FAST-01: 2022 5 Key Takeaways 
What is The FAST-01 Clinical Trial in FLASH Radiotherapy About?
It's radiation that's delivered at ultra high dose rates.
FAST-01: 2022 5 Key Takeaways
Is it possible to relieve the discomfort caused by painful bone metastases in the extremities with proton FLASH irradiation, which is provided at a dose rate that is 1000 times higher than the dose rate of conventional-dose-rate photon radiotherapy?
Proton FLASH was therapeutically feasible and safe, with reduced severity of side effects, as established by this nonrandomized RCT of 10 patients with bone metastases in the extremities. The pain-relieving efficacy of the FLASH treatment appears to be comparable to that of conventional-dose-rate photon irradiation in this small sample.
The findings of this study provide support for the continued investigation of proton FLASH radiotherapy and validate the workflow viability of administering ultra-high-dose-rate proton FLASH radiation therapy in a routine clinical context. Additionally, the findings validate the viability of using proton FLASH radiotherapy to treat patients.
There have not been any clinical trials with ultra-high-dose-rate radiation that has been administered at more than 40 Gy/sec. This treatment is frequently referred to as FLASH therapy. Neither has there been the first use of proton FLASH on people, to the best of our knowledge.
The purpose of this study is to assess the practicality of clinical workflow, as well as the treatment-related toxicity of FLASH and pain relief at the treatment locations.
So what we're talking about is orders of magnitude higher than what we're giving in conventional radiation. So, for example, when we treat our patients here in the clinic using what we're using day in and day out at multiple places across the country, we're treating 1 to 2 Gy a minute in a clinical setting.
But what we're talking about here is about 40 Gy plus per second. So it's very fast, and really the research in FLASH therapy got started in the 60s or so, and what they found is that by delivering radiation at ultra high dose rates, mammalian cells had better survival. And so, as time went on, they did more and more preclinical models.
And what they found is that by delivering the radiation this fast, all of those side effects of radiation, such as scarring and whatnot, are eliminated. Things like, like contracture, lung fibrosis, depending on the model or work we're talking about. They found that if you treated with FLASH therapy versus if you did conventional photons or traditional dose rates, there was a sparing effect in a clinical setting.
So when you deliver FLASH therapy, this normal tissue sparing is called the FLASH effect, and it's been time and again demonstrated that it is novel in humans. I will say no to that question, because, to date, only one patient had been treated with FLASH therapy prior to our study. They used an electron beam, which is a little bit different from our proton FLASH therapy.
And I'll explain this later, but basically, they had a patient in Europe in 2019 who had multiple recurrent cutaneous lymphomas. And so they delivered a ultra high dose rates using an electron FLASH therapy. And they found that the patient did quite well and had a good response. And also, there were minimal side effects.
With regards to proton FLASH therapy, proton FLASH therapy is a little different because instead of using an electron beam or an x-ray, the proton beam has certain benefits. It can be treated deeper into the patient. So with electrons, you can only go three centimeters into the skin, which would make a lot of areas hard to treat with radiation in a human.
Proton FLASH therapy has the advantage of being able to treat deeper. It's also not limited by field size, like electrons can be, and the ultra high dose rates are delivered more homogeneously as well. There's been a lot of data on proton FLASH therapy as well. In those pre-clinical models, one of which was done by one of the people at our institution as well, who showed that with proton FLASH therapy there was reduced leg contracture in mice as compared to the few used conventionals.
The preclinical data is there. And we were only gradually moving towards using this in humans. And. Our trial was really the first clinical trial to deliver FLASH therapy again in humans; it hasn't been, to answer that question, have you used it in any other disease states? Except for that one patient who had an electron FLASH therapy in 2019, everything is fine.
What Is The Current Standard Of Care For Patients With Bone Metastases? And Why FLASH radiotherapy Was Chosen For The FAST-01 Clinical Trial?
