal-avoiding radiotherapy: a systematic review and meta-analysis. Radiother Oncol. 2024;197 doi: 10.1016/j.radonc.2024.110331. [DOI] [PubMed] [Google Scholar]
  • 3.Wujanto C, Vellayappan B, Chang EL, Chao ST, Sahgal A, Lo SS. Radiotherapy to the brain: what are the consequences of this age-old treatment? Ann Palliat Med. 2021;10:936–952. doi: 10.21037/apm-20-856. [DOI] [PubMed] [Google Scholar]
  • 4.Kim JM, Miller JA, Kotecha R, et al. The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies. J Neurooncol. 2017;133:357–368. doi: 10.1007/s11060-017-2442-8. [DOI] [PubMed] [Google Scholar]
  • 5.Minniti G, Clarke E, Lanzetta G, et al. Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol. 2011;6:48. doi: 10.1186/1748-717X-6-48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Layer JP, Shiban E, Brehmer S, et al. Multicentric assessment of safety and efficacy of combinatorial adjuvant brain metastasis treatment by intraoperative radiation therapy and immunotherapy. Int J Radiat Oncol Biol Phys. 2024;118:1552–1562. doi: 10.1016/j.ijrobp.2024.01.009. [DOI] [PubMed] [Google Scholar]
  • 7.Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65:499–508. doi: 10.1016/j.ijrobp.2005.12.002. [DOI] [PubMed] [Google Scholar]
  • 8.Miller JA, Bennett EE, Xiao R, et al. Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int J Radiat Oncol Biol Phys. 2016;96:1060–1069. doi: 10.1016/j.ijrobp.2016.08.039. [DOI] [PubMed] [Google Scholar]
  • 9.Remler MP, Marcussen WH, Tiller-Borsich J. The late effects of radiation on the blood brain barrier. Int J Radiat Oncol Biol Phys. 1986;12:1965–1969. doi: 10.1016/0360-3016(86)90133-1. [DOI] [PubMed] [Google Scholar]
  • 10.Dequesada IM, Quisling RG, Yachnis A, Friedman WA. Can standard magnetic resonance imaging reliably distinguish recurrent tumor from radiation necrosis after radiosurgery for brain metastases? A radiographic-pathological study. Neurosurgery. 2008;63:898–903. doi: 10.1227/01.NEU.0000333263.31870.31. discussion 904. [DOI] [PubMed] [Google Scholar]
  • 11.Ryken TC, Kuo JS, Prabhu RS, Sherman JH, Kalkanis SN, Olson JJ. Congress of Neurological Surgeons systematic review and evidence-based guidelines on the role of steroids in the treatment of adults with metastatic brain tumors. Neurosurgery. 2019;84:E189–E191. doi: 10.1093/neuros/nyy546. [DOI] [PubMed] [Google Scholar]
  • 12.Petrelli F, Signorelli D, Ghidini M, et al. Association of steroids use with survival in patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Cancers (Basel) 2020;12:546. doi: 10.3390/cancers12030546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Jessurun CAC, Hulsbergen AFC, de Wit AE, et al. The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis. Neuro Oncol. 2021;23:1261–1272. doi: 10.1093/neuonc/noab046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Grennan D, Wang S. Steroid side effects. JAMA. 2019;322:282. doi: 10.1001/jama.2019.8506. [DOI] [PubMed] [Google Scholar]
  • 15.Vellayappan B, Lim-Fat MJ, Kotecha R, et al. A systematic review informing the management of symptomatic brain radiation necrosis after stereotactic radiosurgery and International Stereotactic Radiosurgery Society recommendations. Int J Radiat Oncol Biol Phys. 2024;118:14–28. doi: 10.1016/j.ijrobp.2023.07.015. [DOI] [PubMed] [Google Scholar]
  • 16.Barbour AB, Jacobs CD, Williamson H, et al. Radiation therapy practice patterns for brain metastases in the United States in the stereotactic radiosurgery era. Adv Radiat Oncol. 2020;5:43–52. doi: 10.1016/j.adro.2019.07.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Pilkington K, Pilkington GJ. Boswellia: systematically scoping the in vitro, in vivo and clinical research. Eur J Integr Med. 2022;56 [Google Scholar]
  • 18.Safayhi H, Mack T, Sabieraj J, Anazodo MI, Subramanian LR, Ammon HP. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J Pharmacol Exp Ther. 1992;261:1143–1146. [PubMed] [Google Scholar]
  • 19.Safayhi H, Boden SE, Schweizer S, Ammon HP. Concentration-dependent potentiating and inhibitory effects of Boswellia extracts on 5-lipoxygenase product formation in stimulated PMNL. Planta Med. 2000;66:110–113. doi: 10.1055/s-2000-11136. [DOI] [PubMed] [Google Scholar]
