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SAN ANTONIO -- A radiation treatment that delivers therapeutic doses in a fraction of a second appeared to be a promising option in mitigating the side effects associated with conventional radiation therapy, according to results from a first-in-human trial.

The modality, known as ultra-high dose rate (UHDR) radiotherapy or FLASH therapy, was feasible for implementation in a routine clinical setting in the the , presented by Emily C. Daugherty, MD, of the University of Cincinnati Cancer Center, at the annual meeting of the American Society for Radiation Oncology.

None of the 10 patients in the study -- all of whom had bone metastases in the extremities -- experienced severe adverse events, and the technique relieved pain in most of the patients.

"FLASH is a very promising and, potentially in the future, practice-changing treatment modality," said Daugherty during a press briefing. "FAST-01 demonstrated the clinical feasibility of Proton FLASH, achieving efficacy and toxicity profiles qualitatively comparable to the published literature using conventional dose rate proton radiotherapy."

Specifically, seven of the 10 patients who underwent FLASH radiotherapy at 12 metastatic sites experienced complete or partial pain relief. Of the 12 treated sites, pain was relieved completely for six sites and partially for two additional sites. Temporary pain flares occurred in four of the 12 sites treated.

Study Implications

While acknowledging the small size of the study, the results are "quite comparable with what we've seen with conventional palliative radiotherapy," Daugherty said.

Findings from the FAST-01 study were published concurrently in .

"FAST-01 presents us with an opportunity to finally understand how to robustly utilize FLASH to help to serve patients who are in specific patient populations that have easy to treat and easy to reach tumors," said ASTRO session discussant Julianne M. Pollard-Larkin, PhD, of the University of Texas MD Anderson Cancer Center in Houston. However, research shouldn't go "too fast" with FLASH, she warned.

"We still don't understand why [FLASH] works," she said. Also, while the results of show that it works for 13 months in 70% of patients, long-term effect data in human populations is still lacking, she added.

A "slow" trial is needed, "where we look super critically at these patients being treated with FLASH," Pollard-Larkin said.

Study Rationale and Design

"FLASH is the delivery of radiotherapeutic doses at dose rates several orders of magnitude higher than those currently used in routine clinical practice," Daugherty explained, adding that it is essentially 1,000 times faster than what is currently used in practice.

The biologic effects of FLASH therapy were first reported more than 50 years ago and are "well established in animal and preclinical models," she noted. For example, reduced pneumonitis and lung fibrosis have been observed in FLASH-irradiated mice, while the sparing effect of FLASH has been seen in studies involving mouse brain and neurocognition, mouse intestine, and cat and pig skin.

However, up until now, there have been no clinical trials investigating FLASH in humans.

The study included patients ranging in age from 27 to 81, with an equal number of men and women enrolled. Eight patients received treatment to one anatomic site, while two patients received treatment to two distinct anatomic sites. Since this was a safety trial, Daugherty said patients with painful bone metastases in the extremities were selected as trial subjects, since they had a lower risk of experiencing serious treatment-related toxicities. "There's a low risk to critical organs," she pointed out.

Patients were given 8 Gy of radiation in a single fraction, delivered at ≥40 Gy per second via a FLASH-enabled proton therapy system.

Pain, use of pain medications, and adverse events were measured on the day of treatment, 15 days following treatment, and at 1, 2, and 3 months following treatment. Results were measured every 2 months for up to 13 months, with a median follow-up of 4.8 months.

As for workflow feasibility, Daugherty and her colleagues observed there were no FLASH-related technical issues or delays occurred, and that patients spent a median time of just 13 minutes on the treatment table.

There were 12 adverse events – none serious -- that were considered to be associated with FLASH in six patients. Most were related to skin changes, with five cases of mild hyperpigmentation.

In a , Leslie Jarvis, MD, PhD, of Dartmouth Health in Hanover, New Hampshire, and colleagues, noted that one unknown factor regarding the FLASH effect is the minimum dose required to see the benefits of ultra-high dose rate radiotherapy.

While estimates range around 8 Gy, "this question towers over the use of FLASH because determining appropriate fractionation schemes is a key factor in the pathway toward successful clinical implementation," Jarvis and colleagues wrote. "The state of FLASH trials today is in a safety phase, as this one was, but determination of safety in a responsible fractionation scheme will be critical to future studies that will be designed with therapeutic end points."

"It is now imperative that the basic understanding of the FLASH effect and the approaches to ensure optimal delivery and quality assurance of UHDR delivery are in place for future trials that will ultimately use higher delivered doses to treatment sites that have the potential for increased toxic effects," they added.

Further studies are underway, including the FAST-02 trial, which will include bone metastases in the chest, Daugherty noted. "In doing so we will incrementally and systematically have an approach in FLASH in humans where we will very slowly assess toxicity to other organs ... such as the lungs and the heart."