Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

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.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for head and neck cancer: A phase 1 clinical trial.

BACKGROUND AND PURPOSE: Preclinical research demonstrated that the exposure of microbubbles (intravascular gas microspheres) to focussed ultrasound within the targeted tumour upregulates pro-apoptotic pathways and enhances radiation-induced tumour cell death. This study aimed to assess the safety and efficacy of magnetic resonance (MR)-guided focussed ultrasound-stimulated microbubbles (MRgFUS-MB) for head and neck cancers (HN). MATERIALS AND METHODS: This prospective phase 1 clinical trial included patients with newly diagnosed or recurrent HN cancer (except nasopharynx malignancies) for whom locoregional radiotherapy with radical- or palliative-intent as deemed appropriate. Patients with contraindications for microbubble administration or contrast-enhanced MR were excluded. MR-coupled focussed ultrasound sonicated intravenously administered microbubbles within the MR-guided target volume. Patients receiving 5-10 and 33-35 radiation fractions were planned for 2 and 3 MRgFUS-MB treatments, respectively. Primary endpoint was toxicity per CTCAEv5.0. Secondary endpoint was tumour response at 3 months per RECIST 1.1 criteria. RESULTS: Twelve patients were enrolled between Jun/2020 and Nov/2023, but 1 withdrew consent. Eleven patients were included in safety analysis. Median follow-up was 7 months (range, 0.3-38). Most patients had oropharyngeal cancer (55 %) and received 20-30 Gy/5-10 fractions (63 %). No systemic toxicity or MRgFUS-MB-related adverse events occurred. The most severe acute adverse events were radiation-related grade 3 toxicities in 6 patients (55 %; dermatitis in 3, mucositis in 1, dysphagia in 6). No radiation necrosis or grade 4/5 toxicities were reported. 8 patients were included in the 3-month tumour response assessment: 4 had partial response (50 %), 3 had complete response (37.5 %), and 1 had progressive disease (12.5 %). CONCLUSIONS: MRgFUS-MB treatment was safe and associated with high rates of tumour response at 3 months.

Evaluation of the Efficacy of Rotational Corrections for Standard-Fractionation Head and Neck Image-Guided Radiotherapy.

PURPOSE: Modern linear accelerators are equipped with cone beam computed tomography and robotic couches that can correct for errors in the translational (X, Y, Z) and rotational (α, ß, γ) axes prior to treatment delivery. Here, we compared the positional accuracy of 2 cone beam registration approaches: (1) employing translational shifts only in 3 degrees of freedom (X, Y, Z), versus; (2) using translational-rotational shifts in 6 degrees of freedom (X, Y, Z, α, ß, γ). METHODS: This retrospective study examined 140 interfraction cone beam images from 20 patients with head and neck cancer treated with standard intensity-modulated radiation therapy. The cone beam images were matched to planning simulation scans in 3, then in 6 degrees of freedom, using the mandible, clivus, and C2 and C7 vertebrae as surrogate volumes. Statistical analyses included a generalized mixed model and was used to assess whether there were significant differences in acceptable registrations between the 2 correction methods. RESULTS: The rates of improvement with corrections in 6 degrees of freedom for the mandible with a 5-mm expansion margin were 54.55% ( P = .793), for the clivus 85.71% ( P = .222), and for C7 87.50% ( P = .015). There was a 100% increase in acceptability for the C2 vertebra within the 5-mm margin ( P < .001). For the 3-mm expansion margin, the rates of improvement for the mandible, clivus, C2, and C7 were 63.16% ( P = .070), 91.30% ( P = .011), 84.21% ( P = .027), and 76.92% ( P < .001), respectively. CONCLUSIONS: Significant registration improvements with the use of rotational corrections with a 5-mm expansion margin are only seen in the C7 vertebra. At the 3-mm margin, significant improvements are found for the C2, C7, and clivus registrations, suggesting that intensity-modulated radiotherapy treatments for head and neck cancers with 3-mm planning target volume margins may benefit from corrections in 6 degrees of freedom.