Bone Metastases Treated in a FLASH: One Dose of Proton RT

SAN ANTONIO — The first-in-human trial of ultra-high-dose-rate radiotherapy, known as FLASH therapy, found not only that it was feasible for treating bone metastases, but also that it offered pain relief and reduced pain flares, and had few toxicities.

The researchers used the FLASH-enabled ProBeam System (Varian), which has a US Food and Drug Administration (FDA) investigational device exemption for use in clinical research.

The findings come from the FAST-01 study, conducted in 10 patients with cancer and painful bone metastases in the extremities, all of whom received a single dose of 8 Gy proton radiotherapy.  

The research was presented October 24 at the American Society for Radiation Oncology (ASTRO) Annual Meeting 2022, and published simultaneously in JAMA Oncology.

“These results are certainly very exciting and it’s an exciting time for our field,” said study presenter Emily C. Daugherty, MD, an assistant professor of clinical radiation oncology at the University of Cincinnati Cancer Center, Cincinnati, Ohio.

“We acknowledge that, with 10 patients, we are not powered to show significant differences compared to [trial] RTOG 9714,” she said.

“However, the results are quite comparable and very much in line with what’s been seen with standard palliative radiotherapy rates of pain flare pain response, [and] retreatment rates were very similar to previously reported data using the same dose of 8 Gy.”

Dougherty added that this study is “just the first step.”

They will continue to assess the patients for toxicity to bone, muscles, and nerves, whereas FAST-02 will include patients with thoracic bone metastases in the ribs, sternum, scapula, and clavicle, and will look at toxicities in the lung and the heart.

Different to Conventional RT

FLASH therapy has been shown to have “unique biological effects”, offering the “relative protection of normal tissue after single doses” compared with conventional dose-rate radiotherapy, Daugherty commented at a press briefing.

Previous studies have shown that it is associated with reduced pneumonitis and lung fibrosis in mouse models, as well as fewer adverse effects on brain and neurocognition, gastrointestinal, and skin in other experimental models.

FLASH using electron radiotherapy has been tested in humans “but there are disadvantages,” which include low tissue penetration, inconsistent dose distribution, and  limited field sizes.

“Proton flash, however, allows for flash delivery deeper than 3 cm and more homogenous dose distribution,” Daugherty said.

To examine the feasibility of proton FLASH therapy, the researchers conducted the  first-in-human clinical trial, enrolling 10 individuals treated at their institution.

These patients had up to three painful bone metastases in their extremities, but no lesions in the hands, feet, or wrists. They were also required to have a life expectancy of more than 2 months.

There were five male and five female participants, and the median age was 63 years. All of the patients were white, non-Hispanic, and they had a range of primary histologies, including lung, breast, prostate, and thyroid cancer, and multiple myeloma.

All patients received 8 Gy of radiotherapy delivered as a single fraction with a dose rate of ≥40 Gy per second.

In all, 12 metastatic sites were treated, including five in the femur, five in the humerus, and two in the tibia. The mean time per treatment site was 15.8 minutes and the median was 13 minutes.

Daugherty reported that there were no technical issues.

Patients completed the Brief Pain Inventory Short Form Questionnaire, the Treated Sites Pain Questionnaire, and the Pain Flare Questionnaire at baseline and for 10 days post-FLASH treatment. They were also asked on their use of pain medications.

Median follow-up was 4.8 months.

During that time, only four patients experienced pain flare, defined as an increase of 2 points or more in pain from baseline or a 25% or higher increase in analgesic intake, plus a return to baseline in pain and analgesic use following the flare.

In terms of pain relief, 67% of treatment sites were reported to have a reduction in site pain, with 50% having a complete response. A further 25% were stable, whereas 8% had progressive disease.

There were no grade 3 or higher adverse events related to FLASH; 10 patients experienced grade 1 events and one patient experienced extremity pain, a grade 2 event.

These included four cases of skin hyperpigmentation within 3 months of treatment, and two cases of pruritis. Only one patient experienced a long-term adverse event, defined as more than 3 months posttreatment, which was grade 1 skin discoloration.

There were two cases of fracture, neither of which were attributed to FLASH, although one event, an elbow fracture in a patient treated to the ipsilateral humerus, was reclassified by the FDA as ‘possibly related.’

The study is sponsored by Varian. Daugherty reports a relationship with Varian. Other authors also report numerous relationships with industry.

American Society for Radiation Oncology (ASTRO) Annual Meeting 2022: Abstract 6. Presented October 24, 2022.

JAMA Oncol. Published online October 24, 2022. Full text

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