Radiation Enhancement Using Focussed Ultrasound-stimulated Microbubbles for Breast Cancer: A Phase 1 Clinical Trial
Daniel Moore-Palhares, Archya Dasgupta, Murtuza Saifuddin, Mary Lourdes Anzola Pena, Shopnil Prasla, Ling Ho,Lin Lu, Joseph KungEvan McNabb, Lakshmanan Sannachi, Danny Vesprini, Hanbo Chen,Irene Karam, Hany Soliman, Ewa Schumacher, Edward Chow, Sonal Gandhi, Maureen Trudeau, Belinda Curpen, Greg J. Stanisz, Michael Kolios, Gregory J. Czarnota
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.
Introduction
Radiotherapy plays a pivotal role in breast cancer management. It is typically administered in the adjuvant setting to reduce locoregional recurrence or in a palliative scenario to alleviate symptoms such as pain or bleeding [1]. However, there has been a rising interest in utilising radiotherapy in the neoadjuvant setting or as a definitive treatment for older or frail patients who may not be suitable for surgical resection [2–6]. Data from Phase I clinical trials indicate that the pathologic complete response rate following neoadjuvant radiotherapy is under 42%, demonstrating that radiotherapy alone cannot eliminate cancer completely for most patients [2,5]. Therefore, a therapeutic opportunity exists for studying selective agents or methods that could enhance the effectiveness of radiation-induced tumour cell death when treating in situ tumours. In recent years, significant research has been conducted into using focussed ultrasound-stimulated microbubbles to enhance vascular permeability for potential oncological applications [7–14]. Microbubbles are tiny gas-filled spheres primarily used as intravascular contrast agents in ultrasound imaging. When microbubbles are exposed to an acoustic field, bubble cavitation within the targeted area (i.e., tumour) temporarily and reversibly opens endothelial vessel walls [15–17].
Methods
Study design and participants
This prospective Phase 1, single-center, single-arm, investigator-initiated study aimed to evaluate the safety and efficacy of combining MRgFUS-MB, an radioenhancement treatment, with any radiation dose fractionation considered appropriate for the treatment of primary or recurrent breast tumours in situ. This study aimed to enroll 20 patients referred for radiotherapy at Sunnybrook Health Sciences Centre. Eligibility criteria included patients older than 18 years with stages I–IV breast cancer who required radiation therapy to a primary or recurrent breast or chest wall tumour in situ, as determined by a multidisciplinary team of medical, surgical, and radiation oncologists. Exclusion criteria included contraindications to contrast-enhanced MR (i.e., the presence metallic implants), contraindications to microbubbles administration (i.e., prior allergic reaction or significant comorbidities such as cardiac insufficiency or chronic kidney disease), abnormal coagulation profile or liver/renal function, weight over 140 kg, index lesion with relevant ulceration or bleeding, use of anticoagulants, and an Eastern Cooperative Oncology Group (ECOG) performance status ≥3. This study adhered to good clinical practice guidelines and followed the principles outlined in the Helsinki declaration. All study participants provided a written consent form before study participation. Demographic and clinical data were collected from electronic medical records, including the patients’ age, tumour histology and laterality, hormone-receptor status, staging, previous treatments, and radiation therapy details such as prescribed dose and fractionation.
Results
Patient and tumour characteristics
Between August 2020 and November 2022, a total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention (Fig 3). Among them, 3 patients subsequently withdrew consent: the first declined treatment before initiation, the second underwent the first but declined the second MRgFUS-MB treatment, and the third underwent all MRgFUS-MB treatments but withdrew consent after treatment completion, representing the only patient lost to follow-up in our study. The only toxicity reported among these 3 patients while on treatment or follow-up consisted of a single case of grade 1 radiation dermatitis. Consequently, 18 female patients with 20 primary breast tumours (median age 60 years, range 44 to 90) were included in the safety and LC analyses (Table 1). Two patients died due to progressive metastatic breast cancer (unrelated to the treated sites) before 3 months after treatment completion and were excluded from the 3-month tumour response analysis. The median follow-up was 9 months (range, 0.3 to 29). There were no protocol deviations.
Discussion
This study presents the mature outcomes of what is, to our knowledge, an innovative therapy aimed at enhancing radiation efficacy for breast cancer treatment. We observed a safe profile, with no grade≥3 microbubble-related adverse events. Additionally, 83% of tumours achieved partial or complete responses and the LC rate at 2 years was 76% (95% CI [54%, 100%]). Our research addresses a critical unmet need—the development of radiosensitizers capable of selectively enhancing radiation efficacy without increasing toxicity, thereby improving the therapeutic ratio. Our treatment approach is based on mechanical perturbation of the endothelial cells lining the tumour vasculature, which was shown in preclinical data to up-regulate pro-apoptotic pathways, ultimately enhancing tumour cell death [8–14,20]. To our knowledge, this is the first clinical trial to date to combine focussed ultrasound-stimulated microbubbles and external beam radiotherapy.
Acknowledgments
We express our gratitude to the Terry Fox Research Institute, Natural Sciences and Engineering Research Council of Canada, and independent funding from the Varian Grants Program for supporting this research. We extend our sincere appreciation to all the patients, family members, and participating staff from Sunnybrook Health Sciences Center and Sunnybrook Research Institute for their valuable contributions to this study.
Citation: Moore-Palhares D, Dasgupta A, Saifuddin M, Anzola Pena ML, Prasla S, Ho L, et al. (2024) Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial. PLoS Med 21(5): e1004408. https://doi.org/10.1371/journal.pmed.1004408
Academic Editor: Aadel A. Chaudhuri, Washington University in St Louis, UNITED STATES
Received: November 23, 2023; Accepted: April 25, 2024; Published: May 17, 2024
Copyright: © 2024 Moore-Palhares et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Institutional research ethics boards necessitate individual permission for data sharing. De-identified participant data will be accessible to researchers upon submission of a methodologically sound proposal with appropriate ethical approval, as required, and subsequent approval by the Sunnybrook Research Institute. Requests for data access can be directed to the Vice President of Research and Innovation at the Sunnybrook Research Institute ([email protected]).
Funding: Terry Fox Research Institute (“Ultrasound and MRI for Cancer Therapy - IV”, Project Number: 1115, recipient: GC, www.tfri.ca), Natural Sciences and Engineering Research Council of Canada (Discovery Grant: “Biophysics of Ultrasound and Cell Interactions”, RGPIN:2019-06846, recipient: GC, https://www.nserc-crsng.gc.ca/), and Varian Grants Program (“Ultrasound-Stimulated Microbubble Enhancement of Radiation Therapy: Clinical Validation”, Award Number: not applicable, recipient: GC, www.varian.com). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I.K. received honorarium for EMD Serono advisory board on locally advanced Head and neck cancers (Nov 2023)
Abbreviations: 3D-CRT, three-dimensional conformal radiotherapy; ASMase, acid sphingomyelinase; CI, confidence interval; CTCAE, Common Terminology Criteria for Adverse Events; ECOG, Eastern Cooperative Oncology Group; FUS-MB, focussed ultrasound-stimulated microbubble; HER-2, human epidermal growth factor receptor 2; IMRT, intensity-modulated radiotherapy; LC, local control; MR, magnetic resonance; MRgFUS-MB, magnetic resonance-guided focussed ultrasound-stimulated microbubble; RECIST, Response Evaluation Criteria in Solid Tumors V1.1; TARE, transarterial radioembolization; TREND, Transparent Reporting of Evaluations with Nonrandomized Designs
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004408#abstract0
