FLASH forward to an ultra-fast new form of radiation

By Kirsten Weir 

Photos by Peggy Peterson and John Donges 

Researchers at Penn Medicine are pioneering a new type of radiation therapy that could force textbooks to be rewritten. For decades, the concept of “fractionation” has been dogma in radiation oncology. A total dose of radiation is divided into smaller doses, or fractions, delivered to the patient in a series of treatments over days or weeks. But an experimental new form of radiation, known as FLASH, upends that tried-and-true approach. “The traditional idea is that by fractionating radiation, we can kill tumor cells while sparing healthy tissue. FLASH turns this idea on its head,” said Constantinos Koumenis, PhD, the Richard H. Chamberlain Professor of Radiation Oncology at Penn Medicine.

Conventional X-ray and proton therapies deliver a beam of radiation over the course of two to five minutes. FLASH therapy blasts tumors with an ultra-high dose of radiation in less than a second. And instead of spacing out the total dose across dozens of treatments, FLASH could be delivered in just one to five treatments, rather than 30 or 40. “Our research suggests that by delivering an entire dose of radiation in a few ultra-fast treatments, we may be able to kill the tumor while sparing healthy tissue,” Koumenis said.

Koumenis is co-principal investigator of a $12.3 million, five-year grant from the National Institutes of Health (NIH) to study proton FLASH, along with Alexander Lin, MD, the Morton M. Kligerman Professor of Radiation Oncology. The research builds on Penn Medicine’s preclinical research of FLASH radiation, with the goal of launching human clinical trials in late 2024. Making that happen is an interdisciplinary team of more than two dozen scientists, including biologists, physicists, and clinicians in human and veterinary medicine. 

Over the last decade, that team has collaborated to position the University of Pennsylvania as a global leader in this new approach to radiation therapy. “FLASH is still experimental, but it has jumped through every hoop we’ve put it through so far,” said James Metz, MD, chair of Radiation Oncology at the Perelman School of Medicine and leader of the Roberts Proton Therapy Center at the Abramson Cancer Center. “We’re very excited about where this is headed.” 

Breaking new ground in using FLASH radiation

FLASH was born in 2014, when French scientists reported results of a study using ultra-fast, high-dose-rate radiation in laboratory animals. They showed the FLASH technique had the same tumor-fighting effects as a conventional dose rate, but was better at protecting healthy tissue. Those early studies used electrons to produce the FLASH effect. While the technique showed promise, it had limited potential for human treatment, since commercially available electron radiotherapy machines can only treat tumors about 2.5 inches deep inside the human body. But almost immediately, researchers at Penn Medicine recognized the potential of protons. 

By the time the French study was published, the Roberts Proton Therapy Center had already established itself as a world leader in proton therapy, a type of radiation therapy that uses these positively charged particles to treat a tumor. In addition to five proton therapy treatment rooms where more than 100 patients receive care each day, the center includes a dedicated research room for animal and human research on proton therapy. FLASH was an obvious next step for that research, though it took some creativity to get started. To generate and accurately measure the ultra-high proton beam dose rates, Penn scientists incorporated novel design features into their proton beam research room. Later, Penn scientists collaborated with an industry partner to bring FLASH proton radiotherapy into clinical treatment rooms to make it possible to conduct advanced veterinary clinical trials. That unique infrastructure, equipped with small-animal imaging capabilities and located just steps from the clinic, has allowed Penn to spearhead research on FLASH proton therapy. 

In 2020, Penn Medicine researchers published a landmark study in mice, demonstrating that it was feasible to deliver ultra-high-dose proton therapy. The study, led by senior authors Metz, Koumenis, and Keith A. Cengel, MD, PhD, a professor of Radiation Oncology at Penn Medicine, compared FLASH to traditional proton therapy in a mouse model of pancreatic cancer. They found FLASH was just as effective at controlling tumors but spared more healthy tissue. The resulting paper, published in the International Journal of Radiation Oncology, Biology, and Physics, was among the journal’s most-cited papers that year. “The reason proton therapy is so exciting is that it already spares more normal tissue than traditional radiation. Our hope is that with FLASH, we can spare even more,” Koumenis said. 

In a series of additional animal studies, the team found that FLASH radiation might also improve survival—in part because it reduces the incidence of toxic side effects. Rodents treated with FLASH for intestinal cancer were less likely to develop skin infections and lymphedema, a serious condition which is also observed in patients receiving radiation therapy. Those treated for head and neck cancers had lower rates of severe side effects like reduced saliva production or difficulty swallowing, which can interfere with eating and nutrition. In both cases, the reduction of side effects from FLASH treatment led to mice living longer. “We’re cautiously optimistic that if these results translate to human patients, this could have significant benefits for patient survival and quality of life,” Koumenis said.  

FLASH for Fido

Following those promising animal studies, the Department of Radiation Oncology received more than $12 million in new funding from the NIH in 2022 to study FLASH in a collaborative effort with scientists and clinicians at Penn and the Universities of Heidelberg, Oxford, and Toronto. The funding supports a variety of studies on FLASH, including a trial treating pet dogs with the bone cancer osteosarcoma. That study, currently underway, is led jointly by medical school faculty and researchers at the School of Veterinary Medicine. 

In the first phase of the canine study, led by Radiation Oncology Professor Theresa Busch, PhD, the researchers used FLASH to treat pet dogs who were brought to the vet school for treatment of osteosarcoma of the leg. After the FLASH treatment, the affected limb was amputated—the standard treatment for this type of cancer. Researchers then collected the tumor and surrounding tissues to assess them for molecular and immunological changes that occurred as the result of the treatment. Their findings were similar to those in lab animals: Treatment with FLASH reduced markers of skin toxicity in the canine patients.

