We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.
- Authors
Moore-Palhares, Daniel; Dasgupta, Archya; Saifuddin, Murtuza; Anzola Pena, Maria Lourdes; Prasla, Shopnil; Ho, Ling; Lu, Lin; Kung, Joseph; McNabb, Evan; Sannachi, Lakshmanan; Vesprini, Danny; Chen, Hanbo; Karam, Irene; Soliman, Hany; Szumacher, Ewa; Chow, Edward; Gandhi, Sonal; Trudeau, Maureen; Curpen, Belinda; Stanisz, Greg J.
- Abstract
Background: Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. Methods and findings: This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I–IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. Conclusions: MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. Trial registration: clinicaltrials.gov, identifier NCT04431674. Daniel Moore-Palhares and team present the mature safety and efficacy outcomes of magnetic resonance-guided focussed ultrasound-stimulated microbubble (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. Author summary: Why was this study done?: Preclinical studies demonstrated combining radiotherapy with focused ultrasound-stimulated microbubble treatment (FUS-MB) enhances tumour cell death by 10 to 40 times, suggesting a promising radioenhancement therapy. Explanation: The exposure of microbubbles (intravascular gas microspheres) to acoustic waves leads to bubble cavitation, disrupting tumour vasculature and triggering endothelial cell apoptotic pathways. Subsequent irradiation of a microbubble-sensitised tumour significantly increases tumour death. What did the researchers do and find?: This Phase 1 clinical trial analysed 18 patients with stages I–IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was conducted per standard-of-care. Patients underwent 2 to 3 sessions of magnetic resonance (MR)-guided FUS-MB treatment during their radiotherapy regimen. The MR-guided FUS-MB treatment demonstrated safety and achieved high rates of objective response and sustained long-term local control. What do these findings mean?: This is, to our knowledge, the first in-human clinical trial to demonstrate the effectiveness and safety of this radioenhancement therapy. This study opens new avenues for improving treatment outcomes in breast cancer and the possibility of replication in other primary malignancies. The safety and efficacy findings observed in this trial warrant validation in Phase 2 clinical trials.
- Subjects
BREAST cancer; MICROBUBBLES; CLINICAL trials; DOSE fractionation; RADIODERMATITIS; DECOMPRESSION sickness; RADIOTHERAPY; INTRAOPERATIVE radiotherapy
- Publication
PLoS Medicine, 2024, Vol 21, Issue 5, p1
- ISSN
1549-1277
- Publication type
Article
- DOI
10.1371/journal.pmed.1004408