  • 20.Wang H, Syrovets T, Kess D, et al. Targeting NF-kappa B with a natural triterpenoid alleviates skin inflammation in a mouse model of psoriasis. J Immunol. 2009;183:4755–4763. doi: 10.4049/jimmunol.0900521. [DOI] [PubMed] [Google Scholar]
  • 21.Pang X, Yi Z, Zhang X, et al. Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. Cancer Res. 2009;69:5893–5900. doi: 10.1158/0008-5472.CAN-09-0755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Dahmen U, Gu YL, Dirsch O, et al. Boswellic acid, a potent antiinflammatory drug, inhibits rejection to the same extent as high dose steroids. Transplant Proc. 2001;33:539–541. doi: 10.1016/s0041-1345(00)02131-x. [DOI] [PubMed] [Google Scholar]
  • 23.Böker D-K, Winking M. Die Rolle von Boswellia-Säuren in der Therapie maligner Gliome. Dtsch Arztebl. 1997;94:958–960. [Google Scholar]
  • 24.Wong G, Greenhalgh T, Westhorp G, Buckingham J, Pawson R. RAMESES publication standards: meta-narrative reviews. BMC Med. 2013;11:20. doi: 10.1186/1741-7015-11-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Centre for Evidence-Based Medicine. OCEBM Levels of Evidence. Accessed October 31, 2024. https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence.
  • 26.Streffer JR, Bitzer M, Schabet M, Dichgans J, Weller M. Response of radiochemotherapy-associated cerebral edema to a phytotherapeutic agent, H15. Neurology. 2001;56:1219–1221. doi: 10.1212/wnl.56.9.1219. [DOI] [PubMed] [Google Scholar]
  • 27.Kirste S, Treier M, Wehrle SJ, et al. Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial. Cancer. 2011;117:3788–3795. doi: 10.1002/cncr.25945. [DOI] [PubMed] [Google Scholar]
  • 28.Di Pierro F, Simonetti G, Petruzzi A, et al. A novel lecithin-based delivery form of Boswellic acids as complementary treatment of radiochemotherapy-induced cerebral edema in patients with glioblastoma multiforme: a longitudinal pilot experience. J Neurosurg Sci. 2019;63:286–291. doi: 10.23736/S0390-5616.19.04662-9. [DOI] [PubMed] [Google Scholar]
  • 29.Upadhyay R, Elguindy AN, Sengupta S, et al. Initial report of Boswellia Serrata for management of cerebral radiation necrosis after stereotactic radiosurgery for brain metastases. Int J Radiat Oncol. 2023;117:S172–S173. doi: 10.1016/j.ijrobp.2025.02.016. [DOI] [PubMed] [Google Scholar]
  • 30.Upadhyay R, Perlow H, Thomas E, et al. Role of Boswellia Serrata in management of CNS radiation necrosis after radiosurgery for brain metastases. Appl Radiat Oncol. 2023;1:38–41. [Google Scholar]
  • 31.Warnick RE. Treatment of adverse radiation effects with Boswellia serrata after failure of pentoxifylline and vitamin E: illustrative cases. J Neurosurg Case Lessons. 2023;5:CASE22488. doi: 10.3171/CASE22488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Efferth T, Oesch F. Anti-inflammatory and anti-cancer activities of frankincense: targets, treatments and toxicities. Semin Cancer Biol. 2022;80:39–57. doi: 10.1016/j.semcancer.2020.01.015. [DOI] [PubMed] [Google Scholar]
  • 33.Ernst E. Frankincense: systematic review. BMJ. 2008;337:a2813. doi: 10.1136/bmj.a2813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Yadav VR, Prasad S, Sung B, et al. Boswellic acid inhibits growth and metastasis of human colorectal cancer in orthotopic mouse model by downregulating inflammatory, proliferative, invasive and angiogenic biomarkers. Int J Cancer. 2012;130:2176–2184. doi: 10.1002/ijc.26251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Winking M, Sarikaya S, Rahmanian A, Jödicke A, Böker DK. Boswellic acids inhibit glioma growth: a new treatment option? J Neurooncol. 2000;46:97–103. doi: 10.1023/a:1006387010528. [DOI] [PubMed] [Google Scholar]
  • 36.Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–722. doi: 10.1056/NEJMoa1308345. [DOI] [PubMed] [Google Scholar]
  • 37.Herrlinger U, Schäfer N, Steinbach JP, et al. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized GLARIUS trial. J Clin Oncol. 2016;34:1611–1619. doi: 10.1200/JCO.2015.63.4691. [DOI] [PubMed] [Google Scholar]
