Methodological and ethical challenges in the use of focused ultrasound for blood-brain barrier disruption in neuro-oncology

Santhosh G Thavarajasingam; John L Kilgallon; Daniele S C Ramsay; Leila Motedayen Aval; Ishaan Ashwini Tewarie; Andreas Kramer; Dannis Van Vuurden; Marike L D Broekman

doi:10.1007/s00701-023-05782-5

Methodological and ethical challenges in the use of focused ultrasound for blood-brain barrier disruption in neuro-oncology

Acta Neurochir (Wien). 2023 Dec;165(12):4259-4277. doi: 10.1007/s00701-023-05782-5. Epub 2023 Sep 6.

Authors

Santhosh G Thavarajasingam^{1

2

3

4}, John L Kilgallon⁵, Daniele S C Ramsay^{6

7}, Leila Motedayen Aval^{6

7}, Ishaan Ashwini Tewarie^{5

8}, Andreas Kramer⁹, Dannis Van Vuurden¹⁰, Marike L D Broekman^{8

11}

Affiliations

¹ Computational Neurosciences Outcomes Center, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
² Faculty of Medicine, Imperial College London, London, UK. [email protected].
³ Imperial Brain and Spine Initiative, Imperial College London, London, UK. [email protected].
⁴ Department of Neurosurgery, University Medical Centre Mainz, Mainz, Germany. [email protected].
⁵ Computational Neurosciences Outcomes Center, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Faculty of Medicine, Imperial College London, London, UK.
⁷ Imperial Brain and Spine Initiative, Imperial College London, London, UK.
⁸ Department of Neurosurgery, Haaglanden Medical Center, The Hague, Netherlands.
⁹ Department of Neurosurgery, University Medical Centre Mainz, Mainz, Germany.
¹⁰ Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands.
¹¹ Department of Neurosurgery, Leiden Medical Center, Leiden, Netherlands.

Abstract

Background: Focused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting to treat brain tumours. It remains however unclear whether FUS is being introduced in an ethically and methodologically sound manner. The IDEAL-D framework for the introduction of surgical innovations and the SYRCLE and ROBINS-I tools for assessing the risk of bias in animal studies and non-randomized trials, respectively, provide a comprehensive evaluation for this.

Objectives and methods: A comprehensive literature review on FUS in neuro-oncology was conducted. Subsequently, the included studies were evaluated using the IDEAL-D framework, SYRCLE, and ROBINS-I tools.

Results: In total, 19 published studies and 12 registered trials were identified. FUS demonstrated successful BBB disruption, increased drug delivery, and improved survival rates. However, the SYRCLE analysis revealed a high risk of bias in animal studies, while the ROBINS-I analysis found that most human studies had a high risk of bias due to a lack of blinding and heterogeneous samples. Of the 15 pre-clinical stage 0 studies, only six had formal ethical approval, and only five followed animal care policies. Both stage 1 studies and stage 1/2a studies failed to provide information on patient data confidentiality. Overall, no animal or human study reached the IDEAL-D stage endpoint.

Conclusion: FUS holds promise for enhancing drug delivery to the brain, but its development and implementation must adhere to rigorous safety standards using the established ethical and methodological frameworks. The complementary use of IDEAL-D, SYRCLE, and ROBINS-I tools indicates a high risk of bias and ethical limitations in both animal and human studies, highlighting the need for further improvements in study design for a safe implementation of FUS in neuro-oncology.

Keywords: Brain tumor; Focused ultrasound; Glioblastoma; Glioma; IDEAL; Neuro-oncology; ROBINS-I; SYRCLE.

Publication types

Review

MeSH terms

Animals
Blood-Brain Barrier*
Brain
Brain Neoplasms* / drug therapy
Brain Neoplasms* / therapy
Drug Delivery Systems
Humans