Radiation is one the most effective therapies for cancer. However, its use is limited by considerations of risks for side effects, including early onset cardiovascular and lung disease, second cancers, and memory and school performance challenges in the case of children treated for brain tumors.  

In the past several years, major advances in engineering and physics technology have opened possibilities to deliver safer and more effective radiation treatments. A few proton therapy installations, including the state-of-the-art Cincinnati Children’s Proton Therapy Center, are able to deliver ultra-high dose rate radiation, also known as FLASH.  FLASH radiation therapy (FLASH-RT) administers protons at an astonishingly faster rate than regular radiation treatment—over 100 times faster than regular radiation treatment. In early preclinical studies, FLASH reduces the number of individual treatments from 20 or more to one to two. It also appears to have dramatically fewer side effects without compromising cancer elimination. The combination of lower risk for side effects with effective tumor eradication is called the “FLASH effect” and is arguably the hottest topic in cancer therapy. 

“FLASH irradiation is emerging as a promising novel radiation modality for cancer treatment, and it’s a priority area for research since almost half of the people in the U.S. who receive treatment for cancer have radiation therapy,” says John Perentesis, MD, FAAP, director of the Division of Oncology and Proton Research at Cincinnati Children’s. “FLASH opens the door to potentially curative treatments by safely increasing the dose of radiation to tumors that are currently only temporarily controlled by radiation. This is our focus for current research and includes diffuse intrinsic pontine gliomas or DIPG, relapsed brain tumors and sarcomas, advanced stage neuroblastoma, and chemotherapy-resistant lymphomas.” 

As a national referral center for children with relapsed and refractory pediatric cancers, Cincinnati Children’s primary mission is to develop more effective, safe, curative therapies for pediatric and young adult patients. FLASH-RT could help meet the need for strategies that widen the therapeutic window of radiotherapy by reducing normal tissue toxicities while maintaining or maximizing the antitumor effect.  

FLASH is still an emerging area for research—the world’s first and only FLASH clinical studies to treat cancer in humans began in 2021 at the Cincinnati Children’s Proton Therapy Center. Cincinnati Children’s also is a founding member of FlashForward, a consortium of academic centers working together to advance the science. 

Could FLASH-RT and Cancer Immunotherapy Offer a One-Two Punch?

As scientists discover new ways to harness the immune system’s cancer-fighting potential, many are intrigued by the idea of combining immunotherapy drugs with FLASH-RT to improve clinical outcomes. Pre-clinical research at Cincinnati Children’s, a hub for immunotherapy and FLASH research, has shown promising potential for this combined-modality treatment strategy. This work suggests that FLASH may also kill cells that suppress the immune response to tumors.

FLASH studies are based at the hospital’s Proton Therapy Center, one of only 41 proton therapy centers in the U.S. and the only one worldwide with a dedicated research gantry that can deliver ultra-fast FLASH doses via conventional radiation and proton therapy.  Preliminary data from one pre-clinical study, led by Tanya Kalin, MD, PhD, showed that FLASH demonstrates this double benefit compared to conventional proton treatments. In this pre-clinical study of lung cancers, FLASH not only killed the cancer more efficiently, but also activated an immune system response to lung cancer. Other work in our proton therapy center is examining this effect on other pediatric and adult cancers. 

Perentesis recently co-authored a publication that analyzed all published studies investigating the immune-modulatory effects of FLASH-RT (Clinical Oncology, November 2021). The authors’ analysis confirmed the exciting potential of FLASH-RT and concluded that more in-depth studies are needed to better understand:

• FLASH-RT mechanisms underpinning the protection of normal cells 

• The effects of FLASH-RT on immune cells that mask and protect tumors, as well as those that are primed to kill tumors 

• Whether the immune system can be modulated to enhance the benefit of FLASH-RT 

• The effect of combining FLASH-RT and immune-stimulating drugs  

Cincinnati Children’s also has developed a growing number of immunotherapy trials. Some also combine immune-modulating drugs with proton and photon radiation therapy to treat aggressive childhood cancers.  

“Research continues to answer important questions about FLASH, including its biological mechanisms of action and the optimal treatment combinations,” Perentesis says. “It’s exciting for Cincinnati Children’s to lead this groundbreaking work, which could transform our care of children and young adults with cancer.”

Perentesis collaborated with scientists from Varian, maker of the Probeam® proton therapy system at Cincinnati Children’s, on the publication review. He received a research grant from Varian for conducting experiments for FLASH in pediatric cancer at the Cincinnati Children’s Proton Therapy Center.