FOR MORE THAN 100 YEARS, radiation has been a pillar of cancer treatment. But the practice—hitting cancer cells with beams of intense energy—doesn’t come without a cost to the body. Radiation can damage nearby healthy cells and tissue, with hair loss and rashes at the point where the treatment is focused along with a variety of more serious complications depending on where the tumor is located and what kind of tissue receives the collateral damage.

Experiments in the 1960s hinted at a more effective, if counterintuitive, approach: dramatically increasing the dose rate. In animal models, high dose rate radiation delivery was far more toxic to cancer cells and, oddly, less damaging to nearby normal cells. A European team made this discovery by chance while studying the effects of radiation dose rate on oxygen depletion, not cell survival. “But the in vivo ramifications of their finding were not fully appreciated at the time,” says radiobiologist Charles Limoli at the University of California, Irvine.

Other teams soon confirmed the findings using animal models—ultra-high dose rate irradiation caused significantly fewer side effects while controlling tumor growth. Translating the idea to a clinical technique, however, has proved difficult. “A variety of technical challenges remain before this treatment can be applied in clinics throughout the world,” Limoli says.

Ultra-high dose rates can be delivered to a tumor in less than a 10th of a second. Tests on zebrafish, mice, cats and a mini pig have confirmed that this approach can work, and it appears to be as effective as conventional dose rates at controlling malignant growth. Two years ago, the first human patient was treated in this way, and the researchers conducting the study reported that it appeared safe and effective.

“If I can deliver a whole treatment course in less than a second, that completely changes the cancer experience,” says radiation oncologist James Metz at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. “It’s potentially a game changer in how we approach cancer care.”

The vanguard of the current research began in the late 1990s, when radiobiologist Vincent Favaudon at Institut Curie in France reported that ultra-high dose rate radiation caused less chromosomal damage in vitro than conventional dose rate radiation. That observation led his colleague Marie-Catherine Vozenin, who was working at Institut Gustave Roussy at the time, to launch experiments on mice in 2008. The radiation delivered at ultra-high dose rates suppressed lung tumor growth as well as conventional dose rate radiation, but it spared nearby cells in the lung lining.

While conventional radiotherapy delivers a dose rate of less than 0.03 gray per second (“gray” is the unit measure of absorbed energy per kilogram), Vozenin and her group used an electron beam called Oriatron eRT6 that delivered 1,000 times as much, in excess of 40 gray per second. Vozenin, who is now at Lausanne University Hospital in Switzerland, coined the term “FLASH effect” to “describe the differential effect of ultra-high dose rate irradiation on normal tissue and tumors,” she says, and the name stuck.

In 2017, 2018 and 2019, the group published promising studies on brain tumors in mice, showing less damage to nearby cells with the FLASH approach. Those results have been confirmed by several groups in 2020, yet how the protective mechanism works is “still not very well understood at all, unfortunately,” says Kristoffer Petersson of the University of Oxford, who was a postdoctoral researcher with the Vozenin group. Many suspect it is somehow connected to oxygen concentration in tissue and possibly the rapid depletion of oxygen.

FLASH also faces a more tangible barrier to its progress—a shortage of machines that can deliver it. “Labs around the world have replicated and expanded on these promising results,” says radiation oncologist Billy Loo at Stanford University. “But the technology that works in mice does not scale to people. New technology is needed.”

In the mouse studies conducted by her group, Vozenin used one electron beam of 5.5 MeV that penetrates only a few centimeters in tissue. “Technological developments are needed to promote clinical translation,” Vozenin says. Metz’s group in Philadelphia and other researchers are developing FLASH technology for proton beams. Others, including Loo, use X-rays, the mainstay of conventional radiation.

In February, Metz and his colleagues put forward a way to adapt a cyclotron accelerator—the complicated, expensive machines that generate and deliver proton beam therapy—to deliver FLASH doses. That could simplify things for clinics and hospitals with existing proton beam technology.

Metz’s group is testing that approach on dogs with solid tumors, collecting data on how FLASH affects gene expression in normal tissues—and how quickly those tissues heal after radiation. Clinical trials on people could follow in the next year or two.

Loo’s research is addressing another problem—the high cost of special accelerators that may be required to deliver FLASH doses. His team is working on a more compact, economical device that uses X-rays in place of current technologies, making next-generation treatment an option even in low-resource settings.

Even as scientists work on the technology, new questions have been raised about the efficacy of the FLASH approach. In a paper published last year, researchers at MD Anderson Cancer Center in Houston and Mayo Clinic Florida, in Jacksonville, showed that FLASH actually caused more toxicity to healthy heart tissue than conventional radiation did. This suggests that FLASH may be effective in some but not all locations, with its protective effects depending on the local tissue environment.

The timing of clinical trials may depend on the pace of technological advances. But Vozenin says she expects progress within a year. New human trials could not only show how effective FLASH really is in treating a variety of cancers, but also reveal the secrets of what actually accounts for its benefits.