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.

Stereotactic Body Radiation Therapy for Sacral Metastases: Deviation From Recommended Target Volume Delineation Increases the Risk of Local Failure.

PURPOSE: Although spine stereotactic body radiation therapy (SBRT) is considered a standard of care in the mobile spine, mature evidence reporting outcomes specific to sacral metastases is lacking. Furthermore, there is a need to validate the existing sacral SBRT international consensus contouring guidelines to define the optimal contouring approach. We report mature rates of local failure (LF), adverse events, and the effect of contouring deviations in the largest experience to date specific to sacrum SBRT. METHODS AND MATERIALS: Consecutive patients who underwent sacral SBRT from 2010 to 2021 were retrospectively reviewed. The primary endpoint was magnetic resonance imaging-based LF with a focus on adherence to target volume contouring recommendations. Secondary endpoints included vertebral compression fracture and neural toxicity. RESULTS: Of the 215 sacrum segments treated in 112 patients, most received 30 Gy/4 fractions (51%), 24 Gy/2 fractions (31%), or 30 Gy/5 fractions (10%). Sixteen percent of segments were nonadherent to the consensus guideline with a more restricted target volume (undercontoured). The median follow-up was 21.4 months (range, 1.5-116.9 months). The cumulative incidence of LF at 1 and 2 years was 18.4% and 23.1%, respectively. In those with guideline adherent versus nonadherent contours, the LF rate at 1 year was 15.1% versus 31.4% and at 2 years 18.8% versus 40.0% (hazard ratio [HR], 2.5; 95% CI, 1.4-4.6; P = .003), respectively. On multivariable analysis, guideline nonadherence (HR, 2.4; 95% CI, 1.3-4.7; P = .008), radioresistant histology (HR, 2.4; 95% CI, 1.4-4.1; P < .001), and extraosseous extension (HR, 2.5; 95% CI, 1.3-4.7; P = .005) predicted for an increased risk of LF. The cumulative incidence of vertebral compression fracture was 7.1% at 1 year and 12.3% at 2 years. Seven patients (6.3%) developed peripheral nerve toxicity, of whom 4 had been previously radiated. CONCLUSIONS: Sacral SBRT is associated with high efficacy rates and an acceptable toxicity profile. Adhering to consensus guidelines for target volume delineation is recommended to reduce the risk of LF.

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.

Locoregional Ablative Radiation Therapy for Patients With Breast Cancer Unsuitable for Surgical Resection.

PURPOSE: Patients with breast cancer who are unsuitable for surgical resection are typically managed with palliative systemic therapy alone. We report outcomes of 5-fraction ablative radiation therapy for nonresected breast cancers. METHODS AND MATERIALS: This is a retrospective analysis of an institutional registry of patients with breast cancer who were unsuitable for resection and underwent 35 to 40 Gy/5 fractions to the primary breast tumor or regional lymph nodes from 2014 to 2021. Primary outcomes were cumulative incidence of local failure and grade ≥3 toxicity (Common Terminology Criteria for Adverse Events, version 5.0). RESULTS: We reviewed 57 patients who received 61 treatment courses (median age of 81 years; range, 38-99). Unresectable tumor (10%), patient refusal (18%), medical inoperability (35%), and metastatic disease (37%) were the causes of not having surgery. Five patients (8%) had previously undergone adjuvant locoregional radiation therapy. Fifty-four percent (n = 33/61) of treatment courses targeted the breast only, 31% (n = 19/61) both the breast and lymph nodes, and 15% (n = 9/61) the lymph nodes only. Sixty-seven percent (n = 35/52) of the courses that targeted the breast were delivered with partial breast irradiation and 33% (n = 17/52) with whole breast radiation therapy (median dose of 25 Gy in 5 fractions) ± simultaneous integrated boost to the primary tumor. Most primary tumors (65%, n = 34/52) and target lymph nodes (61%, n = 17/28) were treated with a dose of 35 Gy in 5 fractions. Most treatments (52%) were delivered with intensity modulated radiation therapy (IMRT). Radiation therapy was delivered daily (20%), every other day (18%), twice weekly (36%), or weekly (26%). The 2-year cumulative incidence of local failure was 11.4% and grade≥3 toxicity was 15.1%. The grade ≥3 toxicity was 6.5% for IMRT treatments, versus 7.7% for non-IMRT treatments targeting partial breast or lymph nodes (hazard ratio, 1.13, P = .92), versus 38.9% for non-IMRT treatments targeting the entire breast (hazard ratio, 6.91, P = .023). All grade ≥3 toxicity cases were radiation dermatitis. No cases of brachial plexopathy were observed. CONCLUSIONS: Thirty-five to 40 Gy in 5 fractions is a safe and effective breast stereotactic body radiation therapy (SBRT) regimen and may be an attractive option for patients who are not surgical candidates. Highly conformal techniques (ie, IMRT or partial breast irradiation) were associated with a reduced risk of toxicity and should be the preferred treatment approaches.