First-in-human study of proton FLASH radiotherapy produces ‘very promising’ results
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Proton FLASH radiotherapy showed clinical feasibility in a first-in-human study of patients with cancer and painful bone metastases, according to data presented at American Society for Radiation Oncology Annual Meeting.
The results of the FAST-01 trial, published simultaneously in JAMA Oncology, also showed the ultra-high dose-rate radiotherapy had efficacy and toxicity comparable to that of current conventional palliative radiation among the small cohort of patients.
“FLASH is a very promising and potentially, in the future, practice-changing treatment modality,” Emily C. Daugherty, MD, assistant professor at University of Cincinnati Cancer Center, said during a news briefing. “FAST-01 is truly just the first step.”
Background
The dose of conventional radiation to treat cancer is limited because of adverse effects to surrounding organs at risk. FLASH radiotherapy, which delivers radiation at ultra-high dose rates of more than 40 Gy per second, has been shown in preclinical studies to reduce injury to normal tissues compared with radiation at standard dose rates of 1 Gy to 2 Gy per minute, Daugherty said.
“It’s approximately 1,000 times faster than those currently used in practice,” she added. “The studies [of FLASH radiotherapy] actually began in about the 1960s, and more recently there has been a revival of using FLASH.”
In 2019, a patient with cutaneous T-cell lymphoma became the first person to be treated with electron FLASH radiotherapy, which is delivered less deeply than proton FLASH. Researchers reported rapid, durable and complete tumor response, with minimal toxic effects to surrounding skin.
Daugherty and colleagues evaluated the workflow feasibility, efficacy and toxicity of proton FLASH radiotherapy among 10 patients aged 27 to 81 years (median age, 63 years; 50% women; 100% white) with one to three painful bone metastases in the extremities. Patients received 8 Gy (nominal dose rate of 60 Gy/sec) in one treatment — the same prescription as the standard of care for palliation of bone metastases — to a total of 12 metastatic sites.
Workflow feasibility, including time on the treatment table and FLASH-associated treatment delays, and toxicity served as primary objectives. Pain relief served as a secondary objective.
Median follow-up was 4.8 months (range, 2.3-13).
Key findings
No technical issues or treatment delays related to FLASH radiotherapy occurred. Median time on the treatment table was 13 minutes. Two patients who underwent treatment to two anatomic sites spent 32 minutes and 33 minutes on the treatment table.
Researchers observed no serious FLASH-related adverse events, with 11 of the 12 acute adverse events categorized as grade 1. The most common adverse event — transient, mild hyperpigmentation — occurred in four patients.
Half of the treated sites (n = 6) had a complete response, defined as no pain at the treatment site at 3 months. Two sites (17%) had a partial response, three (25%) had stable disease and one (8%) had progressive disease.
Four of the 12 treated sites (33%) had transient pain flares and two of 12 sites (17%) required retreatment.
“I think we can all feel reassured that the results we are seeing are quite comparable with what we see with X-rays,” Daugherty said.
Implications
The FAST-02 trial, which Daugherty said should be enrolling very soon, will examine FLASH radiotherapy among patients with thoracic bone metastases.
“In doing so, we’re going to incrementally and systematically have an approach to FLASH in humans where we’re going to slowly assess toxicity to other organs,” she said. “FAST-01 truly just demonstrates the very first exciting step.”
A basic understanding of the FLASH effect and approaches to optimize and safely deliver ultra-high dose-rate radiotherapy must be in place for future trials that investigate higher delivered doses, according to an editorial in JAMA Oncology by Lesley A. Jarvis, MD, PhD, of the radiation oncology section at Dartmouth Health, and colleagues.
“This trial is the first step of a long journey to bring [ultra-high dose-rate] radiation therapy to clinical use with the hope of seeing value from the FLASH effect,” they wrote.
FAST-01 offers an opportunity to understand how to use FLASH robustly to serve specific populations of patients with easy-to-treat, easy-to-reach tumors, Julianne M. Pollard-Larkin, PhD, associate professor of medical physics at The University of Texas MD Anderson Cancer Center, said after the presentation. However, she also noted the need for further research.
“As enthusiastic as I am about the potential and the possibilities that we have with FAST-01, we don’t want to go too fast with FLASH,” she said. “We do not have long-term effect data in the human population. So we need to have a ‘slow’ trial ... where we look super-critically at these patients that are being treated with FLASH and understand what they are suffering from, because we still don’t understand why it works.”
References:
- Bourhis J, et al. Radiother Oncol. 2019;doi:10.1016/j.radonc.2019.06.019.
- Daugherty EC, et al. Abstract 6. Presented at: American Society for Radiation Oncology Annual Meeting; Oct. 23-26, 2022; San Antonio.
- FLASH radiation therapy shows promise in first-in-human trial (press release). Available at: www.astro.org/News-and-Publications/News-and-Media-Center/News-Releases/2022/FLASH-radiation-therapy-shows-promise-in-first-in . Published Oct. 23, 2022. Accessed Oct. 23, 2022.
- Jarvis LA, et al. JAMA Oncol. 2022;doi:10.1001/jamaoncol.2022.5842.
- Mascia AE, et al. JAMA Oncol. 2022;doi:10.1001/jamaoncol.2022.5843.
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Daugherty EC, et al. Abstract 6. Presented at: American Society for Radiation Oncology Annual Meeting; Oct. 23-26, 2022; San Antonio.
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