The biggest limitation to the radiation doses external-beam radiotherapy can deliver to tumors is the incidental harm inflicted on healthy, nontarget patient tissues adjacent to tumors or sitting along radiation beam pathways. The resulting toxicities can disrupt or halt treatment, and avoiding them in treatment planning can limit the curative potential of doses delivered to tumors.
Several strategies for improving the therapeutic ratio have been developed over recent decades, including intensity-modulated radiotherapy (IMRT), 3-dimensional conformal radiotherapy, and proton therapy (see sidebar, “Modalities Designed to Maximize Radiotherapy Tumor Dose While Minimizing Irradiation of Healthy Tissue”). The latter was developed to exploit proton beams’ depositional “Bragg peak”; beams can deliver the vast majority of their ionizing radiation energy within targeted tumors after penetrating normal tissues, without exit-dose irradiation of nontarget tissues behind the tumor.1
Now, scientists are developing another strategy for optimizing radiotherapy’s therapeutic ratio, called FLASH radiotherapy (FLASH-RT). By delivering prescribed doses of electrons, x-rays, or protons at ultra-high, hypofractionated or single-fraction dose rates that are too quick for healthy, nontarget tissues to absorb toxic levels of ionizing radiation, FLASH-RT is meant to deliver high doses of radiation to tumors while sparing patients damage to healthy tissue and severe side effects.1-5 FLASH-RT is delivered at a dose rate of 40 Gy/second or higher — or 1000 times conventional photon radiotherapy. Radiation doses traditionally delivered to tumors over several minutes can instead be achieved in milliseconds.3
Preclinical modeling and experiments with mice showed superior tumor cell-killing efficacy and reduced toxicity, and in 2019, Swiss researchers reported that a 75-year-old patient with multidrug resistant T-cell cutaneous lymphoma treated with FLASH-RT experienced modest toxicity: transient grade 1 soft-tissue edema and epithelitis near irradiated tumors.2,3,5 However, the molecular mechanisms involved remain unclear, with proposed roles for oxygen depletion and reactive oxygen species (free radicals) or immune and inflammatory responses.6
Now, the first clinical trial in human patients appears to bolster those earlier findings. A nonrandomized, first-in-humans phase 1 clinical feasibility and safety trial for proton FLASH-RT to palliate painful metastatic bone tumors in 10 patients, FAST-01 (ClinicalTrials.gov identifier: NCT04592887), delivered 8 Gy in a single fraction at 51-61 Gy/second dose rates.1,4
Modalities Designed to Maximize Radiotherapy Tumor Dose While Minimizing Irradiation of Healthy Tissue
- 3D conformal radiation therapy (3dCRT) Delivery of high-energy x-rays to a tumor with multiple external radiation beam configurations that together deliver the radiation dose tightly to the tumor’s contours and volumes, and minimize irradiation of healthy tissue.
- Intensity-modulated radiation therapy (IMRT) Shapes beams even more precisely than 3dCRT, better protecting healthy tissue.
- Image-guided radiation therapy (IGRT) Imaging between or during radiotherapy treatment sessions to ensure that beams are hitting the tumor accurately during each treatment session and accommodating treatment-induced changes in tumor shape and size.
- Stereotactic radiosurgery (SRS) High doses of precisely targeted radiation used to destroy small tumors in the brain, spine, or head and neck.
- Proton therapy This is a type of radiation therapy that uses protons instead of x-rays. Protons are positively charged particles that are less likely to damage healthy tissue than x-rays. Proton therapy is used to treat tumors that are close to critical structures, such as the brain and spinal cord.
- FLASH radiation therapy Ultra-high, hypofractionated dose rate delivery of radiation to tumor tissue, the speed of which minimizes nontarget tissue absorption.
