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

Introduction: Focused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), particularly for gliomas. The IDEAL-D framework for the introduction of surgical innovations and the SYRCLE and ROBINS-I tools for assessing risk of bias in animal studies and non-randomized trials, respectively, provide a comprehensive evaluation of methodological quality and safety. This study aims to evaluate the adherence of FUS for BBB disruption in neuro-oncology to the IDEAL-D framework and to assess the risk of bias using the SYRCLE and ROBINS-I tools.

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

Results: A total of 19 published studies and 12 registered trials focusing on glioma, were identified. FUS demonstrated successful BBB disruption, increased drug delivery, improved survival rates, and good safety. However, IDEAL-D analysis showed inadequate investigation or reporting of neurological side effects, randomization, blinding, or ethical considerations in most animal studies. Of the 16 pre-clinical Stage 0 studies, six had formal approval from an animal committee, five followed appropriate animal care policies, and four had no information on approval or animal care. Neither animal nor human studies reached the IDEAL-D stage endpoint. The SYRCLE analysis revealed a high risk of bias in animal studies, while the ROBINS-I analysis found most human studies had a high risk of bias due to a lack of blinding and heterogeneous medication and patient characteristics.

Conclusion : The development of FUS for neuro-oncology must adhere to more rigorous safety standards. 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 to ensure the safe and effective implementation of FUS in neuro-oncology.