So currently, the standard of care for bone metastases is a single fraction of 8 Gy. That was also a wise ASTROS decision.
And again, to take a step back, our study was not designed. There is a clinical trial to say what is better for patients with bone metastases: deliver FLASH therapy or standard x-rays. We use this patient population as a starting point for everything that's going to come further from a place of safety.
So when we're treating bone metastases and the patient in the extremity, the only organs at risk are our muscles, nerves, and bone. But say if we were to treat a bone metastases in the spine in a vertebral body, right? Then we have to worry about spinal toxicity or lung, heart, and so on. The standard of care right now for bone metastases is a single fraction of conventional x-rays. But again, our study's not really designed to compare the two.
Our study is using those patients as a population, as a starting point, and really from safety. Proton FLASH therapy was used in the clinical trial. And again, proton FLASH therapy as opposed to electron FLASH therapy can be delivered deep into a patient's past 3 centimeters. So again, that's another utilization for proton FLASH therapy.
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What Is The Trial Design Of The FAST-01 Clinical Trial Of FLASH Radiotherapy?
As for the FLASH clinical trial design, it was a prospective feasibility study. Again, this is all phase 1. We're starting. It's the first clinical trial in humans, so we're starting from an area of safety and prospective feasibility study. And we plan to enroll 10 patients. They could have multiple cancers. They could have solid malignancies as well as multiple myeloma.
And they had to have painful lesions in the extremity, so no hands, wrists, or feet. They couldn't have prior radiation to the area because, again, we didn't want any confounders in our study. They couldn't have metal implants in the field, and they also couldn't have anything that predisposes to fracture.
If they had tumor lysis of more than 50% of the bony cortex, they could not be enrolled. Or if they had a documented pathologic fracture, they were not enrolled as well. And so what we did is we gave our two main objectives were workflow feasibility to prove that it's, can be clinically feasible, in real life, real practice.
And also with the toxicity, those are the two primary end. Secondary input was pain relief. And so we assessed workflow feasibility by looking at various parameters such as if there were any delays on the FLASH treatment table, delays in getting the FLASH treatment from simulation to treatment. And there were various stopping rules as well that go along with that.
The toxicity was assessed by CTCAE and we assessed for any potential toxicity throughout the whole time patients were enrolled. And we would give proper attribution for that. Pain relief was like. The secondary endpoint, what we looked at there was using the brief pain inventory that has been used in RTOG phase 3 studies before such as RTOG 9714, which was comparing 30 grade, 10 fractions to 8 grade, 1 fraction.
And so we utilized that methodology as well, so we were given them, we gave them a questionnaire. For overall pain, we also gave them a subset of the questionnaire for each treated site so they could have up to 3 metastases treated at a time and say they were treated humorous and femur.
They were given a subset of the BPI for each of those two sites. And then we also assessed for pain flare, we utilize a pain flare question which again was validated in multiple phase 3 studies. Those were basically three questions about their pain and we assessed it from the day of FLASH therapy up until 10 days succeeding in FLASH treatment and follow up to is ongoing. But as of the current report, we have at least 4.8 months of follow up.
What are the specific inclusions and exclusions for this clinical trial in radiation oncology?
Inclusions, the patients had to be over 18, they had to be judged to have a life expectancy of at least or of over two months. We wanted to make sure that we had an adequate follow up to assess how their pain and toxicity they could have up to 3 metastases. I know the task is he had to be in the extremities.
And as for exclusion, so they could not have prior radiation to the area. They could not have any metal implants in the field. They could not have anything that predisposes them to pathologic fracture, such as tumor lysis of more than 50% of the bone cortex or a documented radiological evidence of pathologic.
Final Thoughts On The FAST-01 Clinical Trial About FLASH
So what our FLASH clinical trial found is that most importantly there were no serious adverse events from FLASH.