Pain relief efficacy and adverse events were “comparable” with standard-of-care radiotherapy, the authors reported.4 Patients reported transient pain flares from 2 to 9 days after treatment in 4 of 12 treated bone tumor sites (33%). Patients reported pain relief in the remaining 67% of sites.1 Pain relief was complete (no posttreatment pain) at 50% of treated tumor sites.1
Adverse events attributed by the study authors to FLASH-RT were mild and included grade 1 edema, erythema, and fatigue in 1 patient each (10%), pruritus (skin itch) in 2 patients (20%), and skin discoloration or hyperpigmentation in 5 patients (50%).1 Treatment involved no device-related issues, the authors noted.1
“Based on clinical workflow metrics, treatment efficacy and safety data, we conclude that ultra-high-dose-rate proton FLASH therapy is feasible in a clinical setting,” the authors concluded.1 “Future clinical trials of proton FLASH should extend these findings to other parts of the body (eg, thorax, pelvis, head and neck) to demonstrate the applicability of this technology to multiple cancers.”
However, the optimal dose rate for FLASH remains an open — and crucial — question. The minimum beneficial dose of FLASH is not precisely known but is estimated to be near 8 Gy.4,5
“This question towers over the use of FLASH because determining appropriate fractionation schemes is a key factor in the pathway toward successful clinical implementation,” noted Lesley A. Jarvis, MD, PhD, a radiation oncologist at Dartmouth Health in Lebanon, New Hampshire, and coauthors, in an independent commentary reviewing the study.4 “New planning and delivery technologies are needed to optimize and safely deliver the FLASH effect without compromising what is already achievable in conventional radiotherapy.”
Even if future clinical trials confirm FLASH-RT’s promise, a likely challenge for clinical adoption would be cost. Proton therapy is a newer technology than IMRT or conformal radiotherapy, and thanks to the specialized equipment and training it requires, it’s also more expensive. That is likely to be true for proton FLASH-RT, as well. Insurers will demand evidence of clinical benefits over traditional radiotherapy that justify the added expense, a question that has slowed widespread uptake of traditional proton radiotherapy.7 However, if FLASH-RT can offer routine clinical single-fraction radiotherapy to patients in the years ahead, the costs of repeated patient preparation and fraction delivery can be avoided. That would also offer patients shorter overall treatment times than traditional proton therapy and other radiotherapies.
Small clinical trials of FLASH-RT to treat skin cancer (basal cell carcinoma, cutaneous squamous cell carcinoma, and metastatic malignant melanoma) are planned in Switzerland (ClinicalTrials.gov Identifiers: NCT05724875; NCT04986696). But better understanding the molecular radiobiology of FLASH-RT, and figuring out optimal ultra-high dose rates and quality assurance before large-scale clinical trials are undertaken that employ higher doses delivered near patients’ radiosensitive, nontarget anatomies are “imperative,” Jarvis and coauthors emphasized.4
“This trial is the first step of a long journey to bring UHDR [ultra-high-dose-rate] radiation therapy to clinical use,” they wrote.4
- Mascia AE, Daugherty EC, Zhang Y, et al. Proton FLASH radiotherapy for the treatment of symptomatic bone metastases: the FAST-01 nonrandomized trial. JAMA Oncol. 2023;9(1):62069. doi:10.1001/jamaoncol.2022.5843
- de Kruijff RM. FLASH radiotherapy: ultra-high dose rates to spare healthy tissue. Int J Radiat Biol. 2020;96(4):419-423. doi:10.1080/09553002.2020.1704912
- Bourhis J, Sozzi WJ, Jorge PG, et al. Treatment of a first patient with FLASH-radiotherapy. Radiother Oncol. 2019;139:18-22. doi:10.1016/j.radonc.2019.06.019
- Jarvis LA, Zhang R, Pogue BW. The first FLASH clinical trial — the journey of a thousand miles begins with 1 step. JAMA Oncol. 2023;9(1):69-70.
- Böhlen TT, Germond JF, Bourhis J, et al. Normal tissue sparing by FLASH as a function of single-fraction dose: a quantitative analysis. Int J Radiat Oncol Biol Phys. 2022;114(5):1032-1044. doi:10.1016/j.ijrobp.2022.05.038
- Mali SB, Dahivelkar S. FLASH radiotherapy — Gateway to promised land or another mirage. Oral Oncol. 2023;139:106342.
- Furlow B. Growing pains for US proton therapy. Lancet Oncol. 2018;19:1019-1020.