FLASH radiation therapy shows promise in a first-in-human trial

The first-in-human study on a small number of bone cancer patients suggests that FLASH radiation therapy, which delivers therapeutic quantities of radiation in a fraction of a second, may hold promise as a viable treatment for difficult-to-kill cancers.

The approach was previously tried on animals and shown to be equally safe and effective, with no unexpected side effects. The FAST-01 trial (NCT04592887) results will be discussed today at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

“Our study shows FLASH radiotherapy with protons is a practical modality to reduce pain,” said Emily C. Daugherty, MD, lead author of the study and an assistant professor of clinical radiation oncology at the University of Cincinnati Cancer Center. “It deserves further exploration because of its potential to decrease the side effects associated with conventional radiation treatments.”

When compared to traditional radiation treatments, FLASH radiotherapy (RT) delivers radiation at dose rates that are more than 300 times higher. This causes a phenomenon known as the FLASH effect, which lessens the damage that conventional radiation therapy may do to healthy tissue surrounding a tumour while still killing the cancer cells at the tumour location.

“Because FLASH radiotherapy is given at ultra-high dose rates, it appears to cause less normal tissue injury. This offers the possibility of delivering larger doses of radiation – which could result in higher cure rates for patients with resistant tumours – without increasing side effects,” said John Breneman, MD, FASTRO, principal investigator on the trial and a professor of radiation oncology and neurosurgery at the University of Cincinnati Cancer Center.

Since electron beams don’t enter tissue very deeply, they have mostly been used in early FLASH RT studies, which restricted their usefulness for this therapeutic strategy. Proton beams can penetrate enough to reach tumour sites in most patients when used for ultra-high dose-rate radiation. FLASH-RT had never been evaluated in a clinical study in humans before the FAST-01 trial, despite pre-clinical animal studies suggesting it could deliver high radiation doses safely and with fewer adverse side effects.

In this study, 10 patients having one to three painful bone metastases in their extremities, ranging in age from 27 to 81, received ultra-high dose rate radiation. A total of 12 metastatic spots in the patient’s arms and legs received treatments.

Patients received 8 Gy of radiation in a single fraction, administered using a FLASH-enabled proton therapy device at a rate of about 40 Gy per second. On the day of treatment, 15 days later, and one, two, and three months later, pain, the usage of painkillers, and adverse events were all recorded. For up to 13 months, the researchers checked these outcomes every two months. The follow-up period was on average 4.8 months.

Researchers chose patients who would have received conventional radiation therapy at the same dose as they were given with FLASH RT. “We used the exact same regimen, but with FLASH dose-rate radiation. The patient experience is the same as it would have been receiving conventional radiation, only the treatment delivery process is shorter,” said Dr Daugherty.
Following FLASH RT, seven of the 10 patients experienced complete or partial pain relief. Of the 12 treated sites, the pain was relieved completely for six sites and partially for two additional sites. Temporary pain flares occurred in four of the 12 sites treated.

Side effects from treatment were mild. Four patients experienced mild skin hyperpigmentation (darkening skin tone), one experienced skin discolouration, two experienced mild limb oedema (swelling or puffiness), two experienced pruritis (itchy skin), one experienced fatigue, one experienced erythema (reddening of the skin) and one experienced extremity pain.
Each FLASH treatment takes about 3/10 of a second, Dr Daugherty explained.

Following treatment, “both pain relief and side effects were in-line with what might have happened with conventional radiation. We did not see any unexpected additional toxicity with the substantially shorter treatment.”

In the brain, lungs, or gastrointestinal tract, where healthy tissue surrounding tumours is most sensitive to radiation exposure, FLASH RT may be most helpful in treating difficult-to-treat malignancies. Clinical trials in these locations, however, cannot be approved until research demonstrates that ultra-high dose-rate radiation is both safe and efficient in other, less sensitive regions. The FDA only approved this trial for persons who had bone metastases in their arms and legs, which are locations that are considerably less likely to experience difficulties.

“From a practical standpoint, this is not the type of cancer that FLASH is designed to treat, but we need human data to see if there are any unexpected side effects. Treating arms and legs is not as risky as treating someone’s brain or lungs,” said Dr Breneman, who he also serves as medical director of the Cincinnati Children’s/UC Medical Center Proton Therapy Center.

Since children are more susceptible to the negative effects of radiation therapy, FLASH RT may eventually prove helpful in treating paediatric malignancies, according to the researcher. But before that can happen, much more research must be conducted.

Further study is required to identify the biological principles underlying the FLASH effect because it is yet unclear why FLASH RT eliminates cancers with fewer adverse effects than traditional radiation, according to Dr Daugherty.

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