  • 38.Giordano FA, Layer JP, Leonardelli S, et al. L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial. Nat Commun. 2024;15:4210. doi: 10.1038/s41467-024-48416-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Wiese M, Pohlmeier B, Kubiak K, et al. Boswellic acid formulations are not suitable for treatment of pediatric high-grade glioma due to tumor promoting potential. J Tradit Complement Med. 2024;14:101–108. doi: 10.1016/j.jtcme.2023.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Togni S, Maramaldi G, Bonetta A, Giacomelli L, Di Pierro F. Clinical evaluation of safety and efficacy of Boswellia-based cream for prevention of adjuvant radiotherapy skin damage in mammary carcinoma: a randomized placebo controlled trial. Eur Rev Med Pharmacol Sci. 2015;19:1338–1344. [PubMed] [Google Scholar]
  • 41.Layer K, Layer JP, Glasmacher AR, et al. Risk assessment, surveillance, and nonpharmaceutical prevention of acute radiation dermatitis: results of a multicentric survey among the German-speaking radiation oncology community. Strahlenther Onkol. 2023;199:891–900. doi: 10.1007/s00066-023-02074-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Layer JP, Layer K, Glasmacher AR, et al. Pharmaceutical management of acute radiation dermatitis in the German-speaking radiation oncology community. J Dtsch Dermatol Ges. 2024;22:198–207. doi: 10.1111/ddg.15279. [DOI] [PubMed] [Google Scholar]
  • 43.Dejonckheere CS, Schmeel LC. Navigating trial design in radiation dermatitis research: paths to improvement. Support Care Cancer. 2024;32:754. doi: 10.1007/s00520-024-08959-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Dong F, Zheng L, Zhang X. Alpha-boswellic acid accelerates acute wound healing via NF-κB signaling pathway. PLOS ONE. 2024;19 doi: 10.1371/journal.pone.0308028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Mumaw DA, Nassif TM, Witsil MA, Deraniyagala RL. Boswellia serrata Enhances passive range-of-motion exercises in radiation-induced trismus: a case report. Cureus. 2024;16:e58234. doi: 10.7759/cureus.58234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Sterk V, Büchele B, Simmet T. Effect of food intake on the bioavailability of boswellic acids from a herbal preparation in healthy volunteers. Planta Med. 2004;70:1155–1160. doi: 10.1055/s-2004-835844. [DOI] [PubMed] [Google Scholar]
  • 47.Weber C-C, Reising K, Müller WE, Schubert-Zsilavecz M, Abdel-Tawab M. Modulation of Pgp function by boswellic acids. Planta Med. 2006;72:507–513. doi: 10.1055/s-2006-931536. [DOI] [PubMed] [Google Scholar]
  • 48.Krüger P, Kanzer J, Hummel J, Fricker G, Schubert-Zsilavecz M, Abdel-Tawab M. Permeation of Boswellia extract in the Caco-2 model and possible interactions of its constituents KBA and AKBA with OATP1B3 and MRP2. Eur J Pharm Sci. 2009;36:275–284. doi: 10.1016/j.ejps.2008.10.005. [DOI] [PubMed] [Google Scholar]
  • 49.Kokkiripati PK, Bhakshu LM, Marri S, et al. Gum resin of Boswellia serrata inhibited human monocytic (THP-1) cell activation and platelet aggregation. J Ethnopharmacol. 2011;137:893–901. doi: 10.1016/j.jep.2011.07.004. [DOI] [PubMed] [Google Scholar]
  • 50.Patel JS, Salari E, Chen X, et al. Radiomic analysis of treatment effect for patients with radiation necrosis treated with pentoxifylline and vitamin E. Tomography. 2024;10:1501–1512. doi: 10.3390/tomography10090110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Tang Y, Rong X, Hu W, et al. Effect of edaravone on radiation-induced brain necrosis in patients with nasopharyngeal carcinoma after radiotherapy: a randomized controlled trial. J Neurooncol. 2014;120:441–447. doi: 10.1007/s11060-014-1573-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Mayo ZS, Billena C, Suh JH, Lo SS, Chao ST. The dilemma of radiation necrosis from diagnosis to treatment in the management of brain metastases. Neuro Oncol. 2024;26:S56–S65. doi: 10.1093/neuonc/noad188. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Advances in Radiation Oncology are provided here courtesy of Elsevier

RESOURCES