I think that was something that's the first time we're doing this in humans (this type of radiation oncology). Something we need to figure out and assess before moving forward at all. And no patient had a serious adverse events, overall, what we found that the most common thing that happened was acute mild hyperpigmentation.
Our paper that's now in JAMA Oncology has a picture of this, but basically there was in certain patients a small, subtle area, almost exactly a small square field, where we had delivered the radiation on the entry side that was mild and would typically go away after a few months.
With regards to the other outcomes, We did find that it was clinically feasible, so there were no FLASH treatment-related delays due to FLASH, no intra-fractional delays, like while the patient was on the table. Overall, the patient's median time they were on a table was about 13 minutes.
There was a range, of course, and the patients who had multiple sites treated had about 32 to 33 minutes on the table, which would be expected because they're getting treated to different areas and that was for workflow feasibility, again, for toxicity.
We found that there were no serious adverse events. About 12 patients had an acute event. However, the majority of them, 11 in total, were in grade 1. And again, most of these were hyperpigmented. So we did find that it's clinically safe. Patients did quite well, especially for pain relief and pain flare.
For pain flare, only four of our patients had pain flare, which was very much in line with what we see with conventional what we would expect with conventional radiation. So the rates were about the same as what patients who are being treated these days with an eighth grade would have. So, that was reassuring to find.
We only have 10 patients in our study, so it's certainly not power to say one is better. Again, and that really wasn't the aim of the study, we can compare the numbers that we do have and follow up will be ongoing to see how they did. And we did find that it was quite comparable to what we have now in the literature for radiation oncology.
With regards to pain relief, we found that the pain patients had very adequate pain relief as well. And again, it was around what we would expect with protons. So our overall response was that around 70% of the patients had some pain relief and then 50% actually had a complete pain response, which was very good.
And in general, the overall response rate for us was about 65 to 67%. That is exactly what we see in the RTG study I mentioned earlier. Therefore, efficacy does not seem to be reduced. In fact, to date, there's no evidence for decreased efficacy or decreased durability, either of FLASH. All in all, what we can say here is that now we've treated patient humans with FLASH with proton.
FLASH specifically, we know that it's safe, we know it's clinically feasible, and despite that, we only have, again, 10 patients. However, from this modest start, we haven't found any evidence that it's less effective and more toxic. Patients did quite well. And now what we can really do is utilize this clinical trial as a stepping off point for future trials in FLASH. This clinical trial will really provide the baseline for that. So we have a clinical trial, FAST-02, which is the next step, and what that is looking at is for patients who have thoracic bone metastases. Again, we're limited to just the extremities.
Now we're venturing into thoracic metastases. So, ribs, scapula, sternum, and clavicle. So what we're going to be doing there is delivering FLASH radiation to those metastases. But now we're going to start getting a little bit more toxicity data as those beams pass through the lungs and potentially the heart.
We are not going to include any patient who needs a radiation beam to pass through the spine, so we're not quite there yet. However, we do want to assess things like the patient's motion on the table. What is it like when you treat a human with FLASH and you're near those organs and it's a very stepwise, very systematic approach?
We're taking our time, doing it safely in the right way. But it's certainly very exciting and these 10 patients in our FAST-01 study that I've talked to you about today really are going to provide the basis for all that is to come in humans with FLASH.
Emily Daugherty, MD - About The Author, Credentials, and Affiliations
Dr. Emily C. Daugherty is a radiation oncologist that works in a number of hospitals in the city of Cincinnati, Ohio. These hospitals include the University of Cincinnati Medical Center and the Cincinnati Children's Hospital Medical Center. She received her medical degree from SUNY Upstate Medical University and has been working as a doctor for somewhere between six and 10 years. Her areas of expertise include Lung Cancer, Mesothelioma, Thoracic Malignancies, Oligometastatic Cancers, Breast Cancer, Proton Therapy, and FLASH Radiation Therapy. She is also an Assistant Professor of Clinical Radiation Oncology at the university.