Proton therapy and the FLASH effect

Radiotherapy can be seen as a balance of efficacy, safety, and time, or overall treatment duration—elements that define the therapeutic ratio and determine clinical success. While great advances have been made in therapeutic effectiveness and side effect reduction in radiotherapy, treatment duration has remained a stubborn obstacle of concern. Necessary to ensure the complete ablation of cancer, the span between initiation and conclusion of radiation treatment is an unavoidable burden for many patients.

“Typically, radiation therapy is given five days a week for six to seven weeks,” explains Penn radiation oncologist Alexander Lin, MD. “This makes it very difficult for patients coming from far away, and for those feeling ill over the course of treatment, the regimen can be particularly grueling.” Dr. Lin is the Morton M. Kligerman M.D. Professor of Radiation Oncology at the Perelman School of Medicine.

A FLASH of insight

More than 15 years ago, Penn Radiation Oncology introduced the dosimetric advantages of proton therapy to better spare normal tissue, reduce side effects, and maintain efficacy in radiotherapy. But with a treatment course duration essentially that of standard photon therapy, proton still represented an added disruption to patient life in an otherwise difficult time.

A tantalizing answer to the proton/duration issue arrived in 2014, with the development in France of “FLASH” radiotherapy. Defined by therapeutic dose rates ≥ 40 Gy/s, FLASH is delivered in milliseconds, producing the “FLASH effect,” a phenomenon defined—like that of proton therapy—by markedly reduced normal tissue toxicity and uncompromised tumor control by comparison to standard radiotherapy. [1]

Intrigued by the advantages of FLASH for proton therapy, Penn radiation oncologists published the first study demonstrating the feasibility of proton therapy to generate FLASH doses in January 2020. Two years later, the Roberts Proton Therapy Center received a $12.3 million grant from the National Institutes of Health to further investigate FLASH therapy. With the ultimate goal of achieving a foundation for human trials, Penn researchers then conducted a series of safety and efficacy studies to better understand the effects of FLASH on both normal and malignant tissues, and to develop modifications to the beam optics and other systems employed in proton therapy to accommodate delivering the ultra-high dose rates required of FLASH.

The outcome of these efforts at Penn Medicine is C-FLASH-01 (NCT07644585), the first human feasibility clinical study in ConformalFLASH® proton therapy. The single-institution study is sponsored by IBA Proton Therapy, Inc. and is now enrolling at the Abramson Cancer Center. [2]

ConformalFLASH® Proton Therapy

C-FLASH-01 is evaluating the feasibility of ultra-high dose rate ConformalFLASH® in combination with highly conformal proton therapy for reirradiation of head and neck carcinomas. By contrast to standard proton radiotherapy, the C-FLASH-01 study comprises five treatments over a week and a half.

For Dr. Lin, the trial’s principal investigator, the difference is striking.

“It’s going to be so much easier than the standard way that we treat these patients,” he says. “This will allow for people to come from farther away, because instead of having to stay here for two months and securing housing, they can just be here for less than 2 weeks.”

Enrolling in C-FLASH-01

To refer a patient for C-FLASH-01, please contact Ching Lai at 267-250-9244 (cell) or email Ching.Lai@pennmedicine.upenn.edu.

References

1. Rosini G, Ciarrocchi E, D’Orsi B. Mechanisms of the FLASH effect: current insights and advances. Front Cell Dev Biol. 2025;13:1575678. doi: 10.3389/fcell.2025.1575678.
2. A Pilot Study of Ultra-High Dose Rate (ConformalFLASH®), for Reirradiation of Carcinoma of the Head and Neck (C-FLASH-01).