After demonstrating that the treatment was feasible and safe in those first canine patients, the team began treating pet dogs with tumors of the head and neck where surgical removal was not a good option. Through this phase of the study, the radiation oncology team is honing their technique in preparation for eventual human trials, explained Lillian Duda, VMD, MBE, a clinical professor of Radiation Oncology at Penn Vet. “We’re refining the proton FLASH technology as we go,” Duda said.

The world’s first conformal FLASH radiation for patients

That refinement, in collaboration with industry partners, has not only brought FLASH proton radiotherapy into clinical treatment rooms, but further developed the technology to make the treatment conformal, added Michele Kim, PhD, an assistant professor of Radiation Oncology at Penn Medicine. In conformal radiation, providers use CT scans to create three-dimensional maps of the tumor. Then they use a series of attachments and 3D-printed devices to shape the radiation beam precisely to match the unique shape and size of the tumor while providing customized protection of surrounding normal tissues. While conformal radiation is common in forms of radiation therapy used clinically today, it had never been done with FLASH, Kim said. 

In fact, while there are already human clinical trials underway using proton FLASH at the University of Cincinnati for patients with metastatic bone cancer, the beam of protons in those trials is used in a “shoot through” mode, where the protons do not stop at the site of the tumors (i.e., they hit the target and exit the patient).  

“We’re the first in the world to deliver conformal FLASH on a patient—in this case, a canine patient,” Kim said. This type of innovation is possible thanks to Penn’s foresight and vision, Duda said. The university strategically located the vet school’s facility for treating small animals like cats and dogs near to the medical school to facilitate interdisciplinary research. “This kind of collaboration can happen here because people are willing to listen to one another and cross-pollinate ideas,” she said. 

“In complex diseases like cancer, rodent models can only tell you so much. Companion animals are more genetically variable than rodents, live in the same environments we do, and have spontaneously occurring cancers that more closely mimic human disease,” Duda added. “That makes this research very beneficial, and the data we collect will directly inform efforts to launch a human trial.”  

Human trials of proton FLASH 

Penn researchers hope to launch their own human trial later this year. Unlike trials that have begun to date, the Penn team hopes to use conformal FLASH because they believe it represents the best approach to take full advantage of protons’ physical properties in sparing normal tissues.

Lin will lead the planned FLASH trial for patients with head and neck cancers, his clinical specialty. The study will focus on patients who require re-irradiation because their cancer recurred or because they developed a new cancer. Radiation in the head and neck area can cause significant side effects, including fractures of the jaw, serious wounds in the mouth and throat, and even potentially fatal damage to the carotid artery. “Re-irradiation in this population can be very toxic, and our standard approaches aren’t very effective,” Lin said. “We’re hoping to try something different.” 

Some patients who need a second course of radiation for head and neck cancer can receive treatment in as few as five sessions, with each session lasting several minutes. In the FLASH trial, Lin and his colleagues plan to deliver each session with FLASH radiation in a matter of milliseconds. By doing so, the team hopes to show that FLASH is both safe and feasible. If that first study is a success, they plan to launch a larger trial to assess the treatment’s efficacy. 

How FLASH proton radiation works to heal the body

Meanwhile, Penn scientists are investing heavily in molecular research to understand how and why FLASH might have an advantage over standard radiotherapy, with support from both the NIH grant for FLASH research and the Mark Foundation Center for Immunotherapy, Immune Signaling and Radiation. “There are a lot of hypotheses about why normal tissues are spared with FLASH, but nothing conclusive yet,” Koumenis said. Studies done in collaboration with the lab of Andy Minn, MD, PhD, a professor of Radiation Oncology, showed strong evidence that FLASH appears to spare progenitor stem cells that then allow tissue to regenerate after radiation therapy. “We’re looking into the mechanisms by which that might happen at a single-cell resolution,” Koumenis said. 

The researchers are also pursuing intriguing evidence that FLASH may help protect immune function. Research on medulloblastoma, a type of brain tumor, suggests that treatment with FLASH may change the immune microenvironment around the tumor, making it more vulnerable to treatment with CAR T cell therapy. “So far, trials that attempt to combine radiation therapy and immunotherapy have been disappointing. That’s probably because when we’re giving radiation every day for six or seven weeks, you blunt your body’s immune function and response, which are critical for response to immunotherapy,” Lin said. “We’re hopeful that by treating with FLASH, and better preserving one’s natural immune system, patients may have a better response to immunotherapy.”  

The right place for rigorous FLASH radiation research

There is a lot still to learn, but Penn researchers are moving full speed toward an era of FLASH radiation therapy. If the trials bear fruit, the proton therapy equipment already in use at Penn could be easily adapted to provide FLASH treatment. “We have all the necessary ingredients to investigate this in the most rigorous way, and to take our findings from bench to bedside as safely and effectively as possible,” Lin said. 

From basic research in mice to trials in dogs and eventually humans, advancing the field of FLASH depends on the type of interdisciplinary research that Penn makes possible, Kim added. “This has truly been a team effort with clinicians, biologists, engineers, and physicists. None of us could do this on our own,” she said. “We’re all talking and working and learning together, and it’s sparking a lot of new ideas.” 

The power of protons: related stories

The power of protons: Penn Medicine has treated more than 10,000 cancer patients with proton therapy—while leading the way in research on the healing potential of these positive particles.

Patient-powered proton study looks at long-term side effects: The RadComp study asks, could proton therapy reduce some long-term side effects while maintaining comparable cure rates to traditional radiation? 

Extending the reach of proton therapy: The world’s largest and most advanced center for proton beam radiation is applying its expertise to treat patients in communities beyond Philadelphia.