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Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study

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A Correction to this article was published on 10 April 2024

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Abstract

Introduction

Blood–brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS).

Methods

We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT04988750) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2 h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study.

Results

In mouse GBM model, the survival analysis showed RT-FUS (2 Gy) group was significantly longer than RT (2 Gy) group and control, but not RT (5 Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33 days after RT-FUS, while another three patients had at least stable disease (mean 323 days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis.

Conclusion

Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT04988750) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

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Funding

This study was supported by Chang Gung Medical Research Foundation: CRRPVVK0013, and National Science and Technology Council, Taiwan: MOST 110-2314-B-182A-154-MY3.

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Authors and Affiliations

  1. Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Ko-Ting Chen, Hong-Chieh Tsai, Chi-Cheng Chuang, Peng-Wei Hsu, Cheng-Chi Lee & Kuo-Chen Wei

  2. Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Ko-Ting Chen, Chiung-Yin Huang, Jui-Chin Li & Kuo-Chen Wei

  3. School of Medicine, Chang Gung University, Taoyuan, Taiwan

    Ko-Ting Chen, Hong-Chieh Tsai & Kuo-Chen Wei

  4. Department of Neurosurgery, Gung Medical Foundation, New Taipei Municipal Tucheng Hospital, Chang Gung Medical Foundation, New Taipei, Taiwan

    Chiung-Yin Huang, Jui-Chin Li & Kuo-Chen Wei

  5. Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan

    Ping-Ching Pai & Chen-Kan Tseng

  6. Department of Radiation Oncology, National Taiwan University Cancer Center, Taipei, Taiwan

    Wen-Chi Yang

  7. Gratitude Institute of Oncology, National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan

    Wen-Chi Yang

  8. Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    Wen-Chi Yang

  9. Department of Diagnostic Radiology and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Cheng-Hong Toh

  10. Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan

    Hao-Li Liu

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  1. Ko-Ting Chen
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Correspondence to Hao-Li Liu or Kuo-Chen Wei.

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The original version of this article has been revised: The clinical trial number has been corrected.

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11060_2023_4517_MOESM1_ESM.tif

Supplementary Figure 1. Illustration of preclinical FUS model. (A) The hind view showing the head of the mouse fixed on the stereotactic frame. A reverse pyramid design of water tank transmitted ultrasound waves was mounted on the top of the head with jelly filled between transducer contact and the scalp (arrow). (B) The front view showing the inhaled anesthetic agent coming from the tube and the water tank coming from top (arrow). (C) A schematic illustration of the time points in the preclinical study. GL261 tumor suspensions were implanted transcranially on D0. On D5, every mouse was sent to FUS-RT treatment, during which a 120-second pulsed FUS was given after systemic microbubbles injection. Radiation therapy was followed within 2 hours after sonication. Then the mouse was monitored with weekly MRIs. Supplementary file1 (TIF 1829 kb)

Supplementary Figure 2. Therapeutic protocol of the RT-FUS trial. Supplementary file2 (TIF 3203 kb)

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Chen, KT., Huang, CY., Pai, PC. et al. Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study. J Neurooncol 165, 535–545 (2023). https://doi.org/10.1007/s11060-023-04517-x

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