Proton FLASH Radiotherapy for the Treatment of Symptomatic Bone Metastases: The FAST-01 Nonrandomized Trial

Abstract

Importance: To our knowledge, there have been no clinical trials of ultra-high-dose-rate radiotherapy delivered at more than 40 Gy/sec, known as FLASH therapy, nor first-in-human use of proton FLASH.

Objectives: To assess the clinical workflow feasibility and treatment-related toxic effects of FLASH and pain relief at the treatment sites.

Design, setting, and participants: In the FAST-01 nonrandomized trial, participants treated at Cincinnati Children's/UC Health Proton Therapy Center underwent palliative FLASH radiotherapy to extremity bone metastases. Patients 18 years and older with 1 to 3 painful extremity bone metastases and life expectancies of 2 months or more were eligible. Patients were excluded if they had foot, hand, and wrist metastases; metastases locally treated in the 2 weeks prior; metal implants in the treatment field; known enhanced tissue radiosensitivity; and implanted devices at risk of malfunction with radiotherapy. One of 11 patients who consented was excluded based on eligibility. The end points were evaluated at 3 months posttreatment, and patients were followed up through death or loss to follow-up for toxic effects and pain assessments. Of the 10 included patients, 2 died after the 2-month follow-up but before the 3-month follow-up; 8 participants completed the 3-month evaluation. Data were collected from November 3, 2020, to January 28, 2022, and analyzed from January 28, 2022, to September 1, 2022.

Interventions: Bone metastases were treated on a FLASH-enabled (≥40 Gy/sec) proton radiotherapy system using a single-transmission proton beam. This is consistent with standard of care using the same prescription (8 Gy in a single fraction) but on a conventional-dose-rate (approximately 0.03 Gy/sec) photon radiotherapy system.

Main outcome and measures: Main outcomes included patient time on the treatment couch, device-related treatment delays, adverse events related to FLASH, patient-reported pain scores, and analgesic use.

Results: A total of 10 patients (age range, 27-81 years [median age, 63 years]; 5 [50%] male) underwent FLASH radiotherapy at 12 metastatic sites. There were no FLASH-related technical issues or delays. The average (range) time on the treatment couch was 18.9 (11-33) minutes per patient and 15.8 (11-22) minutes per treatment site. Median (range) follow-up was 4.8 (2.3-13.0) months. Adverse events were mild and consistent with conventional radiotherapy. Transient pain flares occurred in 4 of the 12 treated sites (33%). In 8 of the 12 sites (67%) patients reported pain relief, and in 6 of the 12 sites (50%) patients reported a complete response (no pain).

Conclusions and relevance: In this nonrandomized trial, clinical workflow metrics, treatment efficacy, and safety data demonstrated that ultra-high-dose-rate proton FLASH radiotherapy was clinically feasible. The treatment efficacy and the profile of adverse events were comparable with those of standard-of-care radiotherapy. These findings support the further exploration of FLASH radiotherapy in patients with cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT04592887.

Figure 1.. Sample FLASH Treatment Plan and Bragg Curve Showing Radiation Dose in Color Wash

A, Axial computed tomography (CT) through a lesion treated in the right distal femur. B, Coronal CT through the same lesion. C, The radiation dose, drawn as a blue line, as a function of depth of penetration into the body for FLASH delivery with a 250-MeV transmission beam. The radiation dose is represented on the vertical axis, with depth of penetration into the body on the horizontal axis. The yellow box on the aqua-colored bar represents the position of the tumor in the radiation field, and the brighter red spot is the location of the increased dose at the Bragg peak, occurring outside of the patient’s body. In all panels, darker red color indicates higher dose.

Figure 2.. CONSORT Participant Flow Diagram

Figure 3.. Posttreatment Hyperpigmentation

Photographs of a transient, mild hyperpigmentation adverse event in the area of FLASH treatment in a single patient. The photographs may have been taken under different lighting conditions and/or with different cameras. To facilitate comparison across images, the brightness was uniformly decreased and the warmth uniformly increased in panel C, and the brightness was uniformly increased